Journal articles on the topic 'Calcium channel variance'
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1
Sah, P. "Properties of channels mediating the apamin-insensitive afterhyperpolarization in vagal motoneurons." Journal of Neurophysiology 74, no. 4 (October 1, 1995): 1772–76. http://dx.doi.org/10.1152/jn.1995.74.4.1772.
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1. Whole cell recordings were obtained from neurons of the dorsal motor nucleus of the vagus in transverse slices of guinea pig medulla. From a holding potential of -40 mV, short depolarizing voltage steps activated two calcium-dependent potassium currents, Gk(Ca),1 and Gk(Ca),2. 2. Gk(Ca),1 was completely blocked by apamin (100 nM). Gk(Ca),2 was apamin insensitive, voltage independent, and reversed close to the potassium equilibrium potential. 3. Activation of Gk(Ca),2 was associated with an increase in current variance. The channels underlying the slow component were analyzed by stationary and nonstationary fluctuation analysis. Current variance was linearly related to mean current for small current amplitudes but clearly deviated from linearity near the peak of Gk(Ca),2. The predicted single channel conductance was 6.8 +/- 2.5 (SE) pS. Probability of channel opening rose to at most 0.68. The average number of available Gk(Ca),2 channels on vagal neurons was 4,437 +/- 591. 4. Power spectra were constructed from the peak current. Spectra were well fitted with a single Lorentzian with a corner frequency of 72 +/- 7 Hz. The mean burst duration of the channels was 3.8 +/- 0.5 ms. These results indicate that a new type of calcium-activated channel underlies Gk(Ca),2.
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Meir, A., and R. Rahamimoff. "A voltage-dependent and calcium-permeable ion channel in fused presynaptic terminals of Torpedo." Journal of Neurophysiology 75, no. 5 (May 1, 1996): 1858–70. http://dx.doi.org/10.1152/jn.1996.75.5.1858.
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1. We used a preparation of fused presynaptic nerve terminals of Torpedo electromotor nerve and the patch-clamp technique for characterization of single ion channels. We report here of a large, nonselective ion channel which is highly voltage dependent. 2. The slope conductance of the I-V relation was estimated by either direct measurement of the single-channel current amplitude at different voltages (850 +/- 18 pS (SE); n = 9) or by variance analysis (834 +/- 23 pS; n = 5). 3. The voltage dependence was examined in three ways. At steady-state DC voltage conditions, NPo (the open probability times the number of channels in the patch) was estimated. At potentials < 0 mV, the probability of the channel to open is negligible and increases dramatically, within a very narrow voltage range, to > 50% at +8 mV (n = 8). 4. In pulse experiments, the activation time delay is shorter as the voltage step reaches more positive values. The mean time for half activation (T1/2) decreases from 15 ms at +10 mV to 4 ms at +30 mV (n = 5). 5. Ensemble currents exhibit rectification in response to voltage ramps at negative potentials (n = 10). 6. The channel was found to be nonselective. Its permeability to Na+, K+, Cl-, glutamate, Ba+2, and Ca+2, relative to Na+, was 1.00, 1.00, 1.22, 1.07, 0.85, and 0.62, respectively. 7. Based on the transport number of calcium, the calculated driving force, and the mean channel open time, we estimated the number of calcium ions entering the nerve terminal upon depolarization. This number is not substantially different from the number of ions entering through voltage-dependent, calcium-selective channels in other cells. 8. We speculate that this nonselective ion channel, may serve as a calcium entry route into the nerve terminal and hence be involved in transmitter release.
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Naumovic, Nada, Petar Slankamenac, Danka Filipovic, Vesna Ivetic, Snezana Tomasevic-Todorovic, and Ksenija Boskovic. "Effects of calcium antagonists on brain ischemia." Medical review 64, no. 5-6 (2011): 257–61. http://dx.doi.org/10.2298/mpns1106257n.
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Introduction. Stroke is the second leading cause of death in the world and the leading cause of serious, long term disability in adults; about half of those who survive become dependent on others in performing personal activities of daily living. Ischemia disturbs calcium cellular homeostasis, whereas calcium channel blockers re-establish it. This study was aimed at assessing benefits of calcium channel blockers on the outcome of rehabilitation of the patients afflicted by ischemic stroke. Material and Methods. The functional independence was measured by the Barthel index in 90 patients subjected to rehabilitative therapeutic treatment. The functional recovery of patients treated with calcium channel blockers and with other drugs (control) was compared and tested. Results. The analysis of variance (ANOVA) for the 0.5 confidence interval showed that the increases of the Barthel index values were significantly higher in the patients treated with calcium antagonists (p<0.5). Discussion. According to the literature, such an outcome is the result of improved brain blood f low auto-regulation, increased brain perfusion as well as of neuroprotective, antioxidative, platelet antiaggregatory effects of investigated drugs. Conclusion. The calcium channel blockers improved the outcome of rehabilitative therapeutic treatment significantly in the patients afflicted by ischemic stroke.
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Giannini, G., A. Conti, S. Mammarella, M. Scrobogna, and V. Sorrentino. "The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues." Journal of Cell Biology 128, no. 5 (March 1, 1995): 893–904. http://dx.doi.org/10.1083/jcb.128.5.893.
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Ryanodine receptors (RyRs) are intracellular calcium release channels that participate in controlling cytosolic calcium levels. At variance with the probably ubiquitous inositol 1,4,5-trisphosphate-operated calcium channels (1,4,5-trisphosphate receptors), RyRs have been mainly regarded as the calcium release channels controlling skeletal and cardiac muscle contraction. Increasing evidence has recently suggested that RyRs may be more widely expressed, but this has never been extensively examined. Therefore, we cloned three cDNAs corresponding to murine RyR homologues to carry a comprehensive analysis of their expression in murine tissues. Here, we report that the three genes are expressed in almost all tissues analyzed, where tissue-specific patterns of expression were observed. In the uterus and vas deferens, expression of RyR3 was localized to the smooth muscle component of these organs. In the testis, expression of RyR1 and RyR3 was detected in germ cells. RyR mRNAs were also detected in in vitro-cultured cell lines. RyR1, RyR2, and RyR3 mRNA were detected in the cerebrum and in the cerebellum. In situ analysis revealed a cell type-specific pattern of expression in the different regions of the central nervous system. The differential expression of the three ryanodine receptor genes in the central nervous system was also confirmed using specific antibodies against the respective proteins. This widespread pattern of expression suggests that RyRs may participate in the regulation of intracellular calcium homeostasis in a range of cells wider than previously recognized.
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Prakriya, Murali, and Richard S. Lewis. "Regulation of CRAC Channel Activity by Recruitment of Silent Channels to a High Open-probability Gating Mode." Journal of General Physiology 128, no. 3 (August 28, 2006): 373–86. http://dx.doi.org/10.1085/jgp.200609588.
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CRAC (calcium release-activated Ca2+) channels attain an extremely high selectivity for Ca2+ from the blockade of monovalent cation permeation by Ca2+ within the pore. In this study we have exploited the blockade by Ca2+ to examine the size of the CRAC channel pore, its unitary conductance for monovalent cations, and channel gating properties. The permeation of a series of methylammonium compounds under divalent cation-free conditions indicates a minimum pore diameter of 3.9 Å. Extracellular Ca2+ blocks monovalent flux in a manner consistent with a single intrapore site having an effective Ki of 20 μM at −110 mV. Block increases with hyperpolarization, but declines below −100 mV, most likely due to permeation of Ca2+. Analysis of monovalent current noise induced by increasing levels of block by extracellular Ca2+ indicates an open probability (Po) of ∼0.8. By extrapolating the variance/mean current ratio to the condition of full blockade (Po = 0), we estimate a unitary conductance of ∼0.7 pS for Na+, or three to fourfold higher than previous estimates. Removal of extracellular Ca2+ causes the monovalent current to decline over tens of seconds, a process termed depotentiation. The declining current appears to result from a reduction in the number of active channels without a change in their high open probability. Similarly, low concentrations of 2-APB that enhance ICRAC increase the number of active channels while open probability remains constant. We conclude that the slow regulation of whole-cell CRAC current by store depletion, extracellular Ca2+, and 2-APB involves the stepwise recruitment of silent channels to a high open-probability gating mode.
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Eisner, G. M., I. Yamaguchi, R. A. Felder, L. D. Asico, and P. A. Jose. "Role of renal dopamine D1 receptors in natriuresis induced by calcium channel blockers." American Journal of Physiology-Renal Physiology 267, no. 6 (December 1, 1994): F965—F970. http://dx.doi.org/10.1152/ajprenal.1994.267.6.f965.
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The direct tubular natriuretic effect of calcium channel blockers (CCBs) may be due to an interaction between CCBs and a renal tubular dopamine receptor. We therefore studied the effects of two chemically unrelated CCBs, diltiazem and isradipine, infused into the right renal artery of 5% saline-loaded anesthetized rats alone or in the presence of a D1 antagonist, SKF-83742. Isradipine (0.03 microgram.kg-1.min-1) or diltiazem (20 but not 10 micrograms.kg-1.min-1) alone produced an increase in urine flow and an approximate doubling of absolute and fractional sodium excretion, which was not seen in the left kidney or in the control animals (analysis of variance, Scheffe's test, P < 0.05). SKF-83742 alone given systemically or into the right renal artery did not affect these parameters but did block the actions of diltiazem or isradipine. There was no change in mean arterial pressure, renal blood flow, or glomerular filtration rate in any of the experiments. In additional studies, we found that a combined infusion of dopamine (0.1 microgram.kg-1.min-1) and diltiazem (10 micrograms.kg-1.min-1) (doses that by themselves did not alter renal function) produced a twofold or greater increase in urine flow and absolute and fractional sodium excretion; glomerular filtration rate was not significantly changed. Intrarenal arterial CCBs, without a change in renal hemodynamics, produce a natriuresis that is blocked by a D1 antagonist. Concomitant administration of diltiazem and dopamine (each in subeffective doses when used alone) produces a synergistic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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Hallberg, Pär, Julia Nagy, Malgorzata Karawajczyk, Leif Nordang, Gunilla Islander, Pia Norling, Hans-Erik Johansson, et al. "Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema and Cough." Annals of Pharmacotherapy 51, no. 4 (November 26, 2016): 293–300. http://dx.doi.org/10.1177/1060028016682251.
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Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. Objective: We compared characteristics between patients with ACE inhibitor–induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher’s exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. Results: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10-5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor–induced angioedema rather than cough.
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Harutyunyan, K. R., K. V. Melkumyan, H. T. Abrahamyam, S. H. Adamyan, D. H. Khudaverdyan, and A. S. Ter-Markosyan. "Calcium-regulating hormonal system in cardiac functional activity." NEW ARMENIAN MEDICAL JOURNAL, no. 4 (2022): 54–63. http://dx.doi.org/10.56936/18290825-2022.16.4-54.
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The variance of calcium homeostasis is known as a risk factor for the development of heart failure. A study of calcium-regulating hormones is a crucial element to understand underlying pathophysiological mechanisms of heart failure. Pro-inflammatory factors, released during mechanical, hypoxic or bacterial damage of myocardial cells, lead to an imbalance of calcium and disrupt to heart function. The investigation of mentioned factors influence mechanism on the heart, is an urgent solution for preventing the development of heart failure. Present study aimed to reveal the role of calcium-regulating hormones in heart functional activity and their possible involvement in the development of heart failure. The pharmacological analysis of the action mechanism of bacterial lipopolysaccharides on heart functional activity was carried out using a calcium channel blocker. The concentrations of calcium-regulating hormones in blood serum in patients suffering from heart failure was determined by immunoassay enzyme method, and ionized calcium and inorganic phosphate concentrations - by spectrophotometric method. The photoelectrical method was used to determine the direct effect of calcium-regulating hormones and possible calcium-dependent action mechanism of bacterial lipopolysaccharides on the isolated frog’s heart. Clinical findings show that chronic heart failure is accompanied by shifts in the calcium-regulating hormonal system and blood electrolyte balance. In vitro experiments on isolated frog hearts have shown the potentiating effect of parathyroid hormone, its related protein, calcitonin, and vitamin D3 on myocardial contractility. It has been shown, that bacterial lipopolysaccharides suppress the contractile and rhythmogenic functions of the myocardium, and their action can be mediated through a calcium-dependent mechanism. The increase of parathyroid hormone in chronic heart failure has a protective significance aimed at maintaining the contractile ability of a weakened myocardium and preserving cardiac output. Bacterial lipopolysaccharides are able to suppress functional activity of the heart by calcium-dependent mechanism.
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Barrett, Ravina, and James Hodgkinson. "Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England’s prescription data during the COVID-19 pandemic (January 2019 to October 2020)." Therapeutic Advances in Cardiovascular Disease 16 (January 2022): 175394472211371. http://dx.doi.org/10.1177/17539447221137170.
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Background: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. Aim: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. Methods: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic’s onset. Statistical variation was the outcome of interest. Results: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March–October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. Conclusion: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi
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Harding, S. E., S. M. Jones, P. O'Gara, G. Vescovo, and P. A. Poole-Wilson. "Reduced beta-agonist sensitivity in single atrial cells from failing human hearts." American Journal of Physiology-Heart and Circulatory Physiology 259, no. 4 (October 1, 1990): H1009—H1014. http://dx.doi.org/10.1152/ajpheart.1990.259.4.h1009.
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Human myocytes were isolated from right atrial appendage, and contractile responses to inotropic agents were studied. Responses to inotropic agents of cells isolated from patients with mild heart disease [New York Heart Association (NYHA) classes I and II] were compared with those of myocytes from rabbit atria. Maximally effective concentrations of calcium, forskolin, and isoproterenol increased contraction amplitude to a similar extent (11.9, 11.5, and 11.3% change in cell length, respectively), but histamine produced a smaller effect (7.1%). The maximum responses of rabbit atrial cells to calcium (18.5%) and isoproterenol (15.0%) were significantly greater than human. In human cells, the velocity of contraction or relaxation was accelerated more by isoproterenol (P less than 0.05) or forskolin (P less than 0.01) than by high calcium. Only relaxation velocity was increased by isoproterenol in rabbit cells (P less than 0.05). Rabbit myocytes contracted and relaxed 10-30% faster than human (P less than 0.05). Cells from the atria of patients with New York Heart Association (NYHA) heart failure class III or IV were less responsive to isoproterenol than those from class I or II (P less than 0.01). Omitting data from patients who had been taking calcium-channel blockers or beta-adrenoceptor agonist or antagonist drugs did not affect the conclusions. Analysis of variance revealed a significantly greater between-patient than within-patient variation (P less than 0.001), indicating that cells from the same patient have a tendency to respond in a similar way. Responses to high calcium did not differ among NYHA classes. The effect of forskolin was not reduced in NYHA class III, although there was a decreased response in cells from two patients in NYHA class IV.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lee, B. M., G. S. Lee, and E. B. Jeung. "117 THE REGULATOR OF THE UTERINE TRPV6 GENE DURING PREGNANCY IN RODENTS." Reproduction, Fertility and Development 20, no. 1 (2008): 138. http://dx.doi.org/10.1071/rdv20n1ab117.
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Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) is an epithelial Ca2+ channel protein expressed in calcium-absorbing organs. Recently it was reported that TRPV6 is expressed in female reproductive organs. The present study was performed to investigate the expression and regulation of uterine and placental TRPV6 during gestation in rats. In the uterus, TRPV6 was moderately expressed at pregnancy day (P) 0 and decreased until P4. Its expression level then peaked at P5, implying that TRPV6 may be involved in embryo implantation. Around P13, uterine TRPV6 expression increased slightly a second time, and then gradually decreased until the end of pregnancy at P21. Tissue localization of TRPV6 expression was determined by immunohistochemistry methods. TRPV6 protein was detected in uterine endothelium layers and glands; however, it was not detected in uterine tissues attached to the placenta. In the placenta, TRPV6 mRNA levels increased in mid-gestation, and the tissue distribution of placental TRPV6 protein suggests that it may play a role in transferring calcium to the fetus during pregnancy. To investigate the pathway(s) mediating TRPV6 expression during pregnancy in rats and mice, steroid hormone antagonists ICI 182 780 (ICI) and RU 486 (RU) were injected prior to maximal TRPV6 expression, as anti-estrogen and anti-progesterone agents, respectively. Pregnant rats (P4 for uterine RNA preparation, P19 for placental RNA preparation) received subcutaneous injections of RU (2.5 mg per rat), ICI (0.5 mg per rat), or a combination of RU and ICI. In addition, ICR-mice at P9 were injected with RU (25 µg per mouse) and/or ICI (2 µg per mouse). We measured level of TRPV6 mRNA transcription using semi-quantitative RT-PCR and real-time PCR. Data were analyzed by nonparametric one-way analysis of variance using the Kruskal-Wallis test, followed by Dunnett's test for multiple comparisons to vehicle. In rats, TRPV6 expression was reduced by RU treatment, and in mice ICI treatment blocked TRPV6 expression. Taken together, these results suggest that progesterone in rats and estrogen in mice act to regulate TRPV6 expression in the uterus and placenta during pregnancy. In conclusion, TRPV6 may play a role in embryo implantation in the uterus and in calcium transport between embryo and mother in the placenta.
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Nilius, B., M. Oike, I. Zahradnik, and G. Droogmans. "Activation of a Cl- current by hypotonic volume increase in human endothelial cells." Journal of General Physiology 103, no. 5 (May 1, 1994): 787–805. http://dx.doi.org/10.1085/jgp.103.5.787.
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We have used whole-cell and perforated patches to study ionic currents induced by hypotonic extracellular solutions (HTS, 185 mOsm instead of 290 mOsm) in endothelial cells from human umbilical veins. These currents activated within 30-50 s after application of HTS, reached a maximum value after approximately 50-150 s and recovered completely after re-exposing the cells to normal osmolarity. They slowly inactivated at potentials positive to +50 mV. The same current was also activated by breaking into endothelial cells with a hypertonic pipette solution (377 mOsm instead of 290 mOsm). The reversal potential of these volume-induced currents using different extracellular and intracellular Cl- concentrations was always close to the Cl(-)-equilibrium potential. These currents are therefore mainly carried by Cl-. DIDS only weakly blocked the current (KI = 120 microM), while another Cl(-)-channel blocker, DCDPC (20 microM) was ineffective. We were unable to record single channel activity in cell-attached patches but we always observed an increased current variance during HTS. From the mean current-variance relation of the whole-cell current records, we determined a single channel conductance of 1.1 pS. The size and kinetics of the current were not correlated with the concomitant changes in intracellular calcium. Furthermore, the currents could still be activated in the presence of 10 mmol/liter intracellular EGTA and are thus Ca2+ independent. A similar current was also activated with iso-osmotic pipette solutions containing 300 mumol/liter GTP gamma S. Neomycin (1 mmol/liter), a blocker of PLC, did not prevent activation of this current. TPA (4 mumol/liter) was also ineffective in modulation of this current. The HTS-induced current was completely blocked by 10 mumol/liter pBPB, a PLA2 inhibitor. NDGA (4 mumol/liter) and indomethacin (5 mumol/liter), blockers of lipoxygenase and cyclo-oxygenase respectively, did however not affect the current induced by hypotonic solutions. The effects of arachidonic acid (10 mumol/liter) were variable. In 12 out of 40 cells it either directly activated a Cl- current or potentiated the current activated by HTS. The membrane current was decreased at all potentials in 18 cells, and was not affected in 10 cells. The HTS-induced currents may therefore be modulated by cleavage products of PLA2, but not by messengers downstream of arachidonic acid. Loading the cells with a segment of the heat stable protein kinase A inhibitor PKI (5-24) did not prevent activation of the HTS-induced current.(ABSTRACT TRUNCATED AT 400 WORDS)
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Kukuljan, Manuel, Alison Taylor, Hilary Chouinard, Patricio Olguín, Cecilia V. Rojas, and Angeles B. Ribera. "Selective Regulation of xSlo Splice Variants During Xenopus Embryogenesis." Journal of Neurophysiology 90, no. 5 (November 2003): 3352–60. http://dx.doi.org/10.1152/jn.00398.2003.
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Calcium-activated potassium channels regulate excitability of the adult nervous system. In contrast, little is known about the contribution of calcium-activated potassium channels to excitability of the embryonic nervous system when electrical membrane properties and intracellular calcium levels show dramatic changes. Embryonic Xenopus spinal neurons exhibit a well-characterized developmental program of excitability that involves several different currents including calcium-activated ones. Here, we show that a molecular determinant of calcium-activated potassium channels, xSlo, is expressed during Xenopus embryogenesis even prior to differentiation of excitable tissues. Five different xSlo variants are expressed in embryonic tissues as a consequence of alternative exon usage at a single splice site. One of these variants, xSlo59, is neural-specific, and its expression is limited to late stages of neuronal differentiation. However, expression of the four other variants occurs in both muscle and neurons at all stages of development examined. Electrophysiological analysis of recombinant xSlo channels reveals that the xSlo59 exon serves as a gain-of-function module and allows physiologically relevant levels of membrane potential and intracellular calcium to activate effectively the resultant channel. These results suggest that xSlo59 channels play a unique role in sculpting the excitable membrane properties of Xenopus spinal neurons.
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Ott, Stephanie, Sheila Jedlicka, Stefan Wolf, Mozes Peter, Christine Pudenz, Patrick Merker, Ludwig Schürer, and Christianto Benjamin Lumenta. "Continuous Selective Intra-Arterial Application of Nimodipine in Refractory Cerebral Vasospasm due to Aneurysmal Subarachnoid Hemorrhage." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/970741.
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Background. Cerebral vasospasm is one of the leading courses for disability in aneurysmal subarachnoid hemorrhage. Effective treatment of vasospasm is therefore one of the main priorities for these patients. We report about a case series of continuous intra-arterial infusion of the calcium channel antagonist nimodipine for 1–5 days on the intensive care unit.Methods. In thirty patients with aneurysmal subarachnoid hemorrhage and refractory vasospasm continuous infusion of nimodipine was started on the neurosurgical intensive care unit. The effect of nimodipine on brain perfusion, cerebral blood flow, brain tissue oxygenation, and blood flow velocity in cerebral arteries was monitored.Results. Based on Hunt & Hess grades on admission, 83% survived in a good clinical condition and 23% recovered without an apparent neurological deficit. Persistent ischemic areas were seen in 100% of patients with GOS 1–3 and in 69% of GOS 4-5 patients. Regional cerebral blood flow and computed tomography perfusion scanning showed adequate correlation with nimodipine application and angiographic vasospasm. Transcranial Doppler turned out to be unreliable with interexaminer variance and failure of detecting vasospasm or missing the improvement.Conclusion. Local continuous intra-arterial nimodipine treatment for refractory cerebral vasospasm after aSAH can be recommended as a low-risk treatment in addition to established endovascular therapies.
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Perez, Alexandra, Andrea Levin, and Nowrin Alam. "A Comparison of the Use of Clinical-Guideline–Recommended Antihypertensive Regimens in Mexican American, Non-Hispanic Black, and Non-Hispanic White Adults With Type 2 Diabetes and Hypertension in the United States." Diabetes Educator 42, no. 6 (September 24, 2016): 739–47. http://dx.doi.org/10.1177/0145721716666680.
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Purpose The purpose of this study was to determine the use of clinical-guideline–recommended antihypertensive regimens among Mexican Americans (MAs) and non-Hispanic blacks and whites with type 2 diabetes and hypertension. Methods A secondary data analysis based on National Health and Nutrition Examination Survey 2003-2012 cohort data included 1857 noninstitutionalized civilian MA, black, and white adults with type 2 diabetes and hypertension. Unadjusted and adjusted 2-way analysis of variance models evaluated whether there was a difference in the use of recommended antihypertensive regimens across race/ethnic group. Results There was no difference in the use of recommended regimens across race/ethnic group (MAs, 79.1%; blacks, 81.7%; whites, 82.3%). Similarly, there was no difference between blood pressure goal levels and the use of recommended therapies across race/ethnicity ( P = .632). Mexican Americans were least likely and blacks most likely to be on 3 or more antihypertensive drug classes (16.8% vs 28%). Furthermore, MAs were least likely to be on recommended add-on therapies such as calcium channel blockers and diuretics. Conclusion Racial/ethnic medication use disparities were observed when looking at the number of antihypertensive drug classes per patient regimen, and add-on therapy use was evaluated. Along with lifestyle modifications, frequent antihypertensive regimen reassessment is necessary.
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Pan, Hui, Rong Zhao, Feng-Di Liu, Yi-Lan Wu, Ge-Fei Li, Yan-Hui Shi, Yi-Sheng Liu, et al. "Blood Pressure Variability during Angiography in Patients with Ischemic Stroke and Intracranial Artery Stenosis." International Journal of Hypertension 2020 (September 1, 2020): 1–8. http://dx.doi.org/10.1155/2020/6214581.
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Our aim was to investigate factors predicting blood pressure (BP) variability during diagnostic cerebral angiography and associations between BP variability and clinical outcomes in patients with acute and subacute ischemic stroke and intracranial artery stenosis. 114 patients with ischemic stroke and intracranial artery stenosis (stenosis rate >50%) were recruited. Patients who underwent cerebral angiography within 3 days and 3–14 days of disease onset are referred to be Group A and Group S, respectively. BP variability in Group A was defined as the coefficient of variance (CV) of BP. Univariate and multivariate regression analyses were used to identify predictors of CV of BP and associations between CV of BP and clinical outcomes at discharge. In Group A patients, advanced age was associated with increased CV of SBP and diastolic blood pressure (DBP), and antihypertensive use was associated with lower CV of SBP. Male was associated with lower CV of DBP. In Group S, higher CV of SBP was associated with hypertension and antihypertensive use. Males had lower CV of SBP than females. The calcium channel blocker was associated with lower CV of DBP. Higher scores of the Stroke Scale at admission were significantly associated with poor clinical outcomes for both groups, while BP variability was not. Factors associated with BP variability are significantly different between stroke patients undergoing angiography within 3 days vs. 3–14 days after disease onset. BP variability is not significantly associated with clinical outcomes at discharge.
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Wilkinson, M. F., and S. Barnes. "The dihydropyridine-sensitive calcium channel subtype in cone photoreceptors." Journal of General Physiology 107, no. 5 (May 1, 1996): 621–30. http://dx.doi.org/10.1085/jgp.107.5.621.
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High-voltage activated Ca channels in tiger salamander cone photoreceptors were studied with nystatin-permeabilized patch recordings in 3 mM Ca2+ and 10 mM Ba2+. The majority of Ca channel current was dihydropyridine sensitive, suggesting a preponderance of L-type Ca channels. However, voltage-dependent, incomplete block (maximum 60%) by nifedipine (0.1-100 microM) was evident in recordings of cones in tissue slice. In isolated cones, where the block was more potent, nifedipine (0.1-10 microM) or nisoldipine (0.5-5 microM) still failed to eliminate completely the Ca channel current. Nisoldipine was equally effective in blocking Ca channel current elicited in the presence of 10 mM Ba2+ (76% block) or 3 mM Ca2+ (88% block). 15% of the Ba2+ current was reversibly blocked by omega-conotoxin GVIA (1 microM). After enhancement with 1 microM Bay K 8644, omega-conotoxin GVIA blocked a greater proportion (22%) of Ba2+ current than in control. After achieving partial block of the Ba2+ current with nifedipine, concomitant application of omega-conotoxin GVIA produced no further block. The P-type Ca channel blocker, omega-agatoxin IVA (200 nM), had variable and insignificant effects. The current persisting in the presence of these blockers could be eliminated with Cd2+ (100 microM). These results indicate that photoreceptors express an L-type Ca channel having a distinguishing pharmacological profile similar to the alpha 1D Ca channel subtype. The presence of additional Ca channel subtypes, resistant to the widely used L-, N-, and P-type Ca channel blockers, cannot, however, be ruled out.
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Fisher, R. E., R. Gray, and D. Johnston. "Properties and distribution of single voltage-gated calcium channels in adult hippocampal neurons." Journal of Neurophysiology 64, no. 1 (July 1, 1990): 91–104. http://dx.doi.org/10.1152/jn.1990.64.1.91.
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1. The properties of single voltage-gated calcium channels were investigated in acutely exposed CA3 and CA1 pyramidal neurons and granule cells of area dentata in the adult guinea pig hippocampal formation. 2. Guinea pig hippocampal slices were prepared in a conventional manner, then treated with proteolytic enzymes and gently shaken to expose the somata of the three cell types studied. Standard patch-clamp techniques were used to record current flow through calcium channels in cell-attached membrane patches with isotonic barium as the charge carrier. 3. Single-channel current amplitudes were measured at different membrane potentials. Single-channel current-voltage plots were constructed and single-channel slope conductances were found to fall into three classes. These were (approximately) 8, 14, and 25 pS, and were observed in all three cell types. 4. The three groups of channels differed from each other in voltage dependence of activation: from a holding potential of -80, the small-conductance channel began to activate at about -40 to -30 mV, the medium-conductance channel at about -20 mV, and the large-conductance channel at approximately 0 mV. 5. Ensemble averages of single-channel currents during voltage steps revealed differences in voltage-dependent inactivation. The small-conductance channel inactivated completely within approximately 50 ms during steps from -80 to -10 mV or more positive. Steps to less positive potentials resulted in less inactivation. The medium-conductance channel displayed variable inactivation during steps from -80 to 0 mV. Inactivation of this channel during a 160-ms step ranged from virtually zero to approximately 100%. The large-conductance channel displayed no significant inactivation during steps as long as 400 ms. 6. The large-conductance channel was strikingly affected by the dihydropyridine agonist Bay K8644 (0.5-2.0 microM), resulting in a high probability of channel opening, prolonged openings, and an apparent increase in the number of channels available for activation. The medium and small-conductance channels were not noticeably affected by the drug. 7. The large-conductance channel could be induced to open at very negative membrane potentials by holding the patch for several seconds at 20 or 30 mV and stepping to -30 or -40 mV. This process was enhanced by Bay K8644, resulting in prolonged openings at potentials as negative as -100 mV.(ABSTRACT TRUNCATED AT 400 WORDS)
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Mak, Don-On Daniel, Sean M. J. McBride, Nataliya B. Petrenko, and J. Kevin Foskett. "Novel Regulation of Calcium Inhibition of the Inositol 1,4,5-trisphosphate Receptor Calcium-release Channel." Journal of General Physiology 122, no. 5 (October 27, 2003): 569–81. http://dx.doi.org/10.1085/jgp.200308808.
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The inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R), a Ca2+-release channel localized to the endoplasmic reticulum, plays a critical role in generating complex cytoplasmic Ca2+ signals in many cell types. Three InsP3R isoforms are expressed in different subcellular locations, at variable relative levels with heteromultimer formation in different cell types. A proposed reason for this diversity of InsP3R expression is that the isoforms are differentially inhibited by high cytoplasmic free Ca2+ concentrations ([Ca2+]i), possibly due to their different interactions with calmodulin. Here, we have investigated the possible roles of calmodulin and bath [Ca2+] in mediating high [Ca2+]i inhibition of InsP3R gating by studying single endogenous type 1 InsP3R channels through patch clamp electrophysiology of the outer membrane of isolated Xenopus oocyte nuclei. Neither high concentrations of a calmodulin antagonist nor overexpression of a dominant-negative Ca2+-insensitive mutant calmodulin affected inhibition of gating by high [Ca2+]i. However, a novel, calmodulin-independent regulation of [Ca2+]i inhibition of gating was revealed: whereas channels recorded from nuclei kept in the regular bathing solution with [Ca2+] ∼400 nM were inhibited by 290 μM [Ca2+]i, exposure of the isolated nuclei to a bath solution with ultra-low [Ca2+] (<5 nM, for ∼300 s) before the patch-clamp experiments reversibly relieved Ca2+ inhibition, with channel activities observed in [Ca2+]i up to 1.5 mM. Although InsP3 activates gating by relieving high [Ca2+]i inhibition, it was nevertheless still required to activate channels that lacked high [Ca2+]i inhibition. Our observations suggest that high [Ca2+]i inhibition of InsP3R channel gating is not regulated by calmodulin, whereas it can be disrupted by environmental conditions experienced by the channel, raising the possibility that presence or absence of high [Ca2+]i inhibition may not be an immutable property of different InsP3R isoforms. Furthermore, these observations support an allosteric model in which Ca2+ inhibition of the InsP3R is mediated by two Ca2+ binding sites, only one of which is sensitive to InsP3.
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Kennedy, K. M., S. T. Piper, and H. L. Atwood. "Synaptic vesicle recruitment for release explored by Monte Carlo simulation at the crayfish neuromuscular junction." Canadian Journal of Physiology and Pharmacology 77, no. 9 (October 10, 1999): 634–50. http://dx.doi.org/10.1139/y99-071.
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Neurotransmission at chemically transmitting synapses requires calcium-mediated fusion of synaptic vesicles with the presynaptic membrane. Utilizing ultrastructural information available for the crustacean excitatory neuromuscular junction, we developed a model that employs the Monte Carlo simulation technique to follow the entry and movement of Ca2+ ions at a presynaptic active zone, where synaptic vesicles are preferentially docked for release. The model includes interaction of Ca2+ with an intracellular buffer, and variable separation between calcium channels and vesicle-associated Ca2+-binding targets that react with Ca2+ to trigger vesicle fusion. The end point for vesicle recruitment for release was binding of four Ca2+ ions to the target controlling release. The results of the modeling experiments showed that intracellular structures that interfere with Ca2+ diffusion (in particular synaptic vesicles) influence recruitment or priming of vesicles for release. Vesicular recruitment is strongly influenced by the separation distance between an opened calcium channel and the target controlling release, and by the concentration and binding properties of the intracellular buffers, as in previous models. When a single opened calcium channel is very close to the target, a single synaptic vesicle can be recruited. However, many of the single-channel openings actuated by a nerve impulse are likely to be ineffective for release, although they contribute to the buildup of total intracellular Ca2+. Thus, the overall effectiveness of single calcium channels in causing vesicles to undergo exocytosis is likely quite low.Key words: synapse, Monte Carlo simulation, synaptic vesicle, active zone, vesicle recruitment, crayfish, calcium, calcium buffer.
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Murbartián, Janet, Juan Manuel Arias, and Edward Perez-Reyes. "Functional Impact of Alternative Splicing of Human T-Type Cav3.3 Calcium Channels." Journal of Neurophysiology 92, no. 6 (December 2004): 3399–407. http://dx.doi.org/10.1152/jn.00498.2004.
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Low-voltage-activated T-type (Cav3) Ca2+ channels produce low-threshold spikes that trigger burst firing in many neurons. The CACNA1I gene encodes the Cav3.3 isoform, which activates and inactivates much more slowly than the other Cav3 channels. These distinctive kinetic features, along with its brain-region-specific expression, suggest that Cav3.3 channels endow neurons with the ability to generate long-lasting bursts of firing. The human CACNA1I gene contains two regions of alternative splicing: variable inclusion of exon 9 and an alternative acceptor site within exon 33, which leads to deletion of 13 amino acids (Δ33). The goal of this study is to determine the functional consequences of these variations in the full-length channel. The cDNA encoding these regions were cloned using RT-PCR from human brain, and currents were recorded by whole cell patch clamp. Introduction of the Δ33 deletion slowed the rate of channel opening. Addition of exon 9 had little effect on kinetics, whereas its addition to Δ33 channels unexpectedly slowed both activation and inactivation kinetics. Modeling of neuronal firing showed that exon 9 or Δ33 alone reduced burst firing, whereas the combination enhanced firing. The major conclusions of this study are that the intracellular regions after repeats I and IV play a role in channel gating, that their effects are interdependent, suggesting a direct interaction, and that splice variation of Cav3.3 channels provides a mechanism for fine-tuning the latency and duration of low-threshold spikes.
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Lagrange, Andre. "Genetic Variants in Absence Epilepsy: A Contextual Consideration of Calcium Current Kinetics." Epilepsy Currents 6, no. 3 (May 2006): 99–101. http://dx.doi.org/10.1111/j.1535-7511.2006.00111.x.
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Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants of Cacna1h, a T-Type Calcium Channel Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E J Neurosci 2005;25(19):4844-4855 Sequencing of the T-type Ca2+ channel gene CACNA1H revealed 12 nonsynonymous single nucleotide polymorphisms (SNPs) that were found only in childhood absence epilepsy (CAE) patients. One SNP, G773D, was found in two patients. The present study reports the finding of a third patient with this SNP, as well as analysis of their parents. Because of the role of T-channels in determining the intrinsic firing patterns of neurons involved in absence seizures, it was suggested that these SNPs might alter channel function. The goal of the present study was to test this hypothesis by introducing these polymorphisms into a human Cav3.2a cDNA and then study alterations in channel behavior using whole-cell patch-clamp recording. Eleven SNPs altered some aspect of channel gating. Computer simulations predict that seven of the SNPs would increase firing of neurons, with three of them inducing oscillations at similar frequencies, as observed during absence seizures. Three SNPs were predicted to decrease firing. Some CAE-specific SNPs (e.g., G773D) coexist with SNPs also found in controls (R788C); therefore, the effect of these polymorphisms were studied. The R788C SNP altered activity in a manner that would also lead to enhanced burst firing of neurons. The G773D–R788C combination displayed different behavior than either single SNP. Therefore, common polymorphisms can alter the effect of CAE-specific SNPs, highlighting the importance of sequence background. These results suggest that CACNA1H is a susceptibility gene that contributes to the development of polygenic disorders characterized by thalamocortical dysrhythmia, such as CAE.
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COHEN, ETHAN D. "Voltage-gated calcium and sodium currents of starburst amacrine cells in the rabbit retina." Visual Neuroscience 18, no. 5 (September 2001): 799–809. http://dx.doi.org/10.1017/s0952523801185135.
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The voltage-gated calcium and sodium currents of starburst amacrine cells were examined in slices of the adult rabbit retina. ON-center starburst amacrine cells were targeted for whole-cell recording by prelabeling the retina with the nuclear dye 4′-6-diamidino-2-phenylindole hydrochloride (DAPI). Calcium currents were isolated using an external Ringer that contained tetrodotoxin to block sodium currents and barium to block potassium channels. When starburst amacrine cells were stepped to holding potentials positive to −50 mV, a series of voltage-dependent calcium currents were activated. The calcium current peaked at −10 mV. The calcium currents kinetics were mainly sustained in nature, showing only a small amount of slow inactivation. Nickel (100 μM), a T-type channel blocker, had no effect on the calcium current. Application of the L-type channel agonist BAY K8644 (1–2.5 μM) had small variable effects on the calcium current while the L-type channel antagonist nifedipine (10 μM) had no effect. However, addition of a reported N-type calcium channel antagonist, omega-conotoxin G6A (1 μM), blocked a large portion of the calcium current, as did a more nonselective antagonist, omega-conotoxin M7C (200 nM). Agatoxin 4A (500 nM) reduced a smaller sustained calcium current component, implying a P/Q-type calcium channel was present on these neurons. In addition to the calcium currents, a fast voltage-gated sodium current was observed in many starburst cells. This current could be blocked by tetrodotoxin (200–500 nM). The differing kinetics and durations of the sodium and calcium currents could play important roles in the regulation of synaptic release and in the coordination of spiking by starburst amacrine cell dendrites during retinal development and in the encoding of motion across the retinal surface.
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Heyne, Henrike O., David Baez-Nieto, Sumaiya Iqbal, Duncan S. Palmer, Andreas Brunklaus, Patrick May, Katrine M. Johannesen, et al. "Predicting functional effects of missense variants in voltage-gated sodium and calcium channels." Science Translational Medicine 12, no. 556 (August 12, 2020): eaay6848. http://dx.doi.org/10.1126/scitranslmed.aay6848.
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Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes.
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Liebau, Stefan, Michael Tischendorf, Daniel Ansorge, Leonhard Linta, Marianne Stockmann, Clair Weidgang, Michelina Iacovino, et al. "An Inducible Expression System of the Calcium-Activated Potassium Channel 4 to Study the Differential Impact on Embryonic Stem Cells." Stem Cells International 2011 (2011): 1–12. http://dx.doi.org/10.4061/2011/456815.
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Rationale. The family of calcium-activated potassium channels consists of four members with varying biological functions and conductances. Besides membrane potential modulation, SK channels have been found to be involved in cardiac pacemaker cell development from ES cells and morphological shaping of neural stem cells.Objective. Distinct SK channel subtype expression in ES cells might elucidate their precise impact during cardiac development. We chose SK channel subtype 4 as a potential candidate influencing embryonic stem cell differentiation.Methods. We generated a doxycycline inducible mouse ES cell line via targeted homologous recombination of a cassette expressing a bicistronic construct encoding SK4 and a fluorophore from the murine HPRT locus.Conclusion. We characterized the mouse ES cell line iSK4-AcGFP. The cassette is readily expressed under the control of doxycycline, and the overexpression of SK4 led to an increase in cardiac and pacemaker cell differentiation thereby serving as a unique tool to characterize the cell biological variances due to specific SK channel overexpression.
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Hu, Song, Malgorzata Z. Labuda, Massimo Pandolfo, Greg G. Goss, Heather E. McDermid, and Declan W. Ali. "Variants of the KCNMB3 regulatory subunit of maxi BK channels affect channel inactivation." Physiological Genomics 15, no. 3 (November 11, 2003): 191–98. http://dx.doi.org/10.1152/physiolgenomics.00110.2003.
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The steady-state and kinetic properties of the KCNMB3 regulatory subunits associated with calcium-activated potassium channels (BK channels) are presented. BK channels containing four sequence variants (V1–V4) in the four different isoforms of the β-subunit (β3a, β3b, β3c, and β3d) were expressed in Xenopus oocytes. Reconstituted BK channel inactivation ranged from none to around 90% inactivation. In particular, channels expressing the β3b-V4 variant displayed a right shift in the potassium current voltage-dependence of activation and inactivated to about 30% of the maximum conductance, compared with wild-type β3b channels that showed no inactivation. When the membrane potential was depolarized, BK channels inactivated with a very rapid time course (∼2–6 ms). This same variant was previously demonstrated to show subtly higher incidence in patients with idiopathic epilepsy (IE) compared with controls, especially when combined with variant V2 (combined heterozygotes). Furthermore, the gene maps to a region containing a susceptibility factor for this disorder. Taken together, these data suggest that neurons expressing BK channels composed of the β3b-V4 variant subunit may experience reduced levels of inhibition and may therefore play permissive roles in high levels of neuronal activity that is characteristic of epilepsy.
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Tikhonov, Denis B., and Boris S. Zhorov. "P-Loop Channels: Experimental Structures, and Physics-Based and Neural Networks-Based Models." Membranes 12, no. 2 (February 16, 2022): 229. http://dx.doi.org/10.3390/membranes12020229.
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The superfamily of P-loop channels includes potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. A rapidly increasing number of crystal and cryo-EM structures have revealed conserved and variable elements of the channel structures. Intriguing differences are seen in transmembrane helices of channels, which may include π-helical bulges. The bulges reorient residues in the helices and thus strongly affect their intersegment contacts and patterns of ligand-sensing residues. Comparison of the experimental structures suggests that some π-bulges are dynamic: they may appear and disappear upon channel gating and ligand binding. The AlphaFold2 models represent a recent breakthrough in the computational prediction of protein structures. We compared some crystal and cryo-EM structures of P-loop channels with respective AlphaFold2 models. Folding of the regions, which are resolved experimentally, is generally similar to that predicted in the AlphaFold2 models. The models also reproduce some subtle but significant differences between various P-loop channels. However, patterns of π-bulges do not necessarily coincide in the experimental and AlphaFold2 structures. Given the importance of dynamic π-bulges, further studies involving experimental and theoretical approaches are necessary to understand the cause of the discrepancy.
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Demuro, Angelo, Martin Smith, and Ian Parker. "Single-channel Ca2+ imaging implicates Aβ1–42 amyloid pores in Alzheimer’s disease pathology." Journal of Cell Biology 195, no. 3 (October 24, 2011): 515–24. http://dx.doi.org/10.1083/jcb.201104133.
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Oligomeric forms of Aβ peptides are implicated in Alzheimer’s disease (AD) and disrupt membrane integrity, leading to cytosolic calcium (Ca2+) elevation. Proposed mechanisms by which Aβ mediates its effects include lipid destabilization, activation of native membrane channels, and aggregation of Aβ into Ca2+-permeable pores. We distinguished between these using total internal reflection fluorescence (TIRF) microscopy to image Ca2+ influx in Xenopus laevis oocytes. Aβ1–42 oligomers evoked single-channel Ca2+ fluorescence transients (SCCaFTs), which resembled those from classical ion channels but which were not attributable to endogenous oocyte channels. SCCaFTs displayed widely variable open probabilities (Po) and stepwise transitions among multiple amplitude levels reminiscent of subconductance levels of ion channels. The proportion of high Po, large amplitude SCCaFTs grew with time, suggesting that continued oligomer aggregation results in the formation of highly toxic pores. We conclude that formation of intrinsic Ca2+-permeable membrane pores is a major pathological mechanism in AD and introduce TIRF imaging for massively parallel single-channel studies of the incorporation, assembly, and properties of amyloidogenic oligomers.
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El Ghaleb, Yousra, Pauline E. Schneeberger, Monica L. Fernández-Quintero, Stefanie M. Geisler, Simone Pelizzari, Abeltje M. Polstra, Johanna M. van Hagen, et al. "CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders." Brain 144, no. 7 (March 11, 2021): 2092–106. http://dx.doi.org/10.1093/brain/awab101.
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Abstract T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.
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Tarnovskaya, Svetlana I., Anna A. Kostareva, and Boris S. Zhorov. "L-Type Calcium Channel: Predicting Pathogenic/Likely Pathogenic Status for Variants of Uncertain Clinical Significance." Membranes 11, no. 8 (August 7, 2021): 599. http://dx.doi.org/10.3390/membranes11080599.
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(1) Background: Defects in gene CACNA1C, which encodes the pore-forming subunit of the human Cav1.2 channel (hCav1.2), are associated with cardiac disorders such as atrial fibrillation, long QT syndrome, conduction disorders, cardiomyopathies, and congenital heart defects. Clinical manifestations are known only for 12% of CACNA1C missense variants, which are listed in public databases. Bioinformatics approaches can be used to predict the pathogenic/likely pathogenic status for variants of uncertain clinical significance. Choosing a bioinformatics tool and pathogenicity threshold that are optimal for specific protein families increases the reliability of such predictions. (2) Methods and Results: We used databases ClinVar, Humsavar, gnomAD, and Ensembl to compose a dataset of pathogenic/likely pathogenic and benign variants of hCav1.2 and its 20 paralogues: voltage-gated sodium and calcium channels. We further tested the performance of sixteen in silico tools in predicting pathogenic variants. ClinPred demonstrated the best performance, followed by REVEL and MCap. In the subset of 309 uncharacterized variants of hCav1.2, ClinPred predicted the pathogenicity for 188 variants. Among these, 36 variants were also categorized as pathogenic/likely pathogenic in at least one paralogue of hCav1.2. (3) Conclusions: The bioinformatics tool ClinPred and the paralogue annotation method consensually predicted the pathogenic/likely pathogenic status for 36 uncharacterized variants of hCav1.2. An analogous approach can be used to classify missense variants of other calcium channels and novel variants of hCav1.2.
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Mak, Don-On Daniel, Sean McBride, Viswanathan Raghuram, Yun Yue, Suresh K. Joseph, and J. Kevin Foskett. "Single-Channel Properties in Endoplasmic Reticulum Membrane of Recombinant Type 3 Inositol Trisphosphate Receptor." Journal of General Physiology 115, no. 3 (February 14, 2000): 241–56. http://dx.doi.org/10.1085/jgp.115.3.241.
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The inositol 1,4,5-trisphosphate receptor (InsP3R) is an intracellular Ca2+-release channel localized in endoplasmic reticulum (ER) with a central role in complex Ca2+ signaling in most cell types. A family of InsP3Rs encoded by several genes has been identified with different primary sequences, subcellular locations, variable ratios of expression, and heteromultimer formation. This diversity suggests that cells require distinct InsP3Rs, but the functional correlates of this diversity are largely unknown. Lacking are single-channel recordings of the recombinant type 3 receptor (InsP3R-3), a widely expressed isoform also implicated in plasma membrane Ca2+ influx and apoptosis. Here, we describe functional expression and single-channel recording of recombinant rat InsP3R-3 in its native membrane environment. The approach we describe suggests a novel strategy for expression and recording of recombinant ER-localized ion channels in the ER membrane. Ion permeation and channel gating properties of the rat InsP3R-3 are strikingly similar to those of Xenopus type 1 InsP3R in the same membrane. Using two different two-electrode voltage clamp protocols to examine calcium store-operated calcium influx, no difference in the magnitude of calcium influx was observed in oocytes injected with rat InsP3R-3 cRNA compared with control oocytes. Our results suggest that if cellular expression of multiple InsP3R isoforms is a mechanism to modify the temporal and spatial features of [Ca2+]i signals, then it must be achieved by isoform-specific regulation or localization of various types of InsP3Rs that have relatively similar Ca2+ permeation properties.
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Zullo, Alberto, Giuseppa Perrotta, Rossana D'Angelo, Lucia Ruggiero, Elvira Gravino, Luigi Del Vecchio, Lucio Santoro, Francesco Salvatore, and Antonella Carsana. "RYR1 Sequence Variants in Myopathies: Expression and Functional Studies in Two Families." BioMed Research International 2019 (April 21, 2019): 1–13. http://dx.doi.org/10.1155/2019/7638946.
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The skeletal muscle ryanodine receptor (RyR1), i.e., the Ca2+ channel of the sarco/endoplasmic reticulum (S/ER), and the voltage-dependent calcium channel Cav1.1 are the principal channels involved in excitation-contraction coupling in skeletal muscle. RYR1 gene variants are linked to distinct skeletal muscle disorders, including malignant hyperthermia susceptibility and central core disease (CCD), mainly with autosomal dominant inheritance, and autosomal recessive myopathies with a broad phenotypic and histopathological spectrum. The age at onset of RYR1-related myopathies varies from infancy to adulthood. We report the identification of four RYR1 variants in two Italian families: one with myopathy and variants c.4003C>T (p.R1335C) and c.7035C>A (p.S2345R), and another with CCD and variants c.9293G>T (p.S3098I) and c.14771_14772insTAGACAGGGTGTTGCTCTGTTGCCCTTCTT (p.F4924_V4925insRQGVALLPFF). We demonstrate that, in patient-specific lymphoblastoid cells, the c.4003C>T (p.R1335C) variant is not expressed and the in-frame 30-nucleotide insertion variant is expressed at a low level. Moreover, Ca2+ release in response to the RyR1 agonist 4-chloro-m-cresol and to thapsigargin showed that the c.7035C>A (p.S2345R) variant causes depletion of S/ER Ca2+ stores and that the compound heterozygosity for variant c.9293G>T (p.S3098I) and the 30-nucleotide insertion increases RyR1-dependent Ca2+ release without affecting ER Ca2+ stores. In conclusion, we detected and functionally characterized disease-causing variants of the RyR1 channel in patient-specific lymphoblastoid cells.
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Angermann, Jeff E., Amy R. Sanguinetti, James L. Kenyon, Normand Leblanc, and Iain A. Greenwood. "Mechanism of the Inhibition of Ca2+-Activated Cl− Currents by Phosphorylation in Pulmonary Arterial Smooth Muscle Cells." Journal of General Physiology 128, no. 1 (June 26, 2006): 73–87. http://dx.doi.org/10.1085/jgp.200609507.
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The aim of the present study was to provide a mechanistic insight into how phosphatase activity influences calcium-activated chloride channels in rabbit pulmonary artery myocytes. Calcium-dependent Cl− currents (IClCa) were evoked by pipette solutions containing concentrations between 20 and 1000 nM Ca2+ and the calcium and voltage dependence was determined. Under control conditions with pipette solutions containing ATP and 500 nM Ca2+, IClCa was evoked immediately upon membrane rupture but then exhibited marked rundown to ∼20% of initial values. In contrast, when phosphorylation was prohibited by using pipette solutions containing adenosine 5′-(β,γ-imido)-triphosphate (AMP-PNP) or with ATP omitted, the rundown was severely impaired, and after 20 min dialysis, IClCa was ∼100% of initial levels. IClCa recorded with AMP-PNP–containing pipette solutions were significantly larger than control currents and had faster kinetics at positive potentials and slower deactivation kinetics at negative potentials. The marked increase in IClCa was due to a negative shift in the voltage dependence of activation and not due to an increase in the apparent binding affinity for Ca2+. Mathematical simulations were carried out based on gating schemes involving voltage-independent binding of three Ca2+, each binding step resulting in channel opening at fixed calcium but progressively greater “on” rates, and voltage-dependent closing steps (“off” rates). Our model reproduced well the Ca2+ and voltage dependence of IClCa as well as its kinetic properties. The impact of global phosphorylation could be well mimicked by alterations in the magnitude, voltage dependence, and state of the gating variable of the channel closure rates. These data reveal that the phosphorylation status of the Ca2+-activated Cl− channel complex influences current generation dramatically through one or more critical voltage-dependent steps.
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Bishop, CA, ME Krouse, and JJ Wine. "Peptide potentiation of calcium channel activity can be seasonally variable." Journal of Experimental Biology 156, no. 1 (March 1, 1991): 607–10. http://dx.doi.org/10.1242/jeb.156.1.607.
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Buraei, Zafir, and Jian Yang. "The β Subunit of Voltage-Gated Ca2+ Channels." Physiological Reviews 90, no. 4 (October 2010): 1461–506. http://dx.doi.org/10.1152/physrev.00057.2009.
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Calcium regulates a wide spectrum of physiological processes such as heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+ channels. These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit (Cavα1) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit (Cavβ) plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Cavβ is also crucial for the modulation of HVA Ca2+ channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca2+ channels by binding to Cavβ. There are also indications that Cavβ may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Cavβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Cavβs reveal how they interact with Cavα1, open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Cavβ, with both a historical perspective as well as an emphasis on recent advances.
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Sheehan, Jason P., Zhiyuan Xu, Britney Popp, Leigh Kowalski, and David Schlesinger. "Inhibition of glioblastoma and enhancement of survival via the use of mibefradil in conjunction with radiosurgery." Journal of Neurosurgery 118, no. 4 (April 2013): 830–37. http://dx.doi.org/10.3171/2012.11.jns121087.
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Object The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery. Methods Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor volumes were measured on MR images. Experimental Group 1 received 30 mg/kg of mibefradil intraperitoneally 3 times a day for 1 week starting on postoperative day (POD) 15; Group 2 received 8 Gy of cranial radiation via radiosurgery delivered on POD 15; Group 3 underwent radiosurgery on POD 15, followed by 1 week of mibefradil; and Group 4 received mibefradil on POD 15 for 1 week, followed by radiosurgery sometime from POD 15 to POD 22. Twenty-seven glioma-bearing rats were analyzed. Survival was compared between groups using Kaplan-Meier methodology. Results Median survival in Groups 1, 2, 3, and 4 was 35, 31, 43, and 52 days, respectively (p = 0.036, log-rank test). Two animals in Group 4 survived to POD 60, which is twice the expected survival of untreated animals in this model. Analysis of variance and a post hoc test indicated no tumor volume differences on PODs 15 and 29. However, significant volume differences were found on POD 43; mean tumor volumes for Groups 1, 2, 3, and 4 were 250, 266, 167, and 34 mm3, respectively (p = 0.046, ANOVA). A Cox proportional hazards regression test showed survival was associated with tumor volume on POD 29 (p = 0.001) rather than on POD 15 (p = 0.162). In vitro assays demonstrated an appreciable and dose-dependent increase in apoptosis between 2- and 7-μM concentrations of mibefradil. Conclusions Mibefradil response is schedule dependent and enhances survival and reduces glioblastoma when combined with ionizing radiation.
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Jardin, Isaac, Alejandro Berna-Erro, Joel Nieto-Felipe, Alvaro Macias, Jose Sanchez-Collado, Jose J. Lopez, Gines M. Salido, and Juan A. Rosado. "Similarities and Differences between the Orai1 Variants: Orai1α and Orai1β." International Journal of Molecular Sciences 23, no. 23 (November 23, 2022): 14568. http://dx.doi.org/10.3390/ijms232314568.
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Orai1, the first identified member of the Orai protein family, is ubiquitously expressed in the animal kingdom. Orai1 was initially characterized as the channel responsible for the store-operated calcium entry (SOCE), a major mechanism that allows cytosolic calcium concentration increments upon receptor-mediated IP3 generation, which results in intracellular Ca2+ store depletion. Furthermore, current evidence supports that abnormal Orai1 expression or function underlies several disorders. Orai1 is, together with STIM1, the key element of SOCE, conducting the Ca2+ release-activated Ca2+ (CRAC) current and, in association with TRPC1, the store-operated Ca2+ (SOC) current. Additionally, Orai1 is involved in non-capacitative pathways, as the arachidonate-regulated or LTC4-regulated Ca2+ channel (ARC/LRC), store-independent Ca2+ influx activated by the secretory pathway Ca2+-ATPase (SPCA2) and the small conductance Ca2+-activated K+ channel 3 (SK3). Furthermore, Orai1 possesses two variants, Orai1α and Orai1β, the latter lacking 63 amino acids in the N-terminus as compared to the full-length Orai1α form, which confers distinct features to each variant. Here, we review the current knowledge about the differences between Orai1α and Orai1β, the implications of the Ca2+ signals triggered by each variant, and their downstream modulatory effect within the cell.
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GARRILL, ASHLEY, ROGER R. LEW, and I. BRENT HEATH. "Stretch-Activated Ca2+ and Ca2+-activated K+ Channels in the Hyphal Tip Plasma Membrane of the Oomycete Saprolegnia Ferax." Journal of Cell Science 101, no. 3 (March 1, 1992): 721–30. http://dx.doi.org/10.1242/jcs.101.3.721.
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We have used the patch clamp technique to study ion channels involved in hyphal tip growth in the oomycete Saprolegnia ferax. The development of a technique in which protoplasts are produced in distinct linear arrays has permitted the study of transport proteins in protoplasts derived from different regions of the hypha. Using the cell-attached mode we find two K+ channels of different amplitudes, both of which are activated by Ca2+, as shown by the addition of the Ca2+ ionophore A23187. In nearly all the recordings (95%) there was a characteristic but variable oscillatory nature to the activity of these channels. K+ fluxes through these channels are inward and are of a sufficient magnitude to have a significant impact on cell turgor. Hyphal tip, but rarely distal protoplasts, also contain two stretch-activated channels, one displaying larger amplitudes and permeable to both Ca2+ and K+ and a smaller channel permeable to Mg2+. Stretch-activated ion channels permeable to calcium are of particular interest in relation to tip growth and their concentration at the hyphal tip supports a direct role in the tip growth process. This represents a significant advance toward understanding the mechanisms of regulation of this mode of cellular growth.
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Zouharova, Monika, Petr Herman, Kateřina Hofbauerová, Jiri Vondrasek, and Kristyna Bousova. "TRPM6 N-Terminal CaM- and S100A1-Binding Domains." International Journal of Molecular Sciences 20, no. 18 (September 9, 2019): 4430. http://dx.doi.org/10.3390/ijms20184430.
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Transient receptor potential (TRPs) channels are crucial downstream targets of calcium signalling cascades. They can be modulated either by calcium itself and/or by calcium-binding proteins (CBPs). Intracellular messengers usually interact with binding domains present at the most variable TRP regions—N- and C-cytoplasmic termini. Calmodulin (CaM) is a calcium-dependent cytosolic protein serving as a modulator of most transmembrane receptors. Although CaM-binding domains are widespread within intracellular parts of TRPs, no such binding domain has been characterised at the TRP melastatin member—the transient receptor potential melastatin 6 (TRPM6) channel. Another CBP, the S100 calcium-binding protein A1 (S100A1), is also known for its modulatory activities towards receptors. S100A1 commonly shares a CaM-binding domain. Here, we present the first identified CaM and S100A1 binding sites at the N-terminal of TRPM6. We have confirmed the L520-R535 N-terminal TRPM6 domain as a shared binding site for CaM and S100A1 using biophysical and molecular modelling methods. A specific domain of basic amino acid residues (R526/R531/K532/R535) present at this TRPM6 domain has been identified as crucial to maintain non-covalent interactions with the ligands. Our data unambiguously confirm that CaM and S100A1 share the same binding domain at the TRPM6 N-terminus although the ligand-binding mechanism is different.
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Zhao, Runchen, Alexandros Afthinos, Tian Zhu, Panagiotis Mistriotis, Yizeng Li, Selma A. Serra, Yuqi Zhang, et al. "Cell sensing and decision-making in confinement: The role of TRPM7 in a tug of war between hydraulic pressure and cross-sectional area." Science Advances 5, no. 7 (July 2019): eaaw7243. http://dx.doi.org/10.1126/sciadv.aaw7243.
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How cells sense hydraulic pressure and make directional choices in confinement remains elusive. Using trifurcating Ψ-like microchannels of different hydraulic resistances and cross-sectional areas, we discovered that the TRPM7 ion channel is the critical mechanosensor, which directs decision-making of blebbing cells toward channels of lower hydraulic resistance irrespective of their cross-sectional areas. Hydraulic pressure–mediated TRPM7 activation triggers calcium influx and supports a thicker cortical actin meshwork containing an elevated density of myosin-IIA. Cortical actomyosin shields cells against external forces and preferentially directs cell entrance in low resistance channels. Inhibition of TRPM7 function or actomyosin contractility renders cells unable to sense different resistances and alters the decision-making pattern to cross-sectional area–based partition. Cell distribution in microchannels is captured by a mathematical model based on the maximum entropy principle using cortical actin as a key variable. This study demonstrates the unique role of TRPM7 in controlling decision-making and navigating migration in complex microenvironments.
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Latour, Isabelle, Deon F. Louw, Aaron M. Beedle, Jawed Hamid, Garnette R. Sutherland, and Gerald W. Zamponi. "Expression of T-type calcium channel splice variants in human glioma." Glia 48, no. 2 (2004): 112–19. http://dx.doi.org/10.1002/glia.20063.
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A.D., Achimota, Joseph O.T., Payou T.O., Cameroon O.P., and Williams P.A. "Spatial Variability of Selected Soil Properties of the Lower Niger River Floodplains in Bayelsa State, Nigeria." African Journal of Agriculture and Food Science 4, no. 3 (July 20, 2021): 14–27. http://dx.doi.org/10.52589/ajafs-6rmaxnlv.
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Owing to the influence of topography on soil properties, studies on the variability of soil properties become imperative. This study assessed spatial variability of some selected soil properties in three physiographic units: upper slope, lower slope and recent alluvial soils on channels of present active river in two locations in Bayelsa State. In each unit, one representative soil profile was dug, soil samples collected from generic horizons and analyzed. The results showed varying degree of spatial variability in physical and chemical characteristics, flooding, the source of parent materials and degree of hydromorphism; being the major determining factors. Among the soil separates, clay was highly variable in two physiographic units while sand and silt showed moderate variability. Organic C was moderately to highly variable (CV=20.13 – 112.77%), while total N (36.53 – 90.01%) and available P (41.49 – 58.71%) were highly variable in all the mapping units. Calcium was moderately variable (CV=26.85%) in the upper slope, and highly variable in the middle slope (CV=43.17%) and moderately variable (CV=28.93%) in recent alluvial soils in the channel of the present active river of Elemebiri and in Trofani soils; low (CV=10.01%) in the upper slope, highly variable (CV=41.33%) in the middle slope and moderately variable (CV=22.08%) recent alluvial soils in the channel of the present active river while Mg (CV=66.79 – 80.29%) and K (CV=39.27 – 101.53%) were highly variable in the different physiographic units of the two locations. Flooding, wetness and soil fertility are major constraints to agricultural intensification that requires attention.
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Li, Peiyao, Yong Miao, Adish Dani, and Monika Vig. "α-SNAP regulates dynamic, on-site assembly and calcium selectivity of Orai1 channels." Molecular Biology of the Cell 27, no. 16 (August 15, 2016): 2542–53. http://dx.doi.org/10.1091/mbc.e16-03-0163.
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Orai1 forms a highly calcium-selective pore of the calcium release activated channel, and α-SNAP is necessary for its function. Here we show that α-SNAP regulates on-site assembly of Orai1 dimers into calcium-selective multimers. We find that Orai1 is a dimer in resting primary mouse embryonic fibroblasts but displays variable stoichiometry in the plasma membrane of store-depleted cells. Remarkably, α-SNAP depletion induces formation of higher-order Orai1 oligomers, which permeate significant levels of sodium via Orai1 channels. Sodium permeation in α-SNAP–deficient cells cannot be corrected by tethering multiple Stim1 domains to Orai1 C-terminal tail, demonstrating that α-SNAP regulates functional assembly and calcium selectivity of Orai1 multimers independently of Stim1 levels. Fluorescence nanoscopy reveals sustained coassociation of α-SNAP with Stim1 and Orai1, and α-SNAP–depleted cells show faster and less constrained mobility of Orai1 within ER-PM junctions, suggesting Orai1 and Stim1 coentrapment without stable contacts. Furthermore, α-SNAP depletion significantly reduces fluorescence resonance energy transfer between Stim1 and Orai1 N-terminus but not C-terminus. Taken together, these data reveal a unique role of α-SNAP in the on-site functional assembly of Orai1 subunits and suggest that this process may, in part, involve enabling crucial low-affinity interactions between Orai1 N-terminus and Stim1.
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Hussey, John W., Emily DeMarco, Deborah DiSilvestre, Helene H. Jensen, Mette Nyegaard, Michael T. Overgaard, and Ivy E. Dick. "Disrupted regulation of voltage-gated calcium channels by pathogenic calmodulin variants." Biophysical Journal 121, no. 3 (February 2022): 99a. http://dx.doi.org/10.1016/j.bpj.2021.11.2231.
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Sock, Manja, Eva M. Graf, Jürgen F. Heubach, and Ursula Ravens. "L-type calcium channel splice variants in excitable and non-excitable human tissues." Journal of Molecular and Cellular Cardiology 34, no. 6 (June 2002): A11. http://dx.doi.org/10.1016/s0022-2828(02)90768-6.
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McCarty, N. A., and R. G. O'Neil. "Calcium signaling in cell volume regulation." Physiological Reviews 72, no. 4 (October 1, 1992): 1037–61. http://dx.doi.org/10.1152/physrev.1992.72.4.1037.
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It is evident from the present analysis that although a role for Ca2+ in controlling hypertonic cell volume regulation and RVI mechanisms has not been shown, Ca2+ plays a central role in activating and controlling hypotonic cell volume regulation and RVD mechanisms in most cells. However, this Ca2+ dependency is highly variable among cell types and tissues. Cells can be grouped into three general categories based on the relative dependency of RVD on Ca2+: 1) cells that are highly dependent on extracellular Ca2+ and the activation of Ca2+ influx, supposedly reflecting activation of Ca2+ channels, such as observed for the renal PST cells and osteosarcoma cells; 2) cells that are not dependent on extracellular Ca2+ and Ca2+ influx but that require at least a certain basal intracellular Ca2+ level or transient release of Ca2+ from internal stores, such as observed for the Ehrlich ascites tumor cells and medullary thick ascending limb cells; and 3) cells that display little if any Ca2+ dependency, such as the lymphocytes. There is initial evidence that this variable dependency of RVD on Ca2+ may reflect, in large part, a variable Ca2+ threshold of RVD processes, although this notion has not been fully investigated. The site and mechanism of Ca2+ dependency of RVD are poorly understood. Initial studies pointed to a possible direct control of K+ and/or Cl- channels by Ca2+ to modulate KCl efflux and, hence, RVD. This view appears to be too simplistic, however, as it is increasingly evident that the ion channels involved in RVD may not be directly Ca2+ dependent and that some other regulatory process controlling the channels, perhaps a phosphorylation step, may be the Ca(2+)-dependent event. Given the added complexity of the time-dependent variability of the action of Ca2+, i.e., the Ca2+ window, coupled with the variability of the RVD mechanisms among cell and tissue types, it is likely that the RVD mechanism is a highly complex process involving events and biochemical pathways throughout the cell rather than events simply localized to the inner face of the plasma membrane. It remains for future studies to determine the exact biochemical events that underly the RVD mechanism and its control, and the Ca2+ dependency of each step, before a full understanding will be attained of the role of Ca2+ in modulating RVD.
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Gardner, Kathy, M. Michael Barmada, Louis J. Ptacek, and Eric P. Hoffman. "A new locus for hemiplegic migraine maps to chromosome 1q31." Neurology 49, no. 5 (November 1997): 1231–38. http://dx.doi.org/10.1212/wnl.49.5.1231.
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A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores >3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.
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Fohlmeister, J. F., and R. F. Miller. "Impulse Encoding Mechanisms of Ganglion Cells in the Tiger Salamander Retina." Journal of Neurophysiology 78, no. 4 (October 1, 1997): 1935–47. http://dx.doi.org/10.1152/jn.1997.78.4.1935.
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Fohlmeister, J. F. and R. F. Miller. Impulse encoding mechanisms of ganglion cells in the tiger salamander retina. J. Neurophysiol. 78: 1935–1947, 1997. A study of nerve impulse generation in ganglion cells of the tiger salamander retina is carried out through a combination of experimental and analytic approaches, including computer simulations based on a single-compartment model. Whole cell recordings from ganglion cells were obtained using a superfused retina-eyecup preparation and studied with pharmacological and electrophysiological techniques, including phase plot analysis. Experimental efforts were guided by computer simulation studies of an excitability model consisting of five voltage- or ion-gated channels, which were identified from earlier voltage-clamp data. The ion channels include sodium, calcium, and three types of potassium channels, namely the A type ( I K,A), Ca-activated potassium ( I K,Ca), and the delayed rectifier ( I K). A leakage channel was included to preserve input resistance continuity between model and experiment. Ion channel densities of Na and Ca currents ( I Na and I Ca) for the single-compartment model were independently determined from phase plot analysis. The I K and I K,A current densities were determined from the measured width of impulses. The I K,Ca was modeled to respond to Ca influx, and a variable-rate Ca-sequestering mechanism was implemented to remove cytoplasmic calcium. Impulse frequency increases when either I Ca or I K,Ca is eliminated from the model or blocked pharmacologically in whole cell recording experiments. Faithful simulations of experimental data show that the ionic currents may be grouped into small ( I K,Ca, leakage, and stimulus), and large ( I Na, I K, I A, I Ca) on the basis of their peak magnitudes throughout the impulse train. This division of the currents is reflected in their function of controlling the interspike interval (small currents) and impulse generation (large currents). Although the single-compartmental model is qualitatively successful in simulating impulse frequency behavior and its controlling mechanisms, limitations were found that specifically suggest the need to include morphological details. The spike train analysis points to a role for electrotonic currents in the control of the duration of the interspike intervals, which can be compensated by prolonged activation of g K,Ca in the single-compartment model. A detailed, multicompartmental model of the ganglion cell is presented in the companion paper.
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Teng, Guoqi, Daniyil Svystonyuk, Holly E. M. Mewhort, Jeannine D. Turnbull, Darrell D. Belke, Henry J. Duff, and Paul W. M. Fedak. "Tetrandrine reverses human cardiac myofibroblast activation and myocardial fibrosis." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 12 (June 15, 2015): H1564—H1574. http://dx.doi.org/10.1152/ajpheart.00126.2015.
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Tetrandrine (TTD) is a calcium channel blocker with documented antifibrotic actions. In this study, for the first time, we identified that TTD can directly prevent in vitro human cardiac myofibroblast activation and limit in vivo myocardial fibrosis. In vitro, cardiac myofibroblasts from human atrial biopsies ( N = 10) were seeded in three-dimensional collagen matrices. Cell-collagen constructs were exposed to transforming growth factor-β1 (10 ng/ml), with or without TTD (1 and 5 μM) for 48 h. Collagen gel contraction, myofibroblast activation (α-smooth muscle actin expression), expression of profibrotic mRNAs, and rate of collagen protein synthesis were compared. TTD decreased collagen gel contraction (79.7 ± 1.3 vs 60.1 ± 8.9%, P < 0.01), α-smooth muscle actin expression (flow cytometry), collagen synthesis ([3H]proline incorporation), and collagen mRNA expression. Cell viability was similar between groups (annexin positive cells: 1.7 vs. 1.4%). TTD inhibited collagen gel contraction in the presence of T-type and L-type calcium channel blockers, and the intracellular calcium chelator BAPTA-AM (15 μM), suggesting that the observed effects are not mediated by calcium homeostasis. In vivo, Dahl salt-sensitive hypertensive rats were treated with variable doses of TTD (by intraperitoneal injection over 4 wk) and compared with untreated controls ( N = 12). Systemic blood pressure was monitored by tail cuff. Myocardial fibrosis and left ventricular compliance were assessed by histology and passive pressure-volume analysis. Myocardial fibrosis was attenuated compared with untreated controls (%collagen area: 9.4 ± 7.3 vs 2.1 ± 1.0%, P < 0.01). Left ventricular compliance was preserved. In conclusion, TTD reverses human cardiac myofibroblast activation and myocardial fibrosis, independent of calcium channel blockade.
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Lagrutta, A., K. Z. Shen, R. A. North, and J. P. Adelman. "Functional differences among alternatively spliced variants of Slowpoke, a Drosophila calcium-activated potassium channel." Journal of Biological Chemistry 269, no. 32 (August 1994): 20347–51. http://dx.doi.org/10.1016/s0021-9258(17)31998-1.
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