Journal articles on the topic 'L-typa calcium channels'
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1
Collier, M. L., G. Ji, Y. X. Wang, and M. I. Kotlikoff. "Calcium-Induced Calcium Release in Smooth Muscle." Journal of General Physiology 115, no. 5 (May 1, 2000): 653–62. http://dx.doi.org/10.1085/jgp.115.5.653.
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Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca2+ channels. In heart cells, a tight coupling between the gating of single L-type Ca2+ channels and ryanodine receptors (RYRs) underlies calcium release. Here we demonstrate that L-type Ca2+ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca2+ sparks and propagated Ca2+ waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly linked to the gating of L-type Ca2+ channels. L-type Ca2+ channels can open without triggering Ca2+ sparks and triggered Ca2+ sparks are often observed after channel closure. CICR is a function of the net flux of Ca2+ ions into the cytosol, rather than the single channel amplitude of L-type Ca2+ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca2+ channels are loosely coupled to RYR through an increase in global [Ca2+] due to an increase in the effective distance between L-type Ca2+ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.
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BIEDA, MARK C., and DAVID R. COPENHAGEN. "N-type and L-type calcium channels mediate glycinergic synaptic inputs to retinal ganglion cells of tiger salamanders." Visual Neuroscience 21, no. 4 (July 2004): 545–50. http://dx.doi.org/10.1017/s0952523804214055.
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Synaptically localized calcium channels shape the timecourse of synaptic release, are a prominent site for neuromodulation, and have been implicated in genetic disease. In retina, it is well established that L-type calcium channels play a major role in mediating release of glutamate from the photoreceptors and bipolar cells. However, little is known about which calcium channels are coupled to synaptic exocytosis of glycine, which is primarily released by amacrine cells. A recent report indicates that glycine release from spiking AII amacrine cells relies exclusively upon L-type calcium channels. To identify calcium channel types controlling neurotransmitter release from the population of glycinergic neurons that drive retinal ganglion cells, we recorded electrical and potassium evoked inhibitory synaptic currents (IPSCs) from these postsynaptic neurons in retinal slices from tiger salamanders. The L-channel antagonist nifedipine strongly inhibited release and FPL64176, an L-channel agonist, greatly enhanced it, indicating a significant role for L-channels. ω-Conotoxin MVIIC, an N/P/Q-channel antagonist, strongly inhibited release, indicating an important role for non-L channels. While the P/Q-channel blocker ω-Aga IVA produced only small effects, the N-channel blocker ω-conotoxin GVIA strongly inhibited release. Hence, N-type and L-type calcium channels appear to play major roles, overall, in mediating synaptic release of glycine onto retinal ganglion cells.
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Mangel, A. W., L. Scott, and R. A. Liddle. "Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 2 (February 1, 1996): G287—G290. http://dx.doi.org/10.1152/ajpgi.1996.270.2.g287.
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To examine the role of calcium channels in depolarization-activated cholecystokinin (CCK) release, studies were performed in an intestinal CCK-secreting cell line, STC-1. Blockade of potassium channels with barium chloride (5 mM) increased the release of CCK by 374.6 +/- 46.6% of control levels. Barium-induced secretion was inhibited by the L-type calcium-channel blocker, nicardipine. Nicardipine (10(-9)-10(-5) M) produced a dose-dependent inhibition in barium-stimulated secretion with a half-maximal inhibition (IC50) value of 0.1 microM. A second L-type calcium-channel blocker, diltiazem (10(-9)-10(-4) M), also inhibited barium-induced CCK secretion with an IC50 value of 5.1 microM. By contrast, the T-type calcium-channel blocker, nickel chloride (10(-7)-10(-8) M), failed to significantly inhibit barium-induced CCK secretion. To further evaluate a role for L-type calcium channels in the secretion of CCK, the effects of the L-type calcium channel opener, BAY K 8644, were examined. BAY K 8644 (10(-8)-10(-4) M) produced a dose-dependent stimulation in CCK release with a mean effective concentration value of 0.2 microM. Recordings of single-channel currents from inside-out membrane patches showed activation of calcium channels by BAY K 8644 (1 microM), with a primary channel conductance of 26.0 +/- 1.2 pS. It is concluded that inhibition of potassium channel activity depolarizes the plasma membrane, thereby activating L-type, but not T-type, calcium channels. The corresponding influx of calcium serves to trigger secretion of CCK.
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Isaev, Dmytro, Karisa Solt, Oksana Gurtovaya, John P. Reeves, and Roman Shirokov. "Modulation of the Voltage Sensor of L-type Ca2+ Channels by Intracellular Ca2+." Journal of General Physiology 123, no. 5 (April 26, 2004): 555–71. http://dx.doi.org/10.1085/jgp.200308876.
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Both intracellular calcium and transmembrane voltage cause inactivation, or spontaneous closure, of L-type (CaV1.2) calcium channels. Here we show that long-lasting elevations of intracellular calcium to the concentrations that are expected to be near an open channel (≥100 μM) completely and reversibly blocked calcium current through L-type channels. Although charge movements associated with the opening (ON) motion of the channel's voltage sensor were not altered by high calcium, the closing (OFF) transition was impeded. In two-pulse experiments, the blockade of calcium current and the reduction of gating charge movements available for the second pulse developed in parallel during calcium load. The effect depended steeply on voltage and occurred only after a third of the total gating charge had moved. Based on that, we conclude that the calcium binding site is located either in the channel's central cavity behind the voltage-dependent gate, or it is formed de novo during depolarization through voltage-dependent rearrangements just preceding the opening of the gate. The reduction of the OFF charge was due to the negative shift in the voltage dependence of charge movement, as previously observed for voltage-dependent inactivation. Elevation of intracellular calcium concentration from ∼0.1 to 100–300 μM sped up the conversion of the gating charge into the negatively distributed mode 10–100-fold. Since the “IQ-AA” mutant with disabled calcium/calmodulin regulation of inactivation was affected by intracellular calcium similarly to the wild-type, calcium/calmodulin binding to the “IQ” motif apparently is not involved in the observed changes of voltage-dependent gating. Although calcium influx through the wild-type open channels does not cause a detectable negative shift in the voltage dependence of their charge movement, the shift was readily observable in the Δ1733 carboxyl terminus deletion mutant, which produces fewer nonconducting channels. We propose that the opening movement of the voltage sensor exposes a novel calcium binding site that mediates inactivation.
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Yang, Tingting, Min He, Hailiang Zhang, Paula Q. Barrett, and Changlong Hu. "L- and T-type calcium channels control aldosterone production from human adrenals." Journal of Endocrinology 244, no. 1 (January 2020): 237–47. http://dx.doi.org/10.1530/joe-19-0259.
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Aldosterone, which plays a key role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal cortex. Exaggerated overproduction of aldosterone from ZG cells causes primary hyperaldosteronism. In ZG cells, calcium entry through voltage-gated calcium channels plays a central role in the regulation of aldosterone secretion. Previous studies in animal adrenals and human adrenal adrenocortical cell lines suggest that the T-type but not the L-type calcium channel activity drives aldosterone production. However, recent clinical studies show that somatic mutations in L-type calcium channels are the second most prevalent cause of aldosterone-producing adenoma. Our objective was to define the roles of T and L-type calcium channels in regulating aldosterone secretion from human adrenals. We find that human adrenal ZG cells mainly express T-type CaV3.2/3.3 and L-type CaV1.2/1.3 calcium channels. TTA-P2, a specific inhibitor of T-type calcium channel subtypes, reduced basal aldosterone secretion from acutely prepared slices of human adrenals. Surprisingly, nifedipine, the prototypic inhibitor of L-type calcium channels, also decreased basal aldosterone secretion, suggesting that L-type calcium channels are active under basal conditions. In addition, TTA-P2 or nifedipine also inhibited aldosterone secretion stimulated by angiotensin II- or elevations in extracellular K+. Remarkably, blockade of either L- or T-type calcium channels inhibits basal and stimulated aldosterone production to a similar extent. Low concentrations of TTA-P2 and nifedipine showed additive inhibitory effect on aldosterone secretion. We conclude that T- and L-type calcium channels play equally important roles in controlling aldosterone production from human adrenals.
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Liu, Xiaoyu, Tingting Yang, Langxi Miao, Yan-Ai Mei, and Changlong Hu. "Leukotriene B4 Inhibits L-Type Calcium Channels via p38 Signaling Pathway in Vascular Smooth Muscle Cells." Cellular Physiology and Biochemistry 37, no. 5 (2015): 1903–13. http://dx.doi.org/10.1159/000438551.
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Background/Aims: Arachidonic acid (AA) and its metabolites are important endogenous lipid messengers. In this study, we test the effect of Leukotriene B4 (LTB4), a 5-lipoxygenase metabolite of AA, on L-type calcium channels in A7r5 rat aortic vascular smooth muscle cells. Methods: L-type calcium channel currents were recorded by a patch-clamp technique. The mRNA expression of CaV1.2 was determined by Real-time RT-PCR. The protein expression of CaV1.2 and p38 activity was determined by Western blot analysis. Results: LTB4 inhibits L-type channel currents in A7r5 cells in a dose-and time- dependent manner. LTB4 reduced the mRNA/protein expression of CaV1.2 channels in A7r5 cells. BLT1 receptor antagonist LY29311 abrogated the inhibitory effect of LTB4, while BLT2 receptor antagonist LY255283 had no effect. 5Z-7-oxozeaenol and SB203580, which block TAK1 and p38 kinase respectively, abrogated the LTB4 inhibitory effect on L-type calcium channels. LTB4 increased p38 activity in A7r5 cells. Blockage of Src, PI3K, JNK and NF-κB kinase had no effects on LTB4 inhibition of L-type calcium channel currents in A7r5 cells. Conclusion: We conclude that LTB4 inhibits L-type calcium channels through BLT1-TAk1-p38 signaling pathway. The LTB4 inhibitory effect on L-type calcium channels may be involved in its pathological processes such as atherosclerosis.
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Yarotskyy, Viktor, Guofeng Gao, Blaise Z. Peterson, and Keith S. Elmslie. "Domain III regulates N-type (CaV2.2) calcium channel closing kinetics." Journal of Neurophysiology 107, no. 7 (April 1, 2012): 1942–51. http://dx.doi.org/10.1152/jn.00993.2011.
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CaV2.2 (N-type) and CaV1.2 (L-type) calcium channels gate differently in response to membrane depolarization, which is critical to the unique physiological functions mediated by these channels. We wondered if the source for these differences could be identified. As a first step, we examined the effect of domain exchange between N-type and L-type channels on activation-deactivation kinetics, which were significantly different between these channels. Kinetic analysis of chimeric channels revealed N-channel-like deactivation for all chimeric channels containing N-channel domain III, while activation appeared to be a more distributed function across domains. This led us to hypothesize that domain III was an important regulator of N-channel closing. This idea was further examined with R-roscovitine, which is a trisubstituted purine that slows N-channel deactivation by exclusively binding to activated N-channels. L-channels lack this response to roscovitine, which allowed us to use N-L chimeras to test the role of domain III in roscovitine modulation of N-channel deactivation. In support of our hypothesis, all chimeric channels containing the N-channel domain III responded to roscovitine with slowed deactivation, while those chimeric channels with L-channel domain III did not. Thus a combination of kinetic and pharmacological evidence supports the hypothesis that domain III is an important regulator of N-channel closing. Our results support specialization of gating functions among calcium channel domains.
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Durante, P., C. G. Cardenas, J. A. Whittaker, S. T. Kitai, and R. S. Scroggs. "Low-Threshold L-type Calcium Channels in Rat Dopamine Neurons." Journal of Neurophysiology 91, no. 3 (March 2004): 1450–54. http://dx.doi.org/10.1152/jn.01015.2003.
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Ca2+ channel subtypes expressed by dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) were studied using whole cell patch-clamp recordings and blockers selective for different channel types (L, N, and P/Q). Nimodipine (Nim, 2 μM), ω-conotoxin GVIA (Ctx, 1 μM), or ω-agatoxin IVA (Atx, 50 nM) blocked 27, 36, and 37% of peak whole cell Ca2+ channel current, respectively, indicating the presence of L-, N-, and P-type channels. Nim blocked approximately twice as much Ca2+ channel current near activation threshold compared with Ctx or Atx, suggesting that small depolarizations preferentially opened L-type versus N- or P-type Ca2+ channels. N- and L-channels in DA neurons opened over a significantly more negative voltage range than those in rat dorsal root ganglion cells, recorded from using identical conditions. These data provide an explanation as to why Ca2+-dependent spontaneous oscillatory potentials and rhythmic firing in DA neurons are blocked by L-channel but not N-channel antagonists and suggest that pharmacologically similar Ca2+ channels may exhibit different thresholds for activation in different types of neurons.
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Büschges, A., M. A. Wikström, S. Grillner, and A. El Manira. "Roles of High-Voltage–Activated Calcium Channel Subtypes in a Vertebrate Spinal Locomotor Network." Journal of Neurophysiology 84, no. 6 (December 1, 2000): 2758–66. http://dx.doi.org/10.1152/jn.2000.84.6.2758.
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Lamprey spinal cord neurons possess N-, L-, and P/Q-type high-voltage–activated (HVA) calcium channels. We have analyzed the role of the different HVA calcium channels subtypes in the overall functioning of the spinal locomotor network by monitoring the influence of their specific agonists and antagonists on synaptic transmission and on N-methyl-d-aspartate (NMDA)–elicited fictive locomotion. The N-type calcium channel blocker ω-conotoxin GVIA (ω-CgTx) depressed synaptic transmission from excitatory and inhibitory interneurons. Blocking L-type and P/Q-type calcium channels with nimodipine and ω-agatoxin, respectively, did not affect synaptic transmission. Application of ω-CgTx initially decreased the frequency of the locomotor rhythm, increased the burst duration, and subsequently increased the coefficient of variation and disrupted the motor pattern. These effects were accompanied by a depression of the synaptic drive between neurons in the locomotor network. Blockade of L-type channels by nimodipine also decreased the frequency and increased the duration of the locomotor bursts. Conversely, potentiation of L-type channels increased the frequency of the locomotor activity and decreased the duration of the ventral root bursts. In contrast to blockade of N-type channels, blockade or potentiation of L-type calcium channels had no effect on the stability of the locomotor pattern. The P/Q-type calcium channel blocker ω-agatoxin IVA had little effect on the locomotor frequency or burst duration. The results indicate that rhythm generation in the spinal locomotor network of the lamprey relies on calcium influx through L-type and N-type calcium channels.
10
Rosenberg, R. L., P. Hess, and R. W. Tsien. "Cardiac calcium channels in planar lipid bilayers. L-type channels and calcium-permeable channels open at negative membrane potentials." Journal of General Physiology 92, no. 1 (July 1, 1988): 27–54. http://dx.doi.org/10.1085/jgp.92.1.27.
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Planar lipid bilayer recordings were used to study Ca channels from bovine cardiac sarcolemmal membranes. Ca channel activity was recorded in the absence of nucleotides or soluble enzymes, over a range of membrane potentials and ionic conditions that cannot be achieved in intact cells. The dihydropyridine-sensitive L-type Ca channel, studied in the presence of Bay K 8644, was identified by a detailed comparison of its properties in artificial membranes and in intact cells. L-type Ca channels in bilayers showed voltage dependence of channel activation and inactivation, open and closed times, and single-channel conductances in Ba2+ and Ca2+ very similar to those found in cell-attached patch recordings. Open channels were blocked by micromolar concentrations of external Cd2+. In this cell-free system, channel activity tended to decrease during the course of an experiment, reminiscent of Ca2+ channel "rundown" in whole-cell and excised-patch recordings. A purely voltage-dependent component of inactivation was observed in the absence of Ca2+ stores or changes in intracellular Ca2+. Millimolar internal Ca2+ reduced unitary Ba2+ influx but did not greatly increase the rate or extent of inactivation or the rate of channel rundown. In symmetrical Ba2+ solutions, unitary conductance saturated as the Ba2+ concentration was increased up to 500 mM. The bilayer recordings also revealed activity of a novel Ca2+-permeable channel, termed "B-type" because it may contribute a steady background current at negative membrane potentials, which is distinct from L-type or T-type Ca channels previously reported. Unlike L-type channels, B-type channels have a small unitary Ba2+ conductance (7 pS), but do not discriminate between Ba2+ and Ca2+, show no obvious sensitivity to Bay K 8644, and do not run down. Unlike either L- or T-type channels, B-type channels did not require a depolarization for activation and displayed mean open times of greater than 100 ms.
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McCarthy, R. T., C. M. Isales, W. B. Bollag, H. Rasmussen, and P. Q. Barrett. "Atrial natriuretic peptide differentially modulates T- and L-type calcium channels." American Journal of Physiology-Renal Physiology 258, no. 3 (March 1, 1990): F473—F478. http://dx.doi.org/10.1152/ajprenal.1990.258.3.f473.
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Atrial natriuretic peptide (ANP) inhibits the secretion of aldosterone stimulated by any of these major physiological agonists: angiotensin II, adrenocorticotropic hormone, or K+. The stimulatory actions of each of these agonists depend on calcium influx through voltage-dependent calcium channels. Because two types of calcium channels have been previously described in bovine glomerulosa cells (T- and L-type), the patch-clamp technique was used to evaluate the effect of ANP on each voltage-dependent calcium channel type. ANP was found to differentially modulate these two channel types, stimulating L-current while inhibiting T-current. Inhibition of T-current resulted from a shift in the voltage dependence of inactivation to more negative potentials within the physiological range. These results indicate that the ANP-induced inhibition of aldosterone secretion may be partially mediated via a reduction of the calcium current through T-type channels.
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Taylor, James T., Luping Huang, Brian M. Keyser, Hean Zhuang, Craig W. Clarkson, and Ming Li. "Role of high-voltage-activated calcium channels in glucose-regulated β-cell calcium homeostasis and insulin release." American Journal of Physiology-Endocrinology and Metabolism 289, no. 5 (November 2005): E900—E908. http://dx.doi.org/10.1152/ajpendo.00101.2005.
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High-voltage-activated (HVA) calcium channels are known to be the primary source of calcium for glucose-stimulated insulin secretion. However, few studies have investigated how these channels can be regulated by chronically elevated levels of glucose. In the present study, we determined the level of expression of the four major HVA calcium channels (N-type, P/Q-type, LC-type, and LD-type) in rat pancreatic β-cells. Using quantitative real-time PCR (QRT-PCR), we found the expression of all four HVA genes in rat insulinoma cells (INS-1) and in primary isolated rat islet cells. We then determined the role of each channel in insulin secretion by using channel-selective antagonists. Insulin secretion analysis revealed that N- and L-type channels are both involved in immediate glucose-induced insulin secretion. However, L-type was preferentially coupled to secretion at later time points. P/Q-type channels were not found to play a role in insulin secretion at any stage. It was also found that long-term exposure to elevated glucose increases basal calcium in these cells. Interestingly, chronically elevated glucose decreased the mRNA expression of the channels involved with insulin secretion and diminished the level of stimulated calcium influx in these cells. Using whole cell patch clamp, we found that N- and L-type channel currents increase gradually subsequent to lower intracellular calcium perfusion, suggesting that these channels may be regulated by glucose-induced changes in calcium.
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Barrett, P. Q., C. M. Isales, W. B. Bollag, and R. T. McCarthy. "Modulation of Ca2+ channels by atrial natriuretic peptide in the bovine adrenal glomerulosa cell." Canadian Journal of Physiology and Pharmacology 69, no. 10 (October 1, 1991): 1553–60. http://dx.doi.org/10.1139/y91-231.
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In the bovine adrenal glomerulosa cell, calcium influx through voltage-dependent calcium channels is critical to maintaining an aldosterone secretory response. In patch clamp, atrial natriuretic peptide (ANP) inhibits T-type calcium channel current yet stimulates L-type calcium channel current. In the present study the channel effects of ANP observed in the patch-clamp configuration were extended and related to populations of cells. We observed the following. (i) The effect of ANP on T-channel current resulted in the reduction in the open state probability. ANP decreased the mean open state duration from 14.2 to 1.8 ms/sweep. (ii) In the weakly depolarized cell stimulated by 8 mM K+, ANP reduced the level of aequorin luminescence (a measure of cytosolic calcium) and completely inhibited the stimulated rate of aldosterone secretion, returning it to prestimulation values. These effects are consistent with a decrease in net calcium channel influx and the reported inhibition of T-channel current. In contrast, the calcium channel blocker, nitrendipine, which at low dose selectively blocks L-type calcium channel flux, only slightly reduced luminescence, and partially inhibited the sustained secretory response. (iii) In the strongly depolarized cell, stimulated by 60 mM K+, ANP increased the level of aequorin luminescence consistent with an increase in net calcium channel influx and the reported stimulation of L-channel current. These results indicate that under physiological conditions the inhibition of T-type calcium channels may be involved in the inhibition of the aldosterone secretion induced by ANP.Key words: ANP, aldosterone secretion, calcium channels, intracellular calcium, adrenal glomerulosa.
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Mendelowitz, D., P. J. Reynolds, and M. C. Andresen. "Heterogeneous functional expression of calcium channels at sensory and synaptic regions in nodose neurons." Journal of Neurophysiology 73, no. 2 (February 1, 1995): 872–75. http://dx.doi.org/10.1152/jn.1995.73.2.872.
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1. In the present study we have taken advantage of the unique anatomy of visceral sensory neurons that enabled us to isolate and examine the role of calcium channel subtypes at the soma, central synaptic terminals, and peripheral sensory endings. 2. N-type calcium channels dominated somatic currents (60%), with lesser (16% and 12%) contributions from P- and L-type channels, respectively, in patch-clamped dispersed nodose neurons using toxins selective for each calcium channel subtype. 3. These toxins also blocked the release of neurotransmitters from these visceral synaptic terminals in a brain stem slice. Similar to the profile at the soma, N-type calcium channels were most responsible for neurotransmission at this central glutamatergic synapse (57%), with P- and L-type channels making small contributions (12% and 11%, respectively). 4. In contrast to the soma and central synapses, these calcium channel toxins failed to affect the sensory transduction at aortic baroreceptor endings. 5. Therefore calcium channel subtypes have dramatically heterogenous distributions in sensory neurons that presumably subserve the specialized functions that occur at different cellular regions.
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Ouadid-Ahidouch, Halima. "Voltage-gated calcium channels in Pleurodeles oocytes: classification, modulation and functional roles." Zygote 6, no. 1 (February 1998): 85–95. http://dx.doi.org/10.1017/s0967199400005116.
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SummaryIn unfertilised Pleurodeles oocytes, two distinct types of high voltage-activated Ca2+ channels are expressed: a slowly inactivating Ca2+ channel and a transient one. The first is dihydropyridine-sensitive and is referred to as the L-type Ca2+ channel. The transient channel is highly sensitive to Ni2+. Phosphorylation through protein kinases G and A facilitates and inhibits the L-type Ca2+ channel respectively. The transient type channel is insensitive to stimulation by protein kinases (A and G). The functional expression of L-type and transient Ca2+ channels is modulated by the two maturation seasons. The transient Ca2+ currents are only observed during the resting season, while the L-type current is observed either alone during the breeding season or in association with the transient current during the resting season. Moreover, the current density of the L-type Ca2+ channel is much greater during the breeding season than the resting season. Thus, the wide distribution of L-type Ca2+ channels in Pleurodeles oocytes during the two seasons suggests that the roles of these channels may be important in the regulation of the maturation process.
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Dang, An K., Nathan L. Chaplin, Dilyara A. Murtazina, Ulrich Boehm, Colin M. Clay, and Gregory C. Amberg. "Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes." Journal of Biological Chemistry 293, no. 41 (August 28, 2018): 16028–42. http://dx.doi.org/10.1074/jbc.ra118.001830.
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Gonadotropin-releasing hormone (GnRH) stimulation of its eponymous receptor on the surface of endocrine anterior pituitary gonadotrope cells (gonadotropes) initiates multiple signaling cascades that culminate in the secretion of luteinizing and follicle-stimulating hormones, which have critical roles in fertility and reproduction. Enhanced luteinizing hormone biosynthesis, a necessary event for ovulation, requires a signaling pathway characterized by calcium influx through L-type calcium channels and subsequent activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK). We previously reported that highly localized subplasmalemmal calcium microdomains produced by L-type calcium channels (calcium sparklets) play an essential part in GnRH-dependent ERK activation. Similar to calcium, reactive oxygen species (ROS) are ubiquitous intracellular signaling molecules whose subcellular localization determines their specificity. To investigate the potential influence of oxidant signaling in gonadotropes, here we examined the impact of ROS generation on L-type calcium channel function. Total internal reflection fluorescence (TIRF) microscopy revealed that GnRH induces spatially restricted sites of ROS generation in gonadotrope-derived αT3-1 cells. Furthermore, GnRH-dependent stimulation of L-type calcium channels required intracellular hydrogen peroxide signaling in these cells and in primary mouse gonadotropes. NADPH oxidase and mitochondrial ROS generation were each necessary for GnRH-mediated stimulation of L-type calcium channels. Congruently, GnRH increased oxidation within subplasmalemmal mitochondria, and L-type calcium channel activity correlated strongly with the presence of adjacent mitochondria. Collectively, our results provide compelling evidence that NADPH oxidase activity and mitochondria-derived hydrogen peroxide signaling play a fundamental role in GnRH-dependent stimulation of L-type calcium channels in anterior pituitary gonadotropes.
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Manira, A. El, and N. Bussières. "Calcium Channel Subtypes in Lamprey Sensory and Motor Neurons." Journal of Neurophysiology 78, no. 3 (September 1, 1997): 1334–40. http://dx.doi.org/10.1152/jn.1997.78.3.1334.
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El Manira, A. and N. Bussières. Calcium channel subtypes in lamprey sensory and motor neurons. J. Neurophysiol. 78: 1334–1340, 1997. Pharmacologically distinct calcium channels have been characterized in dissociated cutaneous sensory neurons and motoneurons of the larval lamprey spinal cord. To enable cell identification, sensory dorsal cells and motoneurons were selectively labeled with fluorescein-coupled dextran amine in the intact spinal cord in vitro before dissociation. Calcium channels present in sensory dorsal cells, motoneurons, and other spinal cord neurons were characterized with the use of whole cell voltage-clamp recordings and specific calcium channel agonist and antagonists. The results show that a transient low-voltage-activated (LVA) calcium current was present in a proportion of sensory dorsal cells but not in motoneurons, whereas high-voltage-activated (HVA) calcium currents were seen in all neurons recorded. The different components of HVA current were dissected pharmacologically and similar results were obtained for both dorsal cells and motoneurons. The N-type calcium channel antagonist ω-conotoxin-GVIA(ω-CgTx) blocked >70% of the HVA current. A large part of the ω-CgTx block was reversed after washout of the toxin. The L-type calcium channel antagonist nimodipine blocked ∼15% of the total HVA current. The dihydropyridine agonist (±)-BayK 8644 markedly increased the amplitude of the calcium channel current. The BayK-potentiated current was not affected by ω-CgTx, indicating that the reversibility of the ω-CgTx effect is not due to a blockade of L-type channels. Simultaneous application of ω-CgTx and nimodipine left ∼15% of the HVA calcium channel current, a small part of which was blocked by the P/Q-type channel antagonist ω-agatoxin-IVA. In the presence of the three antagonists, the persistent residual current (∼10%) was completely blocked by cadmium. Our results provide evidence for the existence of HVA calcium channels of the N, L, and P/Q types and other HVA calcium channels in lamprey sensory neurons and motoneurons. In addition, certain types of neurons express LVA calcium channels.
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Fieber, L. A., and E. W. McCleskey. "L-type calcium channels in type I cells of the rat carotid body." Journal of Neurophysiology 70, no. 4 (October 1, 1993): 1378–84. http://dx.doi.org/10.1152/jn.1993.70.4.1378.
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1. Whole-cell and cell-attached patch-clamp recordings were made from enzymatically isolated type I cells from the carotid body of adult rats. Voltage-dependent K+ and Ca2+ channels were observed, but there was no detectable Na+ current. In this respect, rat carotid body cells are unlike those from rabbit, which have Na+ currents and Na(+)-dependent action potentials. 2. The observed Ca2+ channels had the following properties: 1) activation requires voltage steps above -20 mV; 2) little inactivation occurred with holding voltages below -40 mV; 3) one single-channel conductance of 21 pS was found with 90 or 110 mM Ba2+ in the cell-attached pipette and this was the only conductance observed; 4) open probability was increased by the dihydropyridine Ca2+ channel agonist Bay K 8644 and was decreased by the antagonist nifedipine; and 5) omega-conotoxin had little or no effect on the channels. These are properties expected of L-type Ca2+ channels. 3. To investigate whether these voltage-dependent channels would be available for opening on membrane depolarization, we measured the type I cell resting membrane potential noninvasively using unitary openings of the L-type Ca2+ channel with Bay K 8644 in the cell-attached pipette. Resting potentials ranged from -62 to -13 mV, with a mean of -32 mV in 12 cells. 4. Judging from single-channel conductance and pharmacology, the Ca2+ current is mostly, if not solely, carried by L channels. Thus it should be possible to use modulators of L channel activity to determine the role of Ca2+ channels in stimulus-secretion coupling in the rat carotid body.
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Wang, R., E. Karpinski, and P. K. Pang. "Two types of calcium channels in isolated smooth muscle cells from rat tail artery." American Journal of Physiology-Heart and Circulatory Physiology 256, no. 5 (May 1, 1989): H1361—H1368. http://dx.doi.org/10.1152/ajpheart.1989.256.5.h1361.
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Whole cell patch-clamp recordings were carried out on smooth muscle cells from rat tail artery in short-term culture to verify the existence of and to characterize the calcium channels that are present. Two types of voltage-dependent calcium channels were identified in 55 of 63 cells studied. The T-type calcium channel was activated at -50 mV, and the peak inward current occurred at -10 mV, whereas the L-type channel was activated at -20 mV, and the peak inward current occurred at +10 or +20 mV. The T-type channel current inactivated quickly in contrast to the much slower inactivation of the L-channel current. The voltage dependence of steady-state inactivation of the two channels was similar to that reported for other vascular smooth muscle preparations. An internal solution containing Cs2-aspartate maintained the calcium-channel currents for at least 20 min with only a 5-10% decline. BAY K 8644 had no effect on T-channel currents, but the L-channel current was increased by at least a factor of two. In addition, BAY K 8644 shifted the activation threshold, the peak inward current, and the steady-state inactivation-activation curves of L-type channel currents in the direction of hyperpolarization.
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Lyford, Greg L., Peter R. Strege, Allan Shepard, Yijun Ou, Leonid Ermilov, Steven M. Miller, Simon J. Gibbons, James L. Rae, Joseph H. Szurszewski, and Gianrico Farrugia. "α1C (CaV1.2) L-type calcium channel mediates mechanosensitive calcium regulation." American Journal of Physiology-Cell Physiology 283, no. 3 (September 1, 2002): C1001—C1008. http://dx.doi.org/10.1152/ajpcell.00140.2002.
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Smooth muscle exhibits mechanosensitivity independent of neural input, suggesting that mechanosensitive pathways reside within smooth muscle cells. The native L-type calcium current recorded from human intestinal smooth muscle is modulated by stretch. To define mechanosensitive mechanisms involved in the regulation of smooth muscle calcium entry, we cloned the α1C L-type calcium channel subunit (CaV1.2) from human intestinal smooth muscle and expressed the channel in a heterologous system. This channel subunit retained mechanosensitivity when expressed alone or coexpressed with a β2 calcium channel subunit in HEK-293 or Chinese hamster ovary cells. The heterologously expressed human cardiac α1C splice form also demonstrated mechanosensitivity. Inhibition of kinase signaling did not affect mechanosensitivity of the native channel. Truncation of the α1C COOH terminus, which contains an inhibitory domain and a proline-rich domain thought to mediate mechanosensitive signaling from integrins, did not disrupt mechanosensitivity of the expressed channel. These data demonstrate mechanical regulation of calcium entry through molecularly identified L-type calcium channels in mammalian cells and suggest that the mechanosensitivity resides within the pore forming α1C-subunit.
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Liu, Qi-Yi, and Robert L. Rosenberg. "Stimulation of cardiac L-type calcium channels by extracellular ATP." American Journal of Physiology-Cell Physiology 280, no. 5 (May 1, 2001): C1107—C1113. http://dx.doi.org/10.1152/ajpcell.2001.280.5.c1107.
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The co-release of ATP with norepinephrine from sympathetic nerve terminals in the heart may augment adrenergic stimulation of cardiac Ca2+ channel activity. To test for a possible direct effect of extracellular ATP on L-type Ca2+ channels, single channels were reconstituted from porcine sarcolemma into planar lipid bilayers so that intracellular signaling pathways could be controlled. Extracellular ATP (2–100 μM) increased the open probability of the reconstituted channels, with a maximal increase of ∼2.6-fold and an EC50 of 3.9 μM. The increase in open probability was due to an increase in channel availability and a decrease in channel inactivation rate. Other nucleotides displayed a rank order of effectiveness of ATP > α,β-methylene-ATP > 2-methylthio-ATP > UTP > adenosine 5′- O-(3-thiotriphosphate) >> ADP; adenosine had no effect. Several antagonists of P2 receptors had no impact on the ATP-dependent increase in open probability, indicating that receptor activation was not required. These results suggest that extracellular ATP and other nucleotides can stimulate the activity of cardiac L-type Ca2+ channels via a direct interaction with the channels.
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Yazaki, I., E. Tosti, and B. Dale. "Cytoskeletal elements link calcium channel activity and the cell cycle in early sea urchin embryos." Development 121, no. 6 (June 1, 1995): 1827–31. http://dx.doi.org/10.1242/dev.121.6.1827.
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Using the whole-cell clamp technique, we show that L-type calcium channels are activated in early sea urchin blastomeres during M-phase and subsequently inactivated in S-phase. This cyclical channel behaviour occurs in the absence of the nucleus suggesting cytoplasmic regulation independent of the centrosome cycle. Puromycin at 100–400 micromolar does not prevent inactivation of the current showing that this phase, at least, does not require protein synthesis. Cytochalasin B at 2 microgram/ml inhibits the cyclical activity in both M and S phases, while 100 microgram/ml of colchicine inactivates the L-type current in M-phase and activates a large T-type calcium current in S-phase, suggesting that channel behaviour is regulated by cytoskeletal elements. Since, fragmentation experiments show the calcium channels to be clustered in the apical membrane, and some L-type calcium channel inhibitors induced a significant delay in the cell cycle, the channel may play a role in regulating cytokinesis possibly by contributing to local intracellular calcium gradients.
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Rodriguez-Contreras, Adrian, Ping Lv, Jun Zhu, Hyo Jeong Kim, and Ebenezer N. Yamoah. "Effects of Strontium on the Permeation and Gating Phenotype of Calcium Channels in Hair Cells." Journal of Neurophysiology 100, no. 4 (October 2008): 2115–24. http://dx.doi.org/10.1152/jn.90473.2008.
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To minimize the effects of Ca2+ buffering and signaling, this study sought to examine single Ca2+ channel properties using Sr2+ ions, which substitute well for Ca2+ but bind weakly to intracellular Ca2+ buffers. Two single-channel fluctuations were distinguished by their sensitivity to dihydropyridine agonist (L-type) and insensitivity toward dihydropyridine antagonist (non-L-type). The L- and non-L-type single channels were observed with single-channel conductances of 16 and 19 pS at 70 mM Sr2+ and 11 and 13 pS at 5 mM Sr2+, respectively. We obtained KD estimates of 5.2 and 1.9 mM for Sr2+ for L- and non-L-type channels, respectively. At Ca2+ concentration of ∼2 mM, the single-channel conductances of Sr2+ for the L-type channel was ∼1.5 and 4.0 pS for the non-L-type channels. Thus the limits of single-channel microdomain at the membrane potential of a hair cell (e.g., −65 mV) for Sr2+ ranges from 800 to 2,000 ion/ms, assuming an ECa of 100 mV. The channels are ≥4-fold more sensitive at the physiological concentration ranges than at concentrations >10 mM. Additionally, the channels have the propensity to dwell in the closed state at high concentrations of Sr2+, which is reflected in the time constant of the first latency distributions. It is concluded that the concentration of the permeant ion modulates the gating of hair cell Ca2+ channels. Finally, the closed state/s that is/are altered by high concentrations of Sr2+ may represent divalent ion-dependent inactivation of the L-type channel.
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Wang, Jijiang, Mustapha Irnaten, and David Mendelowitz. "Agatoxin-IVA-Sensitive Calcium Channels Mediate the Presynaptic and Postsynaptic Nicotinic Activation of Cardiac Vagal Neurons." Journal of Neurophysiology 85, no. 1 (January 1, 2001): 164–68. http://dx.doi.org/10.1152/jn.2001.85.1.164.
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Whole cell currents and miniature glutamatergic synaptic events (minis) were recorded in vitro from cardiac vagal neurons in the nucleus ambiguus using the patch-clamp technique. We examined whether voltage-dependent calcium channels were involved in the nicotinic excitation of cardiac vagal neurons. Nicotine evoked an inward current, increase in mini amplitude, and increase in mini frequency in cardiac vagal neurons. These responses were inhibited by the nonselective voltage-dependent calcium channel blocker Cd (100 μM). The P-type voltage-dependent calcium channel blocker agatoxin IVA (100 nM) abolished the nicotine-evoked responses. Nimodipine (2 μM), an antagonist of L-type calcium channels, inhibited the increase in mini amplitude and frequency but did not block the ligand gated inward current. The N- and Q-type voltage-dependent calcium channel antagonists conotoxin GVIA (1 μM) and conotoxin MVIIC (5 μM) had no effect. We conclude that the presynaptic and postsynaptic facilitation of glutamatergic neurotransmission to cardiac vagal neurons by nicotine involves activation of agatoxin-IVA-sensitive and possibly L-type voltage-dependent calcium channels. The postsynaptic inward current elicited by nicotine is dependent on activation of agatoxin-IVA-sensitive voltage-dependent calcium channels.
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Fuchs, Andreas, Marcel Rigaud, Constantine D. Sarantopoulos, Patrick Filip, and Quinn H. Hogan. "Contribution of Calcium Channel Subtypes to the Intracellular Calcium Signal in Sensory Neurons." Anesthesiology 107, no. 1 (July 1, 2007): 117–27. http://dx.doi.org/10.1097/01.anes.0000267511.21864.93.
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Abstract Background: Although the activation-induced intracellular Ca2+ signal is disrupted by sensory neuron injury, the contribution of specific Ca2+ channel subtypes is unknown. Methods: Transients in dissociated rat dorsal root ganglion neurons were recorded using fura-2 microfluorometry. Neurons from control rats and from neuropathic animals after spinal nerve ligation were activated either by elevated bath K+ or by field stimulation. Transients were compared before and after application of selective blockers of voltage-activated Ca2+ channel subtypes. Results: Transient amplitude and area were decreased by blockade of the L-type channel, particularly during sustained K+ stimulation. Significant contributions to the Ca2+ transient are attributable to the N-, P/Q-, and R-type channels, especially in small neurons. Results for T-type blockade varied widely between cells. After injury, transients lost sensitivity to N-type and R-type blockers in axotomized small neurons, whereas adjacent small neurons showed decreased responses to blockers of R-type channels. Axotomized large neurons were less sensitive to blockade of N- and P/Q-type channels. After injury, neurons adjacent to axotomy show decreased sensitivity of K+-induced transients to L-type blockade but increased sensitivity during field stimulation. Conclusions: All high-voltage–activated Ca2+ current subtypes contribute to Ca2+ transients in sensory neurons, although the L-type channel contributes predominantly during prolonged activation. Injury shifts the relative contribution of various Ca2+ channel subtypes to the intracellular Ca2+ transient induced by neuronal activation. Because this effect is cell-size specific, selective therapies might potentially be devised to differentially alter excitability of nociceptive and low-threshold sensory neurons.
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Lipscombe, Diane. "L-Type Calcium Channels." Circulation Research 90, no. 9 (May 17, 2002): 933–35. http://dx.doi.org/10.1161/01.res.0000019740.52306.92.
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Triggle, David. "L-Type Calcium Channels." Current Pharmaceutical Design 12, no. 4 (February 1, 2006): 443–57. http://dx.doi.org/10.2174/138161206775474503.
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Hell, J. W., R. E. Westenbroek, C. Warner, M. K. Ahlijanian, W. Prystay, M. M. Gilbert, T. P. Snutch, and W. A. Catterall. "Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits." Journal of Cell Biology 123, no. 4 (November 15, 1993): 949–62. http://dx.doi.org/10.1083/jcb.123.4.949.
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To identify and localize the protein products of genes encoding distinct L-type calcium channels in central neurons, anti-peptide antibodies specific for the class C and class D alpha 1 subunits were produced. Anti-CNC1 directed against class C immunoprecipitated 75% of the L-type channels solubilized from rat cerebral cortex and hippocampus. Anti-CND1 directed against class D immunoprecipitated only 20% of the L-type calcium channels. Immunoblotting revealed two size forms of the class C L-type alpha 1 subunit, LC1 and LC2, and two size forms of the class D L-type alpha 1 subunit, LD1 and LD2. The larger isoforms had apparent molecular masses of approximately 200-210 kD while the smaller isoforms were 180-190 kD, as estimated from electrophoresis in gels polymerized from 5% acrylamide. Immunocytochemical studies using CNC1 and CND1 antibodies revealed that the alpha 1 subunits of both L-type calcium channel subtypes are localized mainly in neuronal cell bodies and proximal dendrites. Relatively dense labeling was observed at the base of major dendrites in many neurons. Staining in more distal dendritic regions was faint or undetectable with CND1, while a more significant level of staining of distal dendrites was observed with CNC1, particularly in the dentate gyrus and the CA2 and CA3 areas of the hippocampus. Class C calcium channels were concentrated in clusters, while class D calcium channels were generally distributed in the cell surface membrane of cell bodies and proximal dendrites. Our results demonstrate multiple size forms and differential localization of two subtypes of L-type calcium channels in the cell bodies and proximal dendrites of central neurons. The differential localization and multiple size forms may allow these two channel subtypes to participate in distinct aspects of electrical signal integration and intracellular calcium signaling in neuronal cell bodies. The preferential localization of these calcium channels in cell bodies and proximal dendrites implies their involvement in regulation of calcium-dependent functions occurring in those cellular compartments such as protein phosphorylation, enzyme activity, and gene expression.
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Krieger, P., A. Büschges, and A. el Manira. "Calcium Channels Involved in Synaptic Transmission From Reticulospinal Axons in Lamprey." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1699–705. http://dx.doi.org/10.1152/jn.1999.81.4.1699.
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Calcium channels involved in synaptic transmission from reticulospinal axons in lamprey. The pharmacology of calcium channels involved in glutamatergic synaptic transmission from reticulospinal axons in the lamprey spinal cord was analyzed with specific agonists and antagonists of different high-voltage activated calcium channels. The N-type calcium channel blocker ω-conotoxin GVIA (ω-CgTx) induced a large decrease of the amplitude of reticulospinal-evoked excitatory postsynaptic potentials (EPSPs). The P/Q-type calcium channel blocker ω-agatoxin IVA (ω-Aga) also reduced the amplitude of the reticulospinal EPSPs, but to a lesser extent than ω-CgTx. The dihydropyridine agonist Bay K and antagonist nimodipine had no effect on the amplitude of the reticulospinal EPSP. Combined application of ω-CgTx and ω-Aga strongly decreased the amplitude the EPSPs but was never able to completely block them, indicating that calcium channels insensitive to these toxins (R-type) are also involved in synaptic transmission from reticulospinal axons. We have previously shown that the group III metabotropic glutamate receptor agonistl(+)-2-amino-4-phosphonobutyric acid (l-AP4) mediates presynaptic inhibition at the reticulospinal synapse. To test if this presynaptic effect is mediated through inhibition of calcium influx, the effect of l-AP4 on reticulospinal transmission was tested before and after blockade of N-type channels, which contribute predominantly to transmitter release at this synapse. Blocking the N-type channels with ω-CgTx did not prevent inhibition of reticulospinal synaptic transmission by l-AP4. In addition, l-AP4 had no affect on the calcium current recorded in the somata of reticulospinal neurons or on the calcium component of action potentials in reticulospinal axons. These results show that synaptic transmission from reticulospinal axons in the lamprey is mediated by calcium influx through N-, P/Q- and R-type channels, with N-type channels playing the major role. Furthermore, presynaptic inhibition of reticulospinal transmission byl-AP4 appears not to be mediated through inhibition of presynaptic calcium channels.
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Feng, Ming-Guo, Ming Li, and L. Gabriel Navar. "T-type calcium channels in the regulation of afferent and efferent arterioles in rats." American Journal of Physiology-Renal Physiology 286, no. 2 (February 2004): F331—F337. http://dx.doi.org/10.1152/ajprenal.00251.2003.
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L-type Ca2+ channels predominantly influence preglomerular arterioles, but there is less information regarding the role of T-type Ca2+ channels in regulating the renal microvasculature. We compared the effects of T- and L-type channel blockade on afferent and efferent arterioles using the in vitro blood-perfused juxtamedullary nephron preparation. Single afferent or efferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing Ca2+ channel blockers. We confirmed that L-type channel blockade with diltiazem dilates afferent arterioles but has no significant effects on efferent arterioles. In contrast, T-type channel blockade with pimozide (10 μmol/l) or mibefradil (1 μmol/l) dilated both afferent (26.8 ± 3.4 and 24.6 ± 1.9%) and efferent (19.2 ± 2.9 and 19.1 ± 4.8%) arterioles. Adding diltiazem did not significantly augment the dilation of afferent arterioles elicited by pimozide and mibefradil, and adding pimozide after diltiazem likewise did not elicit further vasodilation. Diltiazem blocked the depolarization-induced afferent arteriolar constriction elicited by 55 mM KCl; however, the constrictor response to KCl remained intact during treatment with 10 μM pimozide. Pimozide also prevented the afferent arterioles from exhibiting autoregulatory-mediated constrictor responses to increases in perfusion pressure. We conclude that T-type channel blockers dilate efferent arterioles as well as afferent arterioles and diminish afferent arteriolar autoregulatory responses to changes in perfusion pressure. To the extent that these agents exert their effects primarily on T-type Ca2+ channels in our experimental setting, these results indicate that T-type channels are functionally expressed in juxtamedullary afferent and efferent arterioles and may act cooperatively with L-type channels to regulate afferent arteriolar resistance. Because L-type channels are not functionally expressed in efferent arterioles, T-type channels may be particularly significant in the regulation of efferent arteriolar function.
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Friedman, P. A., and F. A. Gesek. "Hormone-responsive Ca2+ entry in distal convoluted tubules." Journal of the American Society of Nephrology 4, no. 7 (January 1994): 1396–404. http://dx.doi.org/10.1681/asn.v471396.
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This editorial review focuses on recent observations regarding the mechanism and regulation of calcium transport in hormone-sensitive distal convoluted tubules. Parathyroid hormone (PTH) and calcitonin increase active calcium absorption by distal convoluted tubules. Occupancy of these peptide hormone receptors results in the activation of both protein kinase A and protein kinase C. The inhibition of either kinase blocks calcium transport. The time course of stimulation of calcium entry in distal convoluted tubules by PTH is slow compared with that by calcitonin. The latency associated with PTH action may be due to the induction of protein synthesis. PTH and calcitonin hyperpolarize membrane voltage, which in turn increases calcium entry. Calcium entry is mediated by calcium channels. These channels exhibit a low, single-channel conductance and are sensitive to dihydropyridine-type calcium channel blockers. Unlike L-type calcium channels, the channel open probability of distal convoluted tubule calcium entry channels is increased upon hyperpolarization. This novel combination of properties suggests that the underlying structure of these calcium entry channels may be unique.
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Tuana, Balwant S., and Brian J. Murphy. "Biochemical analysis of L-type calcium channels from skeletal and cardiac muscle." Canadian Journal of Physiology and Pharmacology 68, no. 11 (November 1, 1990): 1482–88. http://dx.doi.org/10.1139/y90-225.
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The development of specific pharmacological agents that modulate different types of ion channels has prompted an extensive effort to elucidate the molecular structure of these important molecules. The calcium channel blockers that specifically modulate the L-type calcium channel activity have aided in the purification and reconstitution of this channel from skeletal muscle transverse tubules. The L-type calcium channel from skeletal muscle is composed of five subunits designated α1, α2, β, γ, and σ. The α1-subunit is the pore-forming polypeptide and contains the ligand binding and phosphorylation sites through which channel activity can be modulated. The role of the other subunits in channel function remains to be studied. The calcium channel components have also been partially purified from cardiac muscle. The channel consists of at least three subunits that have properties related to the subunits of the calcium channel from skeletal muscle. A core polypeptide that can form a channel and contains ligand binding and phosphorylation sites has been identified in cardiac preparations. Here we summarize recent biochemical and molecular studies describing the structural features of these important ion channels.Key words: dihydropyridine receptor, calcium channel, muscle, molecular structure.
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Dolphin, Annette C. "Voltage-gated calcium channels: Their discovery, function and importance as drug targets." Brain and Neuroscience Advances 2 (January 2018): 239821281879480. http://dx.doi.org/10.1177/2398212818794805.
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This review will first describe the importance of Ca2+ entry for function of excitable cells, and the subsequent discovery of voltage-activated calcium conductances in these cells. This finding was rapidly followed by the identification of multiple subtypes of calcium conductance in different tissues. These were initially termed low- and high-voltage activated currents, but were then further subdivided into L-, N-, PQ-, R- and T-type calcium currents on the basis of differing pharmacology, voltage-dependent and kinetic properties, and single channel conductance. Purification of skeletal muscle calcium channels allowed the molecular identification of the pore-forming and auxiliary α2δ, β and ϒ subunits present in these calcium channel complexes. These advances then led to the cloning of the different subunits, which permitted molecular characterisation, to match the cloned channels with physiological function. Studies with knockout and other mutant mice then allowed further investigation of physiological and pathophysiological roles of calcium channels. In terms of pharmacology, cardiovascular L-type channels are targets for the widely used antihypertensive 1,4-dihydropyridines and other calcium channel blockers, N-type channels are a drug target in pain, and α2δ-1 is the therapeutic target of the gabapentinoid drugs, used in neuropathic pain. Recent structural advances have allowed a deeper understanding of Ca2+ permeation through the channel pore and the structure of both the pore-forming and auxiliary subunits. Voltage-gated calcium channels are subject to multiple pathways of modulation by G-protein and second messenger regulation. Furthermore, their trafficking pathways, subcellular localisation and functional specificity are the subjects of active investigation.
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Bkaily, Ghassan, Levon Avedanian, Johny Al-Khoury, Marc Chamoun, Rana Semaan, Cynthia Jubinville-Leblanc, Pedro D’Orléans-Juste, and Danielle Jacques. "Nuclear membrane R-type calcium channels mediate cytosolic ET-1-induced increase of nuclear calcium in human vascular smooth muscle cells." Canadian Journal of Physiology and Pharmacology 93, no. 4 (April 2015): 291–97. http://dx.doi.org/10.1139/cjpp-2014-0519.
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The objective of this work was to verify whether, as in the case of the plasma membrane of human vascular smooth muscle cells (hVSMCs), cytosolic ET-1-induced increase of nuclear calcium is mediated via the activation of calcium influx through the steady-state R-type calcium channel. Pharmacological tools to identify the R-type calcium channels, as well as real 3-D confocal microscopy imaging techniques coupled to calcium fluorescent probes, were used to study the effect of cytosolic ET-1 on nuclear calcium in isolated nuclei of human hepatocytes and plasma membrane perforated hVSMCs. Our results showed that pre-treatment with pertussis toxin (PTX) or cholera toxin (CTX) prevented cytosolic ET-1 (10−9 mol/L) from inducing a sustained increase in nuclear calcium. Furthermore, the L-type calcium channel blocker nifedipine did not prevent cytosolic ET-1 from inducing an increase in nuclear calcium, as opposed to the dual L- and R-type calcium channel blocker isradipine (PN200-110) (in the presence of nifedipine). In conclusion, the preventative effect with PTX and CTX, and the absence of an effect with nifedipine, as well as the blockade by isradipine on cytosolic ET-1-induced increase in nuclear calcium, suggest that this nuclear calcium influx in hVSMCs is due to activation of the steady-state R-type calcium channel. The sarcolemmal and nuclear membrane R-type calcium channels in hVSMCs are involved in ET-1 modulation of vascular tone in physiology and pathology.
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Rosa, Juliana M., Cristina J. Torregrosa-Hetland, Inés Colmena, Luis M. Gutiérrez, Antonio G. García, and Luis Gandía. "Calcium entry through slow-inactivating L-type calcium channels preferentially triggers endocytosis rather than exocytosis in bovine chromaffin cells." American Journal of Physiology-Cell Physiology 301, no. 1 (July 2011): C86—C98. http://dx.doi.org/10.1152/ajpcell.00440.2010.
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Calcium (Ca2+)-dependent endocytosis has been linked to preferential Ca2+ entry through the L-type (α1D, CaV1.3) of voltage-dependent Ca2+ channels (VDCCs). Considering that the Ca2+-dependent exocytotic release of neurotransmitters is mostly triggered by Ca2+ entry through N-(α1B, CaV2.2) or PQ-VDCCs (α1A, CaV2.1) and that exocytosis and endocytosis are coupled, the supposition that the different channel subtypes are specialized to control different cell functions is attractive. Here we have explored this hypothesis in primary cultures of bovine adrenal chromaffin cells where PQ channels account for 50% of Ca2+ current ( ICa), 30% for N channels, and 20% for L channels. We used patch-clamp and fluorescence techniques to measure the exo-endocytotic responses triggered by long depolarizing stimuli, in 1, 2, or 10 mM concentrations of extracellular Ca2+ ([Ca2+]e). Exo-endocytotic responses were little affected by ω-conotoxin GVIA (N channel blocker), whereas ω-agatoxin IVA (PQ channel blocker) caused 80% blockade of exocytosis as well as endocytosis. In contrast, nifedipine (L channel blocker) only caused 20% inhibition of exocytosis but as much as 90% inhibition of endocytosis. Conversely, FPL67146 (an activator of L VDCCs) notably augmented endocytosis. Photoreleased caged Ca2+ caused substantially smaller endocytotic responses compared with those produced by K+ depolarization. Using fluorescence antibodies, no colocalization between L, N, or PQ channels with clathrin was found; a 20–30% colocalization was found between dynamin and all three channel antibodies. This is incompatible with the view that L channels are coupled to the endocytotic machine. Data rather support a mechanism implying the different inactivation rates of L (slow-inactivating) and N/PQ channels (fast-inactivating). Thus a slow but more sustained Ca2+ entry through L channels could be a requirement to trigger endocytosis efficiently, at least in bovine chromaffin cells.
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Koenig, Xaver, Lena Rubi, Gerald J. Obermair, Rene Cervenka, Xuan B. Dang, Peter Lukacs, Stefan Kummer, et al. "Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 4 (February 15, 2014): H564—H573. http://dx.doi.org/10.1152/ajpheart.00441.2013.
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Duchenne muscular dystrophy (DMD), induced by mutations in the gene encoding for the cytoskeletal protein dystrophin, is an inherited disease characterized by progressive muscle weakness. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with cardiac complications. These include cardiomyopathy development and cardiac arrhythmias. The current understanding of the pathomechanisms in the heart is very limited, but recent research indicates that dysfunctional ion channels in dystrophic cardiomyocytes play a role. The aim of the present study was to characterize abnormalities in L-type calcium channel function in adult dystrophic ventricular cardiomyocytes. By using the whole cell patch-clamp technique, the properties of currents through calcium channels in ventricular cardiomyocytes isolated from the hearts of normal and dystrophic adult mice were compared. Besides the commonly used dystrophin-deficient mdx mouse model for human DMD, we also used mdx-utr mice, which are both dystrophin- and utrophin-deficient. We found that calcium channel currents were significantly increased, and channel inactivation was reduced in dystrophic cardiomyocytes. Both effects enhance the calcium influx during an action potential (AP). Whereas the AP in dystrophic mouse cardiomyocytes was nearly normal, implementation of the enhanced dystrophic calcium conductance in a computer model of a human ventricular cardiomyocyte considerably prolonged the AP. Finally, the described dystrophic calcium channel abnormalities entailed alterations in the electrocardiograms of dystrophic mice. We conclude that gain of function in cardiac L-type calcium channels may disturb the electrophysiology of the dystrophic heart and thereby cause arrhythmias.
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Syamsunarno, Mas Rizky Anggun Adipurna, Alif Bagus Rakhimullah, Uni Gamayani, Masahiko Kurabayasi, Tatsuya Iso, Ratu Safitri, and Ramdan Panigoro. "Iron Administration Affects Cardiac Calcium Channel Expression in Mice: The Role of Cardiac Calcium Channel Expression in The Heart of Iron Overload Mice Model." Indonesian Biomedical Journal 12, no. 3 (September 5, 2020): 261–6. http://dx.doi.org/10.18585/inabj.v12i3.1170.
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BACKGROUND: Iron-overload cardiomyopathy (IOC) is a major comorbidity in patients with chronic repetitive blood transfusion due to myocardial iron uptake that facilitated by calcium channels. As cardiac compensatory mechanism to IOC, we hypothesized the cardiac calcium channels expression would be increased and involved in cardiomyopathy progressivity. This study was aimed to investigate the gene expression of calcium channels in the heart of the iron overload mice model.METHODS: Mice were divided into three groups according to iron administration doses 0, 0.1, and 0.3 mg/day. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured for the representation of cardiovascular outcomes. The heart tissues were harvested. Further mRNA levels of L-type calcium channels (LTCCs) and T-type calcium channels (TTCCs) were examined using semi-quantitative PCR. The expressions of cardiac calcium channels and blood pressure among the three groups were compared.RESULTS: The expressions of TTCCs in the two iron-injected groups were higher than the control group (p=0.018). The expressions of LTCCs were not different (p=0.413) among groups. SBP, DBP, and MAP of the iron-injected group were lower than the control group (p=0.025, p=0.011, and p=0.008, respectively).CONCLUSION: Iron administration affects the expression of TTCCs but not the LTCCs, accompanied by decreasing of systolic and diastolic blood pressure.KEYWORDS: cardiomyopathy, iron overload, L-type calcium channel, T-type calcium channel.
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Wiener, Edith, Roozina Rafique, Arnold Pizzey, Tomas Adejumo, George Chennell, and John B. Porter. "Upregulation of Hepatocellular NTBI Clearance Following Iron Loading Is Associated with Modulation of Membrane T- and L-Type Calcium Channels." Blood 118, no. 21 (November 18, 2011): 1038. http://dx.doi.org/10.1182/blood.v118.21.1038.1038.
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Abstract Abstract 1038 Background and Rationale. Under conditions of iron overload, the iron binding capacity of transferrin is exceeded and non-transferrin-bound iron (NTBI) species appear in the circulation, at concentrations typically within the range of 0.4–10 μM. NTBI species are rapidly cleared, mainly by the liver but also by the heart and endocrine tissues, causing iron overload of these organs. It is known that pre-loading of hepatocytes or cardiomyocytes with iron causes a paradoxical, dose and time-dependent, increase in NTBI clearance by these cells in vitro through mechanisms that are largely undetermined. In an iron overloaded mouse model, the uptake of ferrous iron by myocardium was related to the expression of L-type voltage–gated calcium channels and blockers of these channels reduced iron accumulation in the heart. However, it is unknown whether a similar mechanism underlies NTBI uptake by the liver. Previous work in our laboratory, using the human HuH7 hepatoma cell line, showed that increments in NTBI uptake that occurred following iron pre-loading of cells, were inhibited by the T-calcium channel inhibitor mibefradil. Methods. Flow cytometry and quantitative confocal microscopy were used to assess for changes in the abundance and subcellular distribution of L- and T-type calcium channels by iron-loading (ferric ammonium citrate [FAC]) of HuH7 hepatocytes. These cells were pre-incubated for 24 hours with increasing concentrations of FAC and then fixed (by 4% paraformaldehyde) or fixed and permeabilised (by 0.1% Triton X-100/PBS). Fixed HuH7 cells in suspension were immuno-stained with rabbit polyclonal antibodies against the alpha-1 subunits D (L-type) or H (T-type) and any changes in L- and T-type calcium channels on the cell surface measured by flow cytometry. Confocal microscopy was also performed on fixed and subsequently permeabilised adherent HuH7 cells, which were then immuno-stained by the same antibodies and subjected to fluorescence analysis using the Volocity program (Perkins Elmer) in order to assess intracellular distribution of these channels. Results. At clinically relevant pre-loading concentrations of 2 μM FAC, flow cytometry of fixed cells showed a 38% increase in T-type calcium channels on the outer membrane but no significant change in L-type channels. However, at higher FAC concentrations (20μM and 200 μM), there was a dose dependent rise in the membrane expression of L-type channels but a fall in T-type channels. With 200 μM FAC, the expression of the L-type channel was almost 3x that of the controls (p<0.0001) while the T-type channels were reduced to 65% of the untreated cells (p=0.03). Confocal microscopy of fixed and permeabilised cells showed similar effects on calcium channels following iron pre-loading. At. the clinically relevant concentrations of 2 μM iron, cellular images and line profiles exhibited greater over-all and outer membrane T-type fluorescence than controls, while L-type channels remained unaffected. By contrast, at higher pre-loading concentrations of FAC (20μM and 200μM), dose dependent increases in L-type fluorescence were observed, particularly on the cell membrane, whereas T-type fluorescence was less than that observed at 2 μM iron and similar to that of untreated cells. Conclusions. These findings show that previously demonstrated up-regulation of transferrin independent iron uptake into HuH7 hepatocytes, following cell pre-loading, are associated with an increase in membrane expression of T-type calcium channels at 2μM iron and of L-type channels at concentrations >20μM iron. Previous findings in our laboratory showing up-regulation of NTBI clearance under these conditions, but with no change in mRNA for L or T type channels, and with inhibition of this enhanced uptake by T-type channel blockers, suggest that these effects occur at a post-transcriptional level. These findings also indicate that use of selective calcium channel blockade could be useful in the treatment of iron overload conditions. Disclosures: No relevant conflicts of interest to declare.
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Strege, Peter R., Cheryl E. Bernard, Yijun Ou, Simon J. Gibbons, and Gianrico Farrugia. "Effect of mibefradil on sodium and calcium currents." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 2 (August 2005): G249—G253. http://dx.doi.org/10.1152/ajpgi.00022.2005.
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Interstitial cells of Cajal (ICC) generate the electrical slow wave. The ionic conductances that contribute to the slow wave appear to vary among species. In humans, a tetrodotoxin-resistant Na+ current (NaV1.5) encoded by SCN5A contributes to the rising phase of the slow wave, whereas T-type Ca2+ currents have been reported from cultured mouse intestine ICC and also from canine colonic ICC. Mibefradil has a higher affinity for T-type over L-type Ca2+ channels, and the drug has been used in the gastrointestinal tract to identify T-type currents. However, the selectivity of mibefradil for T-type Ca2+ channels over ICC and smooth muscle Na+ channels has not been clearly demonstrated. The aim of this study was to determine the effect of mibefradil on T-type and L-type Ca2+ and Na+ currents. Whole cell currents were recorded from HEK-293 cells coexpressing green fluorescent protein with either the rat brain T-type Ca2+ channel α13.3b + β2, the human intestinal L-type Ca2+ channel subunits α1C + β2, or NaV1.5. Mibefradil significantly reduced expressed T-type Ca2+ current at concentrations ≥ 0.1 μM (IC50 = 0.29 μM), L-type Ca2+ current at > 1 μM (IC50 = 2.7 μM), and Na+ current at ≥ 0.3 μM (IC50 = 0.98 μM). In conclusion, mibefradil inhibits the human intestinal tetrodotoxin-resistant Na+ channel at submicromolar concentrations. Caution must be used in the interpretation of the effects of mibefradil when several ion channel classes are coexpressed.
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Drígeľová, Mária, Bohumila Tarabová, Gunars Duburs, and Ľubica Lacinová. "The dihydropyridine analogue cerebrocrast blocks both T-type and L-type calcium currents." Canadian Journal of Physiology and Pharmacology 87, no. 11 (November 2009): 923–32. http://dx.doi.org/10.1139/y09-086.
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Cerebrocrast is a novel lipophilic dihydropyridine derivative with potential neuroprotective and antidiabetic properties. We have analyzed its interaction with L-type (CaV1.2b) and T-type (CaV3.1) calcium channels using a whole-cell patch clamp in HEK 293 cells. Cerebrocrast inhibited current flux through both CaV1.2b and CaV3.1 channels. In both cases, the drug was about 10-fold less effective than neutral dihydropyridines, but more efficient than the charged dihydropyridine amlodipine. IC50 values for the CaV1.2b channel were 586 ± 96 nmol/L and 178 ± 78 nmol/L at holding potentials of –80 mV and –50 mV, respectively. Approximately 50 µmol/L of cerebrocrast was needed to block 50% of the current amplitude in the CaV3.1 channel, but this inhibition was not facilitated by shifting the holding potential from –100 mV to –70 mV. Cerebrocrast did not alter current kinetics in either investigated channel, and the inhibition of calcium current was partly reversible or irreversible. In conclusion, the interaction of cerebrocrast with CaV3.1 lacked the typical characteristics of a state-dependent interaction, and voltage-dependent inhibition of CaV1.2b was consistent with partial interaction with the inactivated state of the channel.
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Rodriguez-Tapia, Eileen, Alberto Perez-Medina, Xiaochun Bian, and James J. Galligan. "Upregulation of L-type calcium channels in colonic inhibitory motoneurons of P/Q-type calcium channel-deficient mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 4 (October 1, 2016): G763—G774. http://dx.doi.org/10.1152/ajpgi.00263.2016.
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Enteric inhibitory motoneurons use nitric oxide and a purine neurotransmitter to relax gastrointestinal smooth muscle. Enteric P/Q-type Ca2+ channels contribute to excitatory neuromuscular transmission; their contribution to inhibitory transmission is less clear. We used the colon from tottering mice ( tg/tg, loss of function mutation in the α1A pore-forming subunit of P/Q-type Ca2+ channels) to test the hypothesis that P/Q-type Ca2+ channels contribute to inhibitory neuromuscular transmission and colonic propulsive motility. Fecal pellet output in vivo and the colonic migrating motor complex (ex vivo) were measured. Neurogenic circular muscle relaxations and inhibitory junction potentials (IJPs) were also measured ex vivo. Colonic propulsive motility in vivo and ex vivo was impaired in tg/tg mice. IJPs were either unchanged or somewhat larger in tissues from tg/tg compared with wild-type (WT) mice. Nifedipine (L-type Ca2+ channel antagonist) inhibited IJPs by 35 and 14% in tissues from tg/tg and WT mice, respectively. The contribution of N- and R-type channels to neuromuscular transmission was larger in tissues from tg/tg compared with WT mice. The resting membrane potential of circular muscle cells was similar in tissues from tg/tg and WT mice. Neurogenic relaxations of circular muscle from tg/tg and WT mice were similar. These results demonstrate that a functional deficit in P/Q-type channels does not alter propulsive colonic motility. Myenteric neuron L-type Ca2+ channel function increases to compensate for loss of functional P/Q-type Ca2+ channels. This compensation maintains inhibitory neuromuscular transmission and normal colonic motility.
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Nikitina, Elena, Ayako Kawashima, Masataka Takahashi, Zhen-Du Zhang, Xueyuan Shang, Jinglu Ai, and R. Loch Macdonald. "Alteration in voltage-dependent calcium channels in dog basilar artery after subarachnoid hemorrhage." Journal of Neurosurgery 113, no. 4 (October 2010): 870–80. http://dx.doi.org/10.3171/2010.2.jns091038.
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Object The L-type Ca++ channel antagonists like nimodipine have limited efficacy against vasospasm after subarachnoid hemorrhage (SAH). The authors tested the hypothesis that this is because SAH alters these channels, rendering them less responsible for contraction. Methods Basilar artery smooth muscle cells were isolated 4, 7, and 21 days after SAH in dogs, and Ca++ channel currents were recorded in 10-mmol/L barium. Proteins for α1 subunits of L-type Ca++ channels were measured by immunoblotting and isometric tension recordings done on rings of the basilar artery. Results High voltage–activated (HVA) Ca++ channel currents were significantly decreased and low voltage–activated (LVA) currents increased during vasospasm 4, 7, and 21 days after SAH (p < 0.05). Vasospasm was associated with a significant decrease in the number of cells with negligible LVA current while the number of cells in which the LVA current formed greater than 50% of the maximal current increased (p < 0.01). Window currents through LVA and HVA channels were significantly reduced. All changes correlated with the severity of vasospasm. There was an increase in protein for Cav3.1 and Cav3.3 α1 subunits that comprise T-type Ca++ channels, a decrease in L-type (Cav1.2 and Cav1.3) and an increase in R-type (Cav2.3) Ca++ channel α1 subunits. Functionally, however, isometric tension studies showed vasospastic arteries still relaxed with nimodipine. Conclusions Voltage-dependent Ca++ channels are altered in cerebral arteries after SAH. While decreased L-type channels may account for the lack of efficacy of nimodipine clinically, there may be other reasons such as inadequate dose, effect of nimodipine on other cellular targets, and mechanisms of vasospasm other than smooth muscle contraction mediated by activation of L-type Ca++ channels.
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Haak, Laurel L. "Metabotropic Glutamate Receptor Modulation of Glutamate Responses in the Suprachiasmatic Nucleus." Journal of Neurophysiology 81, no. 3 (March 1, 1999): 1308–17. http://dx.doi.org/10.1152/jn.1999.81.3.1308.
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Metabotropic glutamate receptor modulation of glutamate responses in the suprachiasmatic nucleus. Glutamate is the primary excitatory transmitter in the suprachiasmatic nucleus (SCN). Ionotropic glutamate receptors (iGluRs) mediate transduction of light information from the retina to the SCN, an important circadian clock phase shifting pathway. Metabotropic glutamate receptors (mGluRs) may play a significant modulatory role. mGluR modulation of SCN responses to glutamate was investigated with fura-2 calcium imaging in SCN explant cultures. SCN neurons showed reproducible calcium responses to glutamate, kainate, and N-methyl-d-aspartate (NMDA). Although the type I/II mGluR agonists L-CCG-I and t-ACPD did not evoke calcium responses, they did inhibit kainate- and NMDA-evoked calcium rises. This interaction was insensitive to pertussis toxin. Protein kinase A (PKA) activation by 8-bromo-cAMP significantly reduced iGluR inhibition by mGluR agonists. The inhibitory effect of mGluRs was enhanced by activating protein kinase C (PKC) and significantly reduced in the presence of the PKC inhibitor H7. Previous reports show that L-type calcium channels can be modulated by PKC and PKA. In SCN cells, about one-half of the calcium rise evoked by kainate or NMDA was blocked by the L-type calcium channel antagonist nimodipine. Calcium rises evoked by K+ were used to test whether mGluR inhibition of iGluR calcium rises involved calcium channel modulation. These calcium rises were primarily attributable to activation of voltage-activated calcium channels. PKC activation inhibited K+-evoked calcium rises, but PKC inhibition did not affect L-CCG-I inhibition of these rises. In contrast, 8Br-cAMP had no effect alone but blocked L-CCG-I inhibition. Taken together, these results suggest that activation of mGluRs, likely type II, modulates glutamate-evoked calcium responses in SCN neurons. mGluR inhibition of iGluR calcium rises can be differentially influenced by PKC or PKA activation. Regulation of glutamate-mediated calcium influx could occur at L-type calcium channels, K+ channels, or at GluRs. It is proposed that mGluRs may be important regulators of glutamate responsivity in the circadian system.
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Rosenberg, R. L., and X. H. Chen. "Characterization and localization of two ion-binding sites within the pore of cardiac L-type calcium channels." Journal of General Physiology 97, no. 6 (June 1, 1991): 1207–25. http://dx.doi.org/10.1085/jgp.97.6.1207.
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L-type Ca channels from porcine cardiac sarcolemma were incorporated into planar lipid bilayers. We characterized interactions of permeant and blocking ions with the channel's pore by (a) studying the current-voltage relationships for Ca2+ and Na+ when equal concentrations of the ions were present in both internal and external solutions, (b) testing the dose-dependent block of Ba2+ currents through the channels by internally applied cadmium, and (c) examining the dose and voltage dependence of the block of Na+ currents through the channels by internally and externally applied Ca2+. We found that the I-V relationship for Na+ appears symmetrical through the origin when equal concentrations of Na+ are present on both sides of the channel (gamma = 90 pS in 200 mM NaCl). The conductance for outward Ca2+ currents with 100 mM Ca2+ on both sides of the channel is approximately 8 pS, a value identical to that observed for inward currents when 100 mM Ca2+ was present outside only. This provides evidence that ions pass through the channel equally well regardless of the direction of net flux. In addition, we find that internal Cd2+ is as effective as external Cd2+ in blocking Ba2+ currents through the channels, again suggesting identical interactions of ions with each end of the pore. Finally, we find that micromolar Ca2+, either in the internal or in the external solution, blocks Na+ currents through the channels. The affinity for internally applied Ca2+ appears the same as that for externally applied Ca2+. The voltage dependence of the Ca(2+)-block suggests that the sites to which Ca2+ binds are located approximately 15% and approximately 85% of the electric field into the pore. Taken together, these data provide direct experimental evidence for the existence of at least two ion binding sites with high affinity for Ca2+, and support the idea that the sites are symmetrically located within the electric field across L-type Ca channels.
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Gaur, Shikha, Mary E. Morton, G. Peter Frick, and H. Maurice Goodman. "Growth hormone regulates the distribution of L-type calcium channels in rat adipocyte membranes." American Journal of Physiology-Cell Physiology 275, no. 2 (August 1, 1998): C505—C514. http://dx.doi.org/10.1152/ajpcell.1998.275.2.c505.
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Earlier studies demonstrated that deprivation of growth hormone (GH) for ≥3 h decreased basal and maximally stimulated cytosolic Ca2+ in rat adipocytes and suggested that membrane Ca2+channels might be decreased. Measurement of L-type Ca2+ channels in purified plasma membranes by immunoassay or dihydropyridine binding indicated a two- to fourfold decrease after 3 h of incubation without GH. No such decrease was seen in unfractionated adipocyte membrane preparations. The decrease in plasma membrane channel content was largely accounted for by redistribution of channels to a light microsomal membrane fraction. Immunoassay of α1-, α2/δ-, and β-channel subunits in membrane fractions indicated that the channels redistributed as intact complexes. Addition of GH during the 1st h of incubation prevented channel redistribution, and addition of GH after 3 h restored channel distribution to the GH-replete state of freshly isolated adipocytes. The studies suggest that GH may regulate the abundance of Ca2+ channels in the adipocyte plasma membrane and thereby modulate sensitivity to signals, the expression of which is Ca2+dependent.
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Smith, Carolyn L., Salsabil Abdallah, Yuen Yan Wong, Phuong Le, Alicia N. Harracksingh, Liana Artinian, Arianna N. Tamvacakis, Vincent Rehder, Thomas S. Reese, and Adriano Senatore. "Evolutionary insights into T-type Ca2+ channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue." Journal of General Physiology 149, no. 4 (March 22, 2017): 483–510. http://dx.doi.org/10.1085/jgp.201611683.
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Four-domain voltage-gated Ca2+ (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCav3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCav3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCav3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Cav3 family. We also characterize the channel’s cation permeation properties and find that its pore is less selective for Ca2+ over Na+ compared with the human homologue Cav3.1, yet it exhibits a similar potent block of inward Na+ current by low external Ca2+ concentrations (i.e., the Ca2+ block effect). A comparison of the permeability features of TCav3 with other cloned channels suggests that Ca2+ block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca2+ block and higher Ca2+ selectivity. TCav3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Cav3 channel structure–function properties, ion selectivity, and cellular physiology.
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Seagar, Michael, Christian Lévêque, Nathalie Charvin, Beatrice Marquèze, Nicole Martin–Moutot, Jeanne Andrée Boudier, Jean–Louis Boudier, Yoko Shoji-Kasai, Kazuki Sato, and Masami Takahashi. "Interactions between proteins implicated in exocytosis and voltage–gated calcium channels." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1381 (February 28, 1999): 289–97. http://dx.doi.org/10.1098/rstb.1999.0380.
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Neurotransmitter release from synaptic vesicles is triggered by voltage–gated calcium influx through P/Q–type or N–type calcium channels. Purification of N–type channels from rat brain synaptosomes initially suggested molecular interactions between calcium channels and two key proteins implicated in exocytosis: synaptotagmin I and syntaxin 1. Co–immunoprecipitation experiments were consistent with the hypothesis that both N– and P/Q–type calcium channels, but not L–type channels, are associated with the 7S complex containing syntaxin 1, SNAP–25, VAMP and synaptotagmin I or II. Immunofluorescence confocal microscopy at the frog neuromuscular junction confirmed that calcium channels, syntaxin 1 and SNAP–25 are co–localized at active zones of the presynaptic plasma membrane where transmitter release occurs. Experiments with recombinant proteins were performed to map synaptic protein interaction sites on the α 1 A subunit, which forms the pore of the P/Q–type calcium channel. In vitro –translated 35 S–synaptotagmin I bound to a site located on the cytoplasmic loop linking homologous domains II and III of the α 1 A subunit. This direct link would target synaptotagmin, a putative calcium sensor for exocytosis, to a microdomain of calcium influx close to the channel mouth. Cysteine string proteins (CSPs) contain a J–domain characteristic of molecular chaperones that co–operate with Hsp70. They are located on synaptic vesicles and thought to be involved in modulating the acticity of presynaptic calcium channels. CSPs were found to bind to the same domain of the calcium channel as synaptotagmin, and also to associate with VAMP. CSPs may act as molecular chaperones in association with Hsp70 to direct assembly or dissociation of multi–protein complexes at the calcium channel.
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Shah, Kajol, Sarah Seeley, Castin Schulz, Jacqueline Fisher, and Shubha Gururaja Rao. "Calcium Channels in the Heart: Disease States and Drugs." Cells 11, no. 6 (March 10, 2022): 943. http://dx.doi.org/10.3390/cells11060943.
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Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders.
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Reuter, H., S. Kokubun, and B. Prod'hom. "Properties and modulation of cardiac calcium channels." Journal of Experimental Biology 124, no. 1 (September 1, 1986): 191–201. http://dx.doi.org/10.1242/jeb.124.1.191.
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Voltage-dependent calcium channels are widely distributed in excitable membranes and are involved in the regulation of many cellular functions. These channels can be modulated by neurotransmitters and drugs. There is one particular type of calcium channel in cardiac cells (L-type) whose gating is affected in different ways by beta-adrenoceptor and 1,4-dihydropyridine agonists. We have analysed single calcium channel currents (i) in myocytes from rat hearts in the absence and presence of isoproterenol or 8-bromo-cAMP. We have found that both compounds have similar effects on calcium channel properties. They increase the overall open state probability (po) of individual calcium channels while i remains unaffected. Analysis of the gating kinetics of calcium channels showed: a slight increase in the mean open times of calcium channels, a reduction in time intervals between bursts of channel openings, an increase in burst length and a prominent reduction in failures of calcium channels to open upon depolarization. These kinetic changes caused by isoproterenol and 8-bromo-cAMP can account for the increase in po. Since the macroscopic calcium current, ICa, can be described by ICa = N X po X i, the increase in po accounts for the well-known increase in ICa by beta-adrenergic catecholamines. Cyclic AMP-dependent phosphorylation of calcium channels is a likely metabolic step involved in this modulation. Another class of drug that modulates calcium channel gating is the 1,4-dihydropyridines which can either enhance or reduce ICa, either by prolonging the open state of the channels or by facilitating the inactivated state. Both effects depend strongly on membrane potential and are independent of cyclic AMP-dependent phosphorylation reactions.
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Pérez-García, M. T., T. J. Kamp, and E. Marbán. "Functional properties of cardiac L-type calcium channels transiently expressed in HEK293 cells. Roles of alpha 1 and beta subunits." Journal of General Physiology 105, no. 2 (February 1, 1995): 289–305. http://dx.doi.org/10.1085/jgp.105.2.289.
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The cardiac dihydropyridine-sensitive calcium channel was transiently expressed in HEK293 cells by transfecting the rabbit cardiac calcium channel alpha 1 subunit (alpha 1C) alone or in combination with the rabbit calcium channel beta subunit cloned from skeletal muscle. Transfection with alpha 1C alone leads to the expression of inward, voltage-activated, calcium or barium currents that exhibit dihydropyridine sensitivity and voltage- as well as calcium-dependent inactivation. Coexpression of the skeletal muscle beta subunit increases current density and the number of high-affinity dihydropyridine binding sites and also affects the macroscopic kinetics of the current. Recombinant alpha 1C beta channels exhibit a slowing of activation and a faster inactivation rate when either calcium or barium carries the charge. Our data suggest that both an increase in the number of channels as well as modulatory effects on gating underlie the modifications observed upon beta subunit coexpression.