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Journal articles on the topic 'Sodium channels'
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1
Sula, Altin, and B. A. Wallace. "Interpreting the functional role of a novel interaction motif in prokaryotic sodium channels." Journal of General Physiology 149, no. 6 (May 18, 2017): 613–22. http://dx.doi.org/10.1085/jgp.201611740.
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Voltage-gated sodium channels enable the translocation of sodium ions across cell membranes and play crucial roles in electrical signaling by initiating the action potential. In humans, mutations in sodium channels give rise to several neurological and cardiovascular diseases, and hence they are targets for pharmaceutical drug developments. Prokaryotic sodium channel crystal structures have provided detailed views of sodium channels, which by homology have suggested potentially important functionally related structural features in human sodium channels. A new crystal structure of a full-length prokaryotic channel, NavMs, in a conformation we proposed to represent the open, activated state, has revealed a novel interaction motif associated with channel opening. This motif is associated with disease when mutated in human sodium channels and plays an important and dynamic role in our new model for channel activation.
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Warmke, Jeffrey W., Robert A. G. Reenan, Peiyi Wang, Su Qian, Joseph P. Arena, Jixin Wang, Denise Wunderler, et al. "Functional Expression of Drosophila para Sodium Channels." Journal of General Physiology 110, no. 2 (August 1, 1997): 119–33. http://dx.doi.org/10.1085/jgp.110.2.119.
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The Drosophila para sodium channel α subunit was expressed in Xenopus oocytes alone and in combination with tipE, a putative Drosophila sodium channel accessory subunit. Coexpression of tipE with para results in elevated levels of sodium currents and accelerated current decay. Para/TipE sodium channels have biophysical and pharmacological properties similar to those of native channels. However, the pharmacology of these channels differs from that of vertebrate sodium channels: (a) toxin II from Anemonia sulcata, which slows inactivation, binds to Para and some mammalian sodium channels with similar affinity (Kd ≅ 10 nM), but this toxin causes a 100-fold greater decrease in the rate of inactivation of Para/TipE than of mammalian channels; (b) Para sodium channels are >10-fold more sensitive to block by tetrodotoxin; and (c) modification by the pyrethroid insecticide permethrin is >100-fold more potent for Para than for rat brain type IIA sodium channels. Our results suggest that the selective toxicity of pyrethroid insecticides is due at least in part to the greater affinity of pyrethroids for insect sodium channels than for mammalian sodium channels.
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Barnes, S., and B. Hille. "Veratridine modifies open sodium channels." Journal of General Physiology 91, no. 3 (March 1, 1988): 421–43. http://dx.doi.org/10.1085/jgp.91.3.421.
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The state dependence of Na channel modification by the alkaloid neurotoxin veratridine was investigated with single-channel and whole-cell voltage-clamp recording in neuroblastoma cells. Several tests of whole-cell Na current behavior in the presence of veratridine supported the hypothesis that Na channels must be open in order to undergo modification by the neurotoxin. Modification was use dependent and required depolarizing pulses, the voltage dependence of production of modified channels was similar to that of normal current activation, and prepulses that caused inactivation of normal current had a parallel effect on the generation of modified current. This hypothesis was then examined directly at the single-channel level. Modified channel openings were easily distinguished from normal openings by their smaller current amplitude and longer burst times. The modification event was often seen as a sudden, dramatic reduction of current through an open Na channel and produced a somewhat flickery channel event having a mean lifetime of 1.6 s at an estimated absolute membrane potential of -45 mV (23 degrees C). The modified channel had a slope conductance of 4 pS, which was 20-25% the size of the slope conductance of normal channels with the 300 mM NaCl pipette solution used. Most modified channel openings were initiated by depolarizing pulses, began within the first 10 ms of the depolarizing step, and were closely associated with the prior opening of single normal Na channels, which supports the hypothesis that modification occurs from the normal open state.
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Duch, D. S., E. Recio-Pinto, C. Frenkel, S. R. Levinson, and B. W. Urban. "Veratridine modification of the purified sodium channel alpha-polypeptide from eel electroplax." Journal of General Physiology 94, no. 5 (November 1, 1989): 813–31. http://dx.doi.org/10.1085/jgp.94.5.813.
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In the interest of continuing structure-function studies, highly purified sodium channel preparations from the eel electroplax were incorporated into planar lipid bilayers in the presence of veratridine. This lipoglycoprotein originates from muscle-derived tissue and consists of a single polypeptide. In this study it is shown to have properties analogous to sodium channels from another muscle tissue (Garber, S. S., and C. Miller. 1987. Journal of General Physiology. 89:459-480), which have an additional protein subunit. However, significant qualitative and quantitative differences were noted. Comparison of veratridine-modified with batrachotoxin-modified eel sodium channels revealed common properties. Tetrodotoxin blocked the channels in a voltage-dependent manner indistinguishable from that found for batrachotoxin-modified channels. Veratridine-modified channels exhibited a range of single-channel conductance and subconductance states. The selectivity of the veratridine-modified sodium channels for sodium vs. potassium ranged from 6-8 in reversal potential measurements, while conductance ratios ranged from 12-15. This is similar to BTX-modified eel channels, though the latter show a predominant single-channel conductance twice as large. In contrast to batrachotoxin-modified channels, the fractional open times of these channels had a shallow voltage dependence which, however, was similar to that of the slow interaction between veratridine and sodium channels in voltage-clamped biological membranes. Implications for sodium channel structure are discussed.
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Scheuer, T., and W. A. Catterall. "Control of neuronal excitability by phosphorylation and dephosphorylation of sodium channels." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1299–302. http://dx.doi.org/10.1042/bst0341299.
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Currents through voltage-gated sodium channels drive action potential depolarization in neurons and other excitable cells. Smaller currents through these channels are key components of currents that control neuronal firing and signal integration. Changes in sodium current have profound effects on neuronal firing. Sodium channels are controlled by neuromodulators acting through phosphorylation of the channel by serine/threonine and tyrosine protein kinases. That phosphorylation requires specific molecular interaction of kinases and phosphatases with the channel molecule to form localized signalling complexes. Such localization is required for effective neurotransmitter-mediated regulation of sodium channels by protein kinase A. Analogous molecular complexes between sodium channels, kinases and other signalling molecules are expected to be necessary for specific and localized transmitter-mediated modulation of sodium channels by other protein kinases.
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Huguenard, John R. "Sodium Channels." Neuron 33, no. 4 (February 2002): 492–94. http://dx.doi.org/10.1016/s0896-6273(02)00592-5.
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Wood, John N., and Federico Iseppon. "Sodium channels." Brain and Neuroscience Advances 2 (January 2018): 239821281881068. http://dx.doi.org/10.1177/2398212818810684.
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In 2000, with the completion of the human genome project, nine related channels were found to comprise the complete voltage-gated sodium gene family and they were renamed NaV1.1–NaV1.9. This millennial event reflected the extraordinary impact of molecular genetics on our understanding of electrical signalling in the nervous system. In this review, studies of animal electricity from the time of Galvani to the present day are described. The seminal experiments and models of Hodgkin and Huxley coupled with the discovery of the structure of DNA, the genetic code and the application of molecular genetics have resulted in an appreciation of the extraordinary diversity of sodium channels and their surprisingly broad repertoire of functions. In the present era, unsuspected roles for sodium channels in a huge range of pathologies have become apparent.
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Yatani, A., D. L. Kunze, and A. M. Brown. "Effects of dihydropyridine calcium channel modulators on cardiac sodium channels." American Journal of Physiology-Heart and Circulatory Physiology 254, no. 1 (January 1, 1988): H140—H147. http://dx.doi.org/10.1152/ajpheart.1988.254.1.h140.
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To investigate whether cardiac sodium channels have dihydropyridine (DHP) receptors we studied the effects of the optically pure (greater than 95%) enantiomers of the DHPs PN200–110 and BAY-K 8644 and the racemic DHP nitrendipine (NTD). Whole cell and single-channel sodium currents were recorded from cultured ventricular cells of neonatal rats using the patch-clamp method. NTD reduced cardiac sodium currents in a voltage-dependent manner. Inhibitory effects were due to an increase in traces without activity. The unit conductance remained unchanged. At negative holding potentials, NTD transiently increased the probability of channel opening. Both (+) and (-) PN 200–110 blocked sodium channels, although the (-) isomer was about one order of magnitude less effective. The blocking effects were voltage dependent. (+) BAY-K 8644 had similar blocking effects. (-) BAY-K 8644 produced an increase in sodium currents due to an increased frequency of channel openings and a marked prolongation of open time without any significant change in unit conductance. The DHPs have effects on cardiac sodium whole cell and single-channel currents that appear identical to and are as stereospecific as their effects on cardiac calcium currents, although the concentrations required are larger. In contrast the inwardly rectifying potassium channel (IK1) is unaffected by these DHPs. We conclude that functionally equivalent DHP receptors are present in cardiac sodium and calcium channels but not potassium channels and take this as evidence of the homology between sodium and calcium channels.
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Tomaselli, G. F., A. M. Feldman, G. Yellen, and E. Marban. "Human cardiac sodium channels expressed in Xenopus oocytes." American Journal of Physiology-Heart and Circulatory Physiology 258, no. 3 (March 1, 1990): H903—H906. http://dx.doi.org/10.1152/ajpheart.1990.258.3.h903.
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We report the expression of voltage-dependent Na+ channels in Xenopus oocytes injected with total RNA isolated from explanted human hearts. The expressed channels demonstrate characteristic voltage-dependent gating, inhibition by tetrodotoxin, and selectivity for Na+. Oocytes injected with sterile water or intentionally degraded RNA had no similar channel activity. The antiarrhythmic agent lidocaine (20 microM) inhibits current flow through the channel in a voltage-dependent fashion. Na+ channels expressed by injection of human cardiac RNA into Xenopus oocytes qualitatively resemble channels in the native tissue.
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Hahin, R. "Removal of inactivation causes time-invariant sodium current decays." Journal of General Physiology 92, no. 3 (September 1, 1988): 331–50. http://dx.doi.org/10.1085/jgp.92.3.331.
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The kinetic properties of the closing of Na channels were studied in frog skeletal muscle to obtain information about the dependence of channel closing on the past history of the channel. Channel closing was studied in normal and modified channels. Chloramine-T was used to modify the channels so that inactivation was virtually removed. A series of depolarizing prepulse potentials was used to activate Na channels, and a -140-mV postpulse was used to monitor the closing of the channels. Unmodified channels decay via a biexponential process with time constants of 72 and 534 microseconds at 12 degrees C. The observed time constants do not depend upon the potential used to activate the channels. The contribution of the slow component to the total decay increases as the activating prepulse is lengthened. After inactivation is removed, the biexponential character of the decay is retained, with no change in the magnitude of the time constants. However, increases in the duration of the activating prepulse over the range where the current is maximal 1-75 ms) produce identical biexponential decays. The presence of biexponential decays suggests that either two subtypes of Na channels are found in muscle, or Na channels can exist in one of two equally conductive states. The time-invariant decays observed suggest that channel closure does not depend upon their past history.
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Takahashi, Izumi, and Masami Yoshino. "Functional coupling between sodium-activated potassium channels and voltage-dependent persistent sodium currents in cricket Kenyon cells." Journal of Neurophysiology 114, no. 4 (October 2015): 2450–59. http://dx.doi.org/10.1152/jn.00087.2015.
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In this study, we examined the functional coupling between Na+-activated potassium (KNa) channels and Na+ influx through voltage-dependent Na+ channels in Kenyon cells isolated from the mushroom body of the cricket Gryllus bimaculatus. Single-channel activity of KNa channels was recorded with the cell-attached patch configuration. The open probability ( Po) of KNa channels increased with increasing Na+ concentration in a bath solution, whereas it decreased by the substitution of Na+ with an equimolar concentration of Li+. The Po of KNa channels was also found to be reduced by bath application of a high concentration of TTX (1 μM) and riluzole (100 μM), which inhibits both fast ( INaf) and persistent ( INaP) Na+ currents, whereas it was unaffected by a low concentration of TTX (10 nM), which selectively blocks INaf. Bath application of Cd2+ at a low concentration (50 μM), as an inhibitor of INaP, also decreased the Po of KNa channels. Conversely, bath application of the inorganic Ca2+-channel blockers Co2+ and Ni2+ at high concentrations (500 μM) had little effect on the Po of KNa channels, although Cd2+ (500 μM) reduced the Po of KNa channels. Perforated whole cell clamp analysis further indicated the presence of sustained outward currents for which amplitude was dependent on the amount of Na+ influx. Taken together, these results indicate that KNa channels could be activated by Na+ influx passing through voltage-dependent persistent Na+ channels. The functional significance of this coupling mechanism was discussed in relation to the membrane excitability of Kenyon cells and its possible role in the formation of long-term memory.
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Rehberg, Benno, and Daniel S. Duch. "Suppression of Central Nervous System Sodium Channels by Propofol." Anesthesiology 91, no. 2 (August 1, 1999): 512–20. http://dx.doi.org/10.1097/00000542-199908000-00026.
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Background Previous studies have provided evidence that clinical levels of propofol alter the functions of voltage-dependent sodium channels, thereby inhibiting synaptic release of glutamate. However, most of these experiments were conducted in the presence of sodium-channel activators, which alter channel inactivation. This study electrophysiologically characterized the interactions of propofol with unmodified sodium channels. Methods Sodium currents were measured using whole-cell patch-clamp recordings of rat brain IIa sodium channels expressed in a stably transfected Chinese hamster ovary cell line. Standard electrophysiologic protocols were used to record sodium currents in the presence or absence of externally applied propofol. Results Propofol, at concentrations achieved clinically in the brain, significantly altered sodium channel currents by two mechanisms: a voltage-independent block of peak currents and a concentration-dependent shift in steady-state inactivation to hyperpolarized potentials, leading to a voltage dependence of current suppression. The two effects combined to give an apparent concentration yielding a half-maximal inhibitory effect of 10 microM near the threshold potential of action potential firing (about -60 mV). Propofol inhibition was also use-dependent, causing a further block of sodium currents at these anesthetic concentrations. Conclusions In these experiments with pharmacologically unaltered sodium channels, propofol inhibition of currents occurred at concentrations about eight-fold above clinical plasma levels and thus at brain concentrations reached during clinical anesthesia. Therefore, the results indicate a possible role for sodium-channel suppression in propofol anesthesia.
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Segal, Michael M., and Andrea F. Douglas. "Late Sodium Channel Openings Underlying Epileptiform Activity Are Preferentially Diminished by the Anticonvulsant Phenytoin." Journal of Neurophysiology 77, no. 6 (June 1, 1997): 3021–34. http://dx.doi.org/10.1152/jn.1997.77.6.3021.
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Segal, Michael M. and Andrea F. Douglas. Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin. J. Neurophysiol. 77: 3021–3034, 1997. Late openings of sodium channels were observed in outside-out patch recordings from hippocampal neurons in culture. In previous studies of such neurons, a persistent sodium current appeared to underlie the ictal epileptiform activity. All the channel currents were blocked by tetrodotoxin. In addition to the transient openings of sodium channels making up the peak sodium current, there were two types of late channel openings: brief late and burst openings. These late channel openings occurred throughout voltage pulses that lasted 750 ms, producing a persistent sodium current. At −30 mV, this current was 0.4% of the peak current. The late channel openings occurred throughout the physiological range of trans-membrane voltages. The anticonvulsant phenytoin reduced the late channel openings more than the peak currents. The effect on the persistent current was greatest at more depolarized voltages, whereas the effect on peak currents was not substantially voltage dependent. In the presence of 60 μM phenytoin, peak sodium currents at −30 mV were 40–41% of control, as calculated using different methods of analysis. Late currents were 22–24% of control. Phenytoin primarily decreased the number of channel openings, with less effect on the duration of channel openings and no effect on open channel current. This set of findings is consistent with models in which phenytoin binds to the inactivated state of the channel. The preferential effect of phenytoin on the persistent sodium current suggests that an important pharmacological mechanism for a sodium channel anticonvulsant is to reduce late openings of sodium channels, rather than reducing all sodium channel openings. We hypothesize that pharmacological interventions that are most selective in reducing late openings of sodium channels, while leaving early channel openings relatively intact, will be those that produce an anticonvulsant effect while interfering minimally with normal function.
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Terlau, H., M. Stocker, K. J. Shon, J. M. McIntosh, and B. M. Olivera. "MicroO-conotoxin MrVIA inhibits mammalian sodium channels, but not through site I." Journal of Neurophysiology 76, no. 3 (September 1, 1996): 1423–29. http://dx.doi.org/10.1152/jn.1996.76.3.1423.
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1. A 31-amino-acid peptide from the venom of the snail-hunting species Conus marmoreus, microO-conotoxin MrVIA, inhibits mammalian voltage-gated sodium channels through a novel mechanism distinct from saxitoxin, tetrodotoxin, or mu-conotoxin. 2. MicroO-Conotoxin MrVIA blocks rat brain type II sodium channels expressed in Xenopus oocytes (IC50 approximately 200 nM, Hill coefficient approximately 1.6 +/- 0.2, mean +/- SE). Channel activation/inactivation kinetics and current-voltage relationships were unperturbed. 3. MicroO-Conotoxin MrVIA does not cause phasic or use-dependent inhibition of sodium currents measured in Xenopus oocytes expressing rat brain type II sodium channels, but shifts the steady-state availability of these sodium channels to more hyperpolarized potentials. 4. MicroO-Conotoxin MrVIA inhibited rapidly inactivating sodium channel conductance in rat hippocampal cells in culture. The inhibition was rapidly reversible. 5. MicroO-Conotoxin MrVIA does not displace specific [3H]saxitoxin binding to either rat brain or Electrophorus electric organ sites, indicating inhibitory effects mediated through a binding site distinct from site I.
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Lee, Sora, Samuel J. Goodchild, and Christopher A. Ahern. "Local anesthetic inhibition of a bacterial sodium channel." Journal of General Physiology 139, no. 6 (May 28, 2012): 507–16. http://dx.doi.org/10.1085/jgp.201210779.
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Recent structural breakthroughs with the voltage-gated sodium channel from Arcobacter butzleri suggest that such bacterial channels may provide a structural platform to advance the understanding of eukaryotic sodium channel gating and pharmacology. We therefore set out to determine whether compounds known to interact with eukaryotic NaVs could also inhibit the bacterial channel from Bacillus halodurans and NaChBac and whether they did so through similar mechanisms as in their eukaryotic homologues. The data show that the archetypal local anesthetic (LA) lidocaine inhibits resting NaChBac channels with a dissociation constant (Kd) of 260 µM, and channels displayed a left-shifted steady-state inactivation gating relationship in the presence of the drug. Extracellular application of QX-314 to expressed NaChBac channels had no effect on sodium current, whereas internal exposure via injection of a bolus of the quaternary derivative rapidly reduced sodium conductance, consistent with a hydrophilic cytoplasmic access pathway to an internal binding site. However, the neutral derivative benzocaine applied externally inhibited NaChBac channels, suggesting that hydrophobic pathways can also provide drug access to inhibit channels. Alternatively, ranolazine, a putative preopen state blocker of eukaryotic NaVs, displayed a Kd of 60 µM and left-shifted the NaChBac activation-voltage relationship. In each case, block enhanced entry into the inactivated state of the channel, an effect that is well described by a simple kinetic scheme. The data suggest that although significant differences exist, LA block of eukaryotic NaVs also occurs in bacterial sodium channels and that NaChBac shares pharmacological homology to the resting state of vertebrate NaV homologues.
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Paillart, C., J. L. Boudier, J. A. Boudier, H. Rochat, F. Couraud, and B. Dargent. "Activity-induced internalization and rapid degradation of sodium channels in cultured fetal neurons." Journal of Cell Biology 134, no. 2 (July 15, 1996): 499–509. http://dx.doi.org/10.1083/jcb.134.2.499.
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A regulatory mechanism for neuronal excitability consists in controlling sodium channel density at the plasma membrane. In cultured fetal neurons, activation of sodium channels by neurotoxins, e.g., veratridine and alpha-scorpion toxin (alpha-ScTx) that enhance the channel open state probability induced a rapid down-regulation of surface channels. Evidence that the initial step of activity-induced sodium channel down-regulation is mediated by internalization was provided by using 125I-alpha-ScTx as both a channel probe and activator. After its binding to surface channels, the distribution of 125I-alpha-ScTx into five subcellular compartments was quantitatively analyzed by EM autoradiography. 125I-alpha-ScTx was found to accumulate in tubulovesicular endosomes and disappear from the cell surface in a time-dependent manner. This specific distribution was prevented by addition of tetrodotoxin (TTX), a channel blocker. By using a photoreactive derivative to covalently label sodium channels at the surface of cultured neurons, we further demonstrated that they are degraded after veratridine-induced internalization. A time-dependent decrease in the amount of labeled sodium channel alpha subunit was observed after veratridine treatment. After 120 min of incubation, half of the alpha subunits were cleaved. This degradation was prevented totally by TTX addition and was accompanied by the appearance of an increasing amount of a 90-kD major proteolytic fragment that was already detected after 45-60 min of veratridine treatment. Exposure of the photoaffinity-labeled cells to amphotericin B, a sodium ionophore, gave similar results. In this case, degradation was prevented when Na+ ions were substituted by choline ions and not blocked by TTX. After veratridine- or amphotericin B-induced internalization of sodium channels, breakdown of the labeled alpha subunit was inhibited by leupeptin, while internalization was almost unaffected. Thus, cultured fetal neurons are capable of adjusting sodium channel density by an activity-dependent endocytotic process that is triggered by Na+ influx.
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Waxman, Stephen G. "The neuron as a dynamic electrogenic machine: modulation of sodium–channel expression as a basis for functional plasticity in neurons." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1394 (February 29, 2000): 199–213. http://dx.doi.org/10.1098/rstb.2000.0559.
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Neurons signal each other via regenerative electrical impulses (action potentials) and thus can be thought of as electrogenic machines. V oltage–gated sodium channels produce the depolarizations necessary for action potential activity in most neurons and, in this respect, lie close to the heart of the electrogenic machinery. Although classical neurophysiological doctrine accorded ‘the’ sodium channel a crucial role in electrogenesis, it is now clear that nearly a dozen genes encode distinct sodium channels with different molecular structures and functional properties, and the majority of these channels are expressed within the mammalian nervous system. The transcription of these sodium–channel genes, and the deployment of the channels that they encode, can change significantly within neurons following various injuries. Moreover, the transcription of these genes and the deployment of various types of sodium channels within neurons of the normal nervous system can change markedly as neurons respond to changing milieus or physiological inputs. As a result of these changes in sodium–channel expression, the membranes of neurons may be retuned so as to alter their transductive and/or encoding properties. Neurons within the normal and injured nervous system can thus function as dynamic electrogenic machines with electroresponsive properties that change not only in response to pathological insults, but also in response to shifting functional needs.
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Tousson, A., C. D. Alley, E. J. Sorscher, B. R. Brinkley, and D. J. Benos. "Immunochemical localization of amiloride-sensitive sodium channels in sodium-transporting epithelia." Journal of Cell Science 93, no. 2 (June 1, 1989): 349–62. http://dx.doi.org/10.1242/jcs.93.2.349.
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The localization of amiloride-sensitive Na+ channels in Na+-transporting epithelia was examined using antibodies made against amiloride-binding Na+ channel protein purified from bovine kidney. The distribution of the channel protein was determined in thick frozen sections at the light-microscopic level using indirect immunofluorescence, and at the electron-microscopic level using immunogold labelling. In the cells of both the intact bovine collecting tubule and A6 confluent monolayers, only the luminal or apical-facing surface membranes showed staining. Sodium channel protein was characteristically localized on microvillar domains of the apical plasma membrane. Little or no basolateral membrane staining was evident. Channel protein was also absent from subapical vesicles and tight junctions, and was not found in bovine renal proximal tubules, cultured human secretory sweat coils, non-epithelial Chinese hamster ovary (CHO) cells or human skin fibroblasts. Trypsinization of intact A6 monolayers prior to cell fixation abolished specific staining with antibody. Pretreatment with amiloride protected against this loss of staining. Thus, our probes are specific for amiloride-binding Na+ channel protein, and this channel protein is largely or completely confined to the apical membrane of Na+-transporting epithelia. The level and distribution of specific immunostaining in A6 cells was unchanged by aldosterone treatment, although channel activity, as measured by short-circuit current, increased threefold. This result demonstrates that Na+ channel protein is ever present at the cell surface and exists in both an active and an inactive form. We find no evidence that stimulation of Na+ uptake by aldosterone involves recruitment of new channels from a cytoplasmic pool.
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Garty, H., and L. G. Palmer. "Epithelial sodium channels: function, structure, and regulation." Physiological Reviews 77, no. 2 (April 1, 1997): 359–96. http://dx.doi.org/10.1152/physrev.1997.77.2.359.
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The apical (outward-facing) membranes of high-resistance epithelia contain Na+ channels, traditionally identified by their sensitivity to block by the K(+)-sparing diuretic amiloride. Such channels have been characterized in amphibian skin and urinary bladder, renal collecting duct, distal colon, sweat and salivary glands, lung, and taste buds. They mediate the first step of active Na+ reabsorption and play a major role in the maintenance of electrolyte and water homeostasis in all vertebrates. In the past, these channels were classified according to their biophysical and pharmacological properties. The recent cloning of the three homologous channel subunits denoted alpha-, beta-, and gamma-epithelial Na+ channels (ENaC) has provided a molecular definition of at least one class of amiloride-blockable channels. Subsequent studies have established that ENaC is a major Na(+)-conducting pathway in both absorbing and secretory epithelia and is related to one type of channel involved in mechanosensation. This review summarizes the biophysical characteristics, molecular properties, and regulatory mechanisms of epithelial amiloride-blockable Na+ channels. Special emphasis is given to recent studies utilizing cloned ENaC subunits and purified amiloride-binding proteins.
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Ban, Yue, Benjamin E. Smith, and Michael R. Markham. "A highly polarized excitable cell separates sodium channels from sodium-activated potassium channels by more than a millimeter." Journal of Neurophysiology 114, no. 1 (July 2015): 520–30. http://dx.doi.org/10.1152/jn.00475.2014.
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The bioelectrical properties and resulting metabolic demands of electrogenic cells are determined by their morphology and the subcellular localization of ion channels. The electric organ cells (electrocytes) of the electric fish Eigenmannia virescens generate action potentials (APs) with Na+ currents >10 μA and repolarize the AP with Na+-activated K+ (KNa) channels. To better understand the role of morphology and ion channel localization in determining the metabolic cost of electrocyte APs, we used two-photon three-dimensional imaging to determine the fine cellular morphology and immunohistochemistry to localize the electrocytes' ion channels, ionotropic receptors, and Na+-K+-ATPases. We found that electrocytes are highly polarized cells ∼1.5 mm in anterior-posterior length and ∼0.6 mm in diameter, containing ∼30,000 nuclei along the cell periphery. The cell's innervated posterior region is deeply invaginated and vascularized with complex ultrastructural features, whereas the anterior region is relatively smooth. Cholinergic receptors and Na+ channels are restricted to the innervated posterior region, whereas inward rectifier K+ channels and the KNa channels that terminate the electrocyte AP are localized to the anterior region, separated by >1 mm from the only sources of Na+ influx. In other systems, submicrometer spatial coupling of Na+ and KNa channels is necessary for KNa channel activation. However, our computational simulations showed that KNa channels at a great distance from Na+ influx can still terminate the AP, suggesting that KNa channels can be activated by distant sources of Na+ influx and overturning a long-standing assumption that AP-generating ion channels are restricted to the electrocyte's posterior face.
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Althaus, Mike, Wolfgang G. Clauss, and Martin Fronius. "Amiloride-Sensitive Sodium Channels and Pulmonary Edema." Pulmonary Medicine 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/830320.
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The development of pulmonary edema can be considered as a combination of alveolar flooding via increased fluid filtration, impaired alveolar-capillary barrier integrity, and disturbed resolution due to decreased alveolar fluid clearance. An important mechanism regulating alveolar fluid clearance is sodium transport across the alveolar epithelium. Transepithelial sodium transport is largely dependent on the activity of sodium channels in alveolar epithelial cells. This paper describes how sodium channels contribute to alveolar fluid clearance under physiological conditions and how deregulation of sodium channel activity might contribute to the pathogenesis of lung diseases associated with pulmonary edema. Furthermore, sodium channels as putative molecular targets for the treatment of pulmonary edema are discussed.
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Vinson, Valda. "Targeting sodium channels." Science 363, no. 6433 (March 21, 2019): 1296.7–1297. http://dx.doi.org/10.1126/science.363.6433.1296-g.
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Rossier, Bernard C., Cecilia M. Canessa, Laurent Schild, and Jean-Daniel Horisberger. "Epithelial sodium channels." Current Opinion in Nephrology and Hypertension 3, no. 5 (September 1994): 487–96. http://dx.doi.org/10.1097/00041552-199409000-00003.
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Davis, Scott F., and Cindy L. Linn. "Mechanism linking NMDA receptor activation to modulation of voltage-gated sodium current in distal retina." American Journal of Physiology-Cell Physiology 284, no. 5 (May 1, 2003): C1193—C1204. http://dx.doi.org/10.1152/ajpcell.00256.2002.
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In this study, we investigated the mechanism that links activation of N-methyl-D-aspartate (NMDA) receptors to inhibition of voltage-gated sodium channels in isolated catfish cone horizontal cells. NMDA channels were activated in voltage-clamped cells incubated in low-calcium saline or dialyzed with the calcium chelator BAPTA to determine that calcium influx through NMDA channels is required for sodium channel modulation. To determine whether calcium influx through NMDA channels triggers calcium-induced calcium release (CICR), cells were loaded with the calcium-sensitive dye calcium green 2 and changes in relative fluorescence were measured in response to NMDA. Responses were compared with measurements obtained when caffeine depleted stores. Voltage-clamp studies demonstrated that CICR modulated sodium channels in a manner similar to that of NMDA. Blocking NMDA receptors with AP-7, blocking CICR with ruthenium red, depleting stores with caffeine, or dialyzing cells with calmodulin antagonists W-5 or peptide 290–309 all prevented sodium channel modulation. These results support the hypothesis that NMDA modulation of voltage-gated sodium channels in horizontal cells requires CICR and activation of a calmodulin-dependent signaling pathway.
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Rehberg, Benno, Yong-Hong Xiao, and Daniel S. Duch. "Central Nervous System Sodium Channels Are Significantly Suppressed at Clinical Concentrations of Volatile Anesthetics." Anesthesiology 84, no. 5 (May 1, 1996): 1223–33. http://dx.doi.org/10.1097/00000542-199605000-00025.
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Background Although voltage-dependent sodium channels have been proposed as possible molecular sites of anesthetic action, they generally are considered too insensitive to be likely molecular targets. However, most previous molecular studies have used peripheral sodium channels as models. To examine the interactions of volatile anesthetics with mammalian central nervous system voltage-gated sodium channels, rat brain IIA sodium channels were expressed in a stably transfected Chinese hamster ovary cell line, and their modification by volatile anesthetics was examined. Methods Sodium currents were measured using whole cell patch clamp recordings. Test solutions were equilibrated with the test anesthetics and perfused externally on the cells. Anesthetic concentrations in the perfusion solution were determined by gas chromatography. Results All anesthetics significantly suppressed sodium currents at clinical concentrations. This suppression occurred through at least two mechanisms: (1) a potential-independent suppression of resting or open sodium channels, and (2) a hyperpolarizing shift in the voltage-dependence of channel inactivation resulting in a potential-dependent suppression of sodium currents. The voltage-dependent interaction results in IC50 values for anesthetic suppression of sodium channels that are close to clinical concentrations at potentials near the resting membrane potential.
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Keller, B. U., R. P. Hartshorne, J. A. Talvenheimo, W. A. Catterall, and M. Montal. "Sodium channels in planar lipid bilayers. Channel gating kinetics of purified sodium channels modified by batrachotoxin." Journal of General Physiology 88, no. 1 (July 1, 1986): 1–23. http://dx.doi.org/10.1085/jgp.88.1.1.
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Single channel currents of sodium channels purified from rat brain and reconstituted into planar lipid bilayers were recorded. The kinetics of channel gating were investigated in the presence of batrachotoxin to eliminate inactivation and an analysis was conducted on membranes with a single active channel at any given time. Channel opening is favored by depolarization and is strongly voltage dependent. Probability density analysis of dwell times in the closed and open states of the channel indicates the occurrence of one open state and several distinct closed states in the voltage (V) range-120 mV less than or equal to V less than or equal to +120 mV. For V less than or equal to 0, the transition rates between stages are exponentially dependent on the applied voltage, as described in mouse neuroblastoma cells (Huang, L. M., N. Moran, and G. Ehrenstein. 1984. Biophysical Journal. 45:313-322). In contrast, for V greater than or equal to 0, the transition rates are virtually voltage independent. Autocorrelation analysis (Labarca, P., J. Rice, D. Fredkin, and M. Montal. 1985. Biophysical Journal. 47:469-478) shows that there is no correlation in the durations of successive open or closing events. Several kinetic schemes that are consistent with the experimental data are considered. This approach may provide information about the mechanism underlying the voltage dependence of channel activation.
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Payandeh, Jian. "Crystallographic studies of voltage-gated sodium and calcium channels." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1488. http://dx.doi.org/10.1107/s2053273314085118.
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Voltage-gated ion channels (VGICs) mediate electrical signaling within the nervous system and regulate a wide range of physiological processes. Voltage-gated sodium (Nav) channels are responsible for initiating action potentials and their rapid activation, sodium selectivity, and drug sensitivity are unique among VGICs. Nav channels are the molecular targets of drugs used in local anaesthesia and in the treatment of genetic and sporadic Nav channelopathies including inherited epilepsy, migraine, periodic paralysis, cardiac arrhythmia, and chronic pain syndromes. Recent crystal structures of a Nav channel from the bacterium Arcobacter butzleri (NavAb) have revealed surprising insights into the structural basis for voltage-dependent activation, sodium selectivity, drug block, and slow inactivation (1,2). The available structures of NavAb will be described alongside complementary functional and molecular dynamic studies. Distinct from Nav channels, the closely related voltage-gated calcium (Cav) channels initiate processes such as synaptic transmission, muscle contraction, and hormone secretion in response to membrane depolarization. Cav channels catalyze the rapid and highly selective influx of calcium ions into cells despite a 70-fold higher extracellular concentration of sodium. By grafting a Cav channel selectivity filter onto NavAb, crystallographic and functional analyses of the resulting CavAb channel will be described that have revealed a multi-ion selectivity filter which establishes a structural framework for understanding the mechanisms of ion selectivity and conductance in vertebrate Cav channels (3).
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Stocker, Patrick J., and Eric S. Bennett. "Differential Sialylation Modulates Voltage-gated Na+ Channel Gating throughout the Developing Myocardium." Journal of General Physiology 127, no. 3 (February 13, 2006): 253–65. http://dx.doi.org/10.1085/jgp.200509423.
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Voltage-gated sodium channel function from neonatal and adult rat cardiomyocytes was measured and compared. Channels from neonatal ventricles required an ∼10 mV greater depolarization for voltage-dependent gating events than did channels from neonatal atria and adult atria and ventricles. We questioned whether such gating shifts were due to developmental and/or chamber-dependent changes in channel-associated functional sialic acids. Thus, all gating characteristics for channels from neonatal atria and adult atria and ventricles shifted significantly to more depolarized potentials after removal of surface sialic acids. Desialylation of channels from neonatal ventricles did not affect channel gating. After removal of the complete surface N-glycosylation structures, gating of channels from neonatal atria and adult atria and ventricles shifted to depolarized potentials nearly identical to those measured for channels from neonatal ventricles. Gating of channels from neonatal ventricles were unaffected by such deglycosylation. Immunoblot gel shift analyses indicated that voltage-gated sodium channel α subunits from neonatal atria and adult atria and ventricles are more heavily sialylated than α subunits from neonatal ventricles. The data are consistent with approximately 15 more sialic acid residues attached to each α subunit from neonatal atria and adult atria and ventricles. The data indicate that differential sialylation of myocyte voltage-gated sodium channel α subunits is responsible for much of the developmental and chamber-specific remodeling of channel gating observed here. Further, cardiac excitability is likely impacted by these sialic acid–dependent gating effects, such as modulation of the rate of recovery from inactivation. A novel mechanism is described by which cardiac voltage-gated sodium channel gating and subsequently cardiac rhythms are modulated by changes in channel-associated sialic acids.
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Vais, Horia, Martin S. Williamson, Susannah J. Goodson, Alan L. Devonshire, Jeffrey W. Warmke, Peter N. R. Usherwood, and Charles J. Cohen. "Activation of Drosophila Sodium Channels Promotes Modification by Deltamethrin." Journal of General Physiology 115, no. 3 (February 28, 2000): 305–18. http://dx.doi.org/10.1085/jgp.115.3.305.
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kdr and super-kdr are mutations in houseflies and other insects that confer 30- and 500-fold resistance to the pyrethroid deltamethrin. They correspond to single (L1014F) and double (L1014F+M918T) mutations in segment IIS6 and linker II(S4–S5) of Na channels. We expressed Drosophila para Na channels with and without these mutations and characterized their modification by deltamethrin. All wild-type channels can be modified by <10 nM deltamethrin, but high affinity binding requires channel opening: (a) modification is promoted more by trains of brief depolarizations than by a single long depolarization, (b) the voltage dependence of modification parallels that of channel opening, and (c) modification is promoted by toxin II from Anemonia sulcata, which slows inactivation. The mutations reduce channel opening by enhancing closed-state inactivation. In addition, these mutations reduce the affinity for open channels by 20- and 100-fold, respectively. Deltamethrin inhibits channel closing and the mutations reduce the time that channels remain open once drug has bound. The super-kdr mutations effectively reduce the number of deltamethrin binding sites per channel from two to one. Thus, the mutations reduce both the potency and efficacy of insecticide action.
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Ratnakumari, Lingamaneni, and Hugh C. Hemmings. "Inhibition of Presynaptic Sodium Channels by Halothane." Anesthesiology 88, no. 4 (April 1, 1998): 1043–54. http://dx.doi.org/10.1097/00000542-199804000-00025.
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Background Recent electrophysiologic studies indicate that clinical concentrations of volatile general anesthetic agents inhibit central nervous system sodium (Na+) channels. In this study, the biochemical effects of halothane on Na+ channel function were determined using rat brain synaptosomes (pinched-off nerve terminals) to assess the role of presynaptic Na+ channels in anesthetic effects. Methods Synaptosomes from adult rat cerebral cortex were used to determine the effects of halothane on veratridine-evoked Na+ channel-dependent Na+ influx (using 22Na+), changes in intrasynaptosomal [Na+] (using ion-specific spectrofluorometry), and neurotoxin interactions with specific receptor sites of the Na+ channel (by radioligand binding). The potential physiologic and functional significance of these effects was determined by measuring the effects of halothane on veratridine-evoked Na+ channel-dependent glutamate release (using enzyme-coupled spectrofluorometry). Results Halothane inhibited veratridine-evoked 22Na+ influx (IC50 = 1.1 mM) and changes in intrasynaptosomal [Na+] (concentration for 50% inhibition [IC50] = 0.97 mM), and it specifically antagonized [3H]batrachotoxinin-A 20-alpha-benzoate binding to receptor site two of the Na+ channel (IC50 = 0.53 mM). Scatchard and kinetic analysis revealed an allosteric competitive mechanism for inhibition of toxin binding. Halothane inhibited veratridine-evoked glutamate release from synaptosomes with comparable potency (IC50 = 0.67 mM). Conclusions Halothane significantly inhibited Na+ channel-mediated Na influx, increases in intrasynaptosomal [Na+] and glutamate release, and competed with neurotoxin binding to site two of the Na+ channel in synaptosomes at concentrations within its clinical range (minimum alveolar concentration, 1-2). These findings support a role for presynaptic Na+ channels as a molecular target for general anesthetic effects.
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Worley, J. F., R. J. French, and B. K. Krueger. "Trimethyloxonium modification of single batrachotoxin-activated sodium channels in planar bilayers. Changes in unit conductance and in block by saxitoxin and calcium." Journal of General Physiology 87, no. 2 (February 1, 1986): 327–49. http://dx.doi.org/10.1085/jgp.87.2.327.
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Single batrachotoxin-activated sodium channels from rat brain were modified by trimethyloxonium (TMO) after incorporation in planar lipid bilayers. TMO modification eliminated saxitoxin (STX) sensitivity, reduced the single channel conductance by 37%, and reduced calcium block of inward sodium currents. These effects always occurred concomitantly, in an all-or-none fashion. Calcium and STX protected sodium channels from TMO modification with potencies similar to their affinities for block. Calcium inhibited STX binding to rat brain membrane vesicles and relieved toxin block of channels in bilayers, apparently by competing with STX for the toxin binding site. These results suggest that toxins, permeant cations, and blocking cations can interact with a common site on the sodium channel near the extracellular surface. It is likely that permeant cations transiently bind to this superficial site, as the first of several steps in passing inward through the channel.
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Stern, M., R. Kreber, and B. Ganetzky. "Dosage effects of a Drosophila sodium channel gene on behavior and axonal excitability." Genetics 124, no. 1 (January 1, 1990): 133–43. http://dx.doi.org/10.1093/genetics/124.1.133.
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Abstract The effects of para mutations on behavior and axonal excitability in Drosophila suggested that para specifically affects sodium channels. This hypothesis was confirmed by molecular analysis of the para locus, which demonstrates that the encoded para product is a sodium channel polypeptide. Here we characterize the effects of altered para+ dosage on behavior and axonal excitability, both in an otherwise wild-type background and in combination with two other mutations: napts, which also affects sodium channels, and ShKS133, which specifically affects potassium channels. Whereas it was previously shown that decreased dosage of para+ is unconditionally lethal in a napts background, we find that increased dosage of para+ suppresses napts. Similarly, we find that para hypomorphs or decreased dosage of para+ suppresses ShKS133, whereas increased dosage of para+ enhances ShKS133). The electrophysiological basis for these effects is investigated. Other genes in Drosophila that have sequence homology to sodium channels do not show such dosage effects, which suggests that the para+ product has a function distinct from that of other putative Drosophila sodium channel genes. We conclude that the number of sodium channels present in at least some Drosophila neurons can be affected by changes in para+ gene dosage, and that the level of para+ expression can strongly influence neuronal excitability.
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Wu, Xin, and Liang Hong. "Calmodulin Interactions with Voltage-Gated Sodium Channels." International Journal of Molecular Sciences 22, no. 18 (September 10, 2021): 9798. http://dx.doi.org/10.3390/ijms22189798.
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Calmodulin (CaM) is a small protein that acts as a ubiquitous signal transducer and regulates neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. CaM modulates the voltage-gated sodium channel gating process, alters sodium current density, and regulates sodium channel protein trafficking and expression. Many mutations in the CaM-binding IQ domain give rise to diseases including epilepsy, autism, and arrhythmias by interfering with CaM interaction with the channel. In the present review, we discuss CaM interactions with the voltage-gated sodium channel and modulators involved in CaM regulation, as well as summarize CaM-binding IQ domain mutations associated with human diseases in the voltage-gated sodium channel family.
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McEwen, Dyke P., and Lori L. Isom. "Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules." Journal of Biological Chemistry 279, no. 50 (October 4, 2004): 52744–52. http://dx.doi.org/10.1074/jbc.m405990200.
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Voltage-gated sodium channels localize at high density in axon initial segments and nodes of Ranvier in myelinated axons. Sodium channels consist of a pore-forming α subunit and at least one β subunit. β1 is a member of the immunoglobulin superfamily of cell adhesion molecules and interacts homophilically and heterophilically with contactin and Nf186. In this study, we characterized β1 interactions with contactin and Nf186 in greater detail and investigated interactions of β1 with NrCAM, Nf155, and sodium channel β2 and β3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that β1 interacts with the fibronectin-like domains of contactin. β1 also interacts with NrCAM, Nf155, sodium channel β2, and Nf186 but not with sodium channel β3. The interaction of the extracellular domains of β1 and β2 requires the region169TEEEGKTDGEGNA181located in the intracellular domain of β2. Interaction of β1 with Nf186 results in increased Nav1.2 cell surface density over α alone, similar to that shown previously for contactin and β2. We propose that β1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrinG.
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Qiu, W., B. Lee, M. Lancaster, W. Xu, S. Leung, and S. E. Guggino. "Cyclic nucleotide-gated cation channels mediate sodium and calcium influx in rat colon." American Journal of Physiology-Cell Physiology 278, no. 2 (February 1, 2000): C336—C343. http://dx.doi.org/10.1152/ajpcell.2000.278.2.c336.
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We found mRNA for the three isoforms of the cyclic nucleotide-gated nonselective cation channel expressed in the mucosal layer of the rat intestine from the duodenum to the colon and in intestinal epithelial cell lines in culture. Because these channels are permeable to sodium and calcium and are stimulated by cGMP or cAMP, we measured 8-bromo-cGMP-stimulated sodium-mediated short-circuit current ( I sc) in proximal and distal colon and unidirectional45Ca2+fluxes in proximal colon to determine whether these channels could mediate transepithelial sodium and calcium absorption across the colon. Sodium-mediated I sc, stimulated by 8-bromo-cGMP, were inhibited by dichlorobenzamil and l-cis-diltiazem, blockers of cyclic nucleotide-gated cation channels, suggesting that these ion channels can mediate transepithelial sodium absorption. Sodium-mediated I sc and net transepithelial45Ca2+absorption were stimulated by heat-stable toxin from Escherichia coli that increases cGMP. Addition of l-cis-diltiazem inhibited the enhanced transepithelial absorption of both ions. These results suggest that cyclic nucleotide-gated cation channels simultaneously increase net sodium and calcium absorption in the colon of the rat.
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Stadnicka, Anna, Wai-Meng Kwok, Hali A. Hartmann, and Zeljko J. Bosnjak. "Effects of Halothane and Isoflurane on Fast and Slow Inactivation of Human Heart hH1a Sodium Channels." Anesthesiology 90, no. 6 (June 1, 1999): 1671–83. http://dx.doi.org/10.1097/00000542-199906000-00024.
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Background Cloning and heterologous expression of ion channels allow biophysical and molecular studies of the mechanisms of volatile anesthetic interactions with human heart sodium channels. Volatile anesthetics may influence the development of arrhythmias arising from cardiac sodium channel dysfunction. For that reason, understanding the mechanisms of interactions between these anesthetics and cardiac sodium channels is important. This study evaluated the mechanisms of volatile anesthetic actions on the cloned human cardiac sodium channel (hH1a) alpha subunit. Methods Inward sodium currents were recorded from human embryonic kidney (HEK293) cells stably expressing hH1a channels. The effects of halothane and isoflurane on current and channel properties were evaluated using the whole cell voltage-clamp technique. Results Halothane at 0.47 and 1.1 mM and isoflurane at 0.54 and 1.13 mM suppressed the sodium current in a dose- and voltage-dependent manner. Steady state activation was not affected, but current decay was accelerated. The voltage dependence of steady state fast and slow inactivations was shifted toward more hyperpolarized potentials. The slope factor of slow but not fast inactivation curves was reduced significantly. Halothane increased the time constant of recovery from fast inactivation. The recovery from slow inactivation was not affected significantly by either anesthetic. Conclusions In a heterologous expression system, halothane and isoflurane interact with the hH1a channels and suppress the sodium current. The mechanisms involve acceleration of the transition from the open to the inactivated state, stabilization of the fast and slow inactivated states, and prolongation of the inactivated state by delayed recovery from the fast inactivated to the resting state.
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Liin, Sara I., Per-Eric Lund, Johan E. Larsson, Johan Brask, Björn Wallner, and Fredrik Elinder. "Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors." Journal of General Physiology 150, no. 8 (July 12, 2018): 1215–30. http://dx.doi.org/10.1085/jgp.201711942.
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Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential–generating sodium and calcium channels and open an action potential–dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.
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Duszyk, Marek, Andrew S. French, and S. F. Paul Man. "Cystic fibrosis affects chloride and sodium channels in human airway epithelia." Canadian Journal of Physiology and Pharmacology 67, no. 10 (October 1, 1989): 1362–65. http://dx.doi.org/10.1139/y89-217.
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Abnormalities of epithelial function in cystic fibrosis (CF) have been linked to defects in cell membrane permeability to chloride or sodium ions. Recently, a class of chloride channels in airway epithelial cells have been reported to lack their usual sensitivity to phosphorylation via cAMP-dependent protein kinase, suggesting that CF could be due to a single genetic defect in these channels. We have examined single chloride and sodium channels in control and CF human nasal epithelia using the patch-clamp technique. The most common chloride channel was not the one previously associated with CF, but it was also abnormal in CF cells. In addition, the number of sodium channels was unusually high in CF. These findings suggest a wider disturbance of ion channel properties in CF than would be produced by a defect in a single type of channel.Key words: ion channels, cystic fibrosis, airway, epithelium.
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Gray, Richard, and Daniel Johnston. "Sodium sensitivity of KNa channels in mouse CA1 neurons." Journal of Neurophysiology 125, no. 5 (May 1, 2021): 1690–97. http://dx.doi.org/10.1152/jn.00064.2021.
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We studied KNa channels in mouse hippocampal CA1 neurons. Excised inside-out patches showed the channels to be prevalent and active in most patches in the presence of Na+. Cell-attached recordings from intact neurons, however, showed little channel activity. Increasing cytoplasmic sodium in intact cells showed a small effect on channel activity compared with that seen in inside-out excised patches. Blockade of the Na+/K+ pump with ouabain, however, restored the activity of the channels to that seen in inside-out patches.
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Campos, Fabiana V., Baron Chanda, Paulo S. L. Beirão, and Francisco Bezanilla. "β-Scorpion Toxin Modifies Gating Transitions in All Four Voltage Sensors of the Sodium Channel." Journal of General Physiology 130, no. 3 (August 13, 2007): 257–68. http://dx.doi.org/10.1085/jgp.200609719.
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Several naturally occurring polypeptide neurotoxins target specific sites on the voltage-gated sodium channels. Of these, the gating modifier toxins alter the behavior of the sodium channels by stabilizing transient intermediate states in the channel gating pathway. Here we have used an integrated approach that combines electrophysiological and spectroscopic measurements to determine the structural rearrangements modified by the β-scorpion toxin Ts1. Our data indicate that toxin binding to the channel is restricted to a single binding site on domain II voltage sensor. Analysis of Cole-Moore shifts suggests that the number of closed states in the activation sequence prior to channel opening is reduced in the presence of toxin. Measurements of charge–voltage relationships show that a fraction of the gating charge is immobilized in Ts1-modified channels. Interestingly, the charge–voltage relationship also shows an additional component at hyperpolarized potentials. Site-specific fluorescence measurements indicate that in presence of the toxin the voltage sensor of domain II remains trapped in the activated state. Furthermore, the binding of the toxin potentiates the activation of the other three voltage sensors of the sodium channel to more hyperpolarized potentials. These findings reveal how the binding of β-scorpion toxin modifies channel function and provides insight into early gating transitions of sodium channels.
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Vanoye, Carlos G., Christoph Lossin, Thomas H. Rhodes, and Alfred L. George. "Single-channel Properties of Human NaV1.1 and Mechanism of Channel Dysfunction in SCN1A-associated Epilepsy." Journal of General Physiology 127, no. 1 (December 27, 2005): 1–14. http://dx.doi.org/10.1085/jgp.200509373.
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Mutations in genes encoding neuronal voltage-gated sodium channel subunits have been linked to inherited forms of epilepsy. The majority of mutations (>100) associated with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) occur in SCN1A encoding the NaV1.1 neuronal sodium channel α-subunit. Previous studies demonstrated functional heterogeneity among mutant SCN1A channels, revealing a complex relationship between clinical and biophysical phenotypes. To further understand the mechanisms responsible for mutant SCN1A behavior, we performed a comprehensive analysis of the single-channel properties of heterologously expressed recombinant WT-SCN1A channels. Based on these data, we then determined the mechanisms for dysfunction of two GEFS+-associated mutations (R1648H, R1657C) both affecting the S4 segment of domain 4. WT-SCN1A has a slope conductance (17 pS) similar to channels found in native mammalian neurons. The mean open time is ∼0.3 ms in the −30 to −10 mV range. The R1648H mutant, previously shown to display persistent sodium current in whole-cell recordings, exhibited similar slope conductance but had an increased probability of late reopening and a subfraction of channels with prolonged open times. We did not observe bursting behavior and found no evidence for a gating mode shift to explain the increased persistent current caused by R1648H. Cells expressing R1657C exhibited conductance, open probability, mean open time, and latency to first opening similar to WT channels but reduced whole-cell current density, suggesting decreased number of functional channels at the plasma membrane. In summary, our findings define single-channel properties for WT-SCN1A, detail the functional phenotypes for two human epilepsy-associated sodium channel mutants, and clarify the mechanism for increased persistent sodium current induced by the R1648H allele.
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Ratnakumari, L., and H. C. Hemmings. "Effects of Propofol on Sodium Channel-dependent Sodium Influx and Glutamate Release in Rat Cerebrocortical Synaptosomes." Anesthesiology 86, no. 2 (February 1, 1997): 428–39. http://dx.doi.org/10.1097/00000542-199702000-00018.
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Background Previous electrophysiologic studies have implicated voltage-dependent Na+ channels as a molecular site of action for propofol. This study considered the effects of propofol on Na+ channel-mediated Na+ influx and neurotransmitter release in rat brain synaptosomes (isolated presynaptic nerve terminals). Methods Purified cerebrocortical synaptosomes from adult rats were used to determine the effects of propofol on Na+ influx through voltage-dependent Na+ channels (measured using 22Na+) and intracellular [Na+] (measured by ion-specific spectrofluorimetry). For comparison, the effects of propofol on synaptosomal glutamate release evoked by 4-aminopyridine (Na+ channel dependent), veratridine (Na+ channel dependent), KCi (Na+ channel independent) were studied using enzyme-coupled fluorimetry. Results Propofol inhibited veratridine-evoked 22Na+ influx (inhibitory concentration of 50% [IC50] = 46 microM; 8.9 microM free) and changes in intracellular [Na+] (IC50 = 13 microM; 6.3 microM free) in synaptosomes in a dose-dependent manner. Propofol also inhibited 4-aminopyridine-evoked (IC50 = 39 microM; 19 microM free) and veratridine (20 microM)-evoked (IC50 = 30 microM; 14 microM free), but not KCi-evoked (up to 100 microM) glutamate release from synaptosomes. Conclusions Inhibition of Na+ channel-mediated Na+ influx, increased in intracellular [Na+], and glutamate release occurred in synaptosomes at concentrations of propofol achieved clinically. These results support a role for neuronal voltage-dependent Na+ channels as a molecular target for presynaptic general anesthetic effects.
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Ghovanloo, Mohammad-Reza, Noah Gregory Shuart, Janette Mezeyova, Richard A. Dean, Peter C. Ruben, and Samuel J. Goodchild. "Inhibitory effects of cannabidiol on voltage-dependent sodium currents." Journal of Biological Chemistry 293, no. 43 (September 14, 2018): 16546–58. http://dx.doi.org/10.1074/jbc.ra118.004929.
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Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1–1.7 currents, with an IC50 of 1.9–3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD's mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.
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Eaton, Douglas C., Andrea Becchetti, Heping Ma, and Brian N. Ling. "Renal sodium channels: Regulation and single channel properties." Kidney International 48, no. 4 (October 1995): 941–49. http://dx.doi.org/10.1038/ki.1995.375.
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Perez-Pinzon, M. A., M. Rosenthal, T. J. Sick, P. L. Lutz, J. Pablo, and D. Mash. "Downregulation of sodium channels during anoxia: a putative survival strategy of turtle brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 262, no. 4 (April 1, 1992): R712—R715. http://dx.doi.org/10.1152/ajpregu.1992.262.4.r712.
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In contrast to mammalian brain, which exhibits rapid degeneration during anoxia, the brains of certain species of turtles show an extraordinary capacity to survive prolonged anoxia. The decrease in energy expenditure shown by the anoxic turtle brain is likely to be a key factor for anoxic survival. The "channel arrest" hypothesis proposes that ion channels, which regulate brain electrical activity in normoxia, may be altered during anoxia in the turtle brain as a mechanism to spare energy. Goals of present research were to test this hypothesis and to determine whether down-regulation of sodium channels is a possible explanation for spike threshold shifts seen during anoxia in isolated turtle cerebellum. We report here that anoxia induced a significant (42%) decline in voltage-gated sodium channel density as determined by studies of the binding of a sodium channel ligand, [3H]brevetoxin. This study demonstrates that sodium channel densities in brain may be regulated by tissue oxygenation or by physiological events associated with anoxia. Moreover, it also suggests that downregulation of sodium channels may be a basis for changes in action potential thresholds, the electrical depression and energy conservation that provide the unique anoxic tolerance of turtle brain.
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Ahern, Christopher A., Jian Payandeh, Frank Bosmans, and Baron Chanda. "The hitchhiker’s guide to the voltage-gated sodium channel galaxy." Journal of General Physiology 147, no. 1 (December 28, 2015): 1–24. http://dx.doi.org/10.1085/jgp.201511492.
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Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure–function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na+ selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts.
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JEZIORSKI, M. C., R. M. GREENBERG, and P. A. V. ANDERSON. "Cloning of a putative voltage-gated sodium channel from the turbellarian flatworm Bdelloura candida." Parasitology 115, no. 3 (September 1997): 289–96. http://dx.doi.org/10.1017/s0031182097001388.
Full textAbstract:
The neuromuscular sodium currents of early invertebrates such as platyhelminths display distinctive kinetic and pharmacological properties. We have cloned a cDNA from the horseshoe crab flatworm Bdelloura candida that encodes a protein homologous to the primary subunit of voltage-gated sodium channels. The B. candida protein, named BdNa1, exhibits amino acid identity of 40–47% to sodium channels of vertebrates and higher invertebrates. BdNa1 has the multidomain structure characteristic of sodium channels, and is most highly conserved in the hydrophobic transmembrane segments and the regions that form the pore of the channel. Northern blot analysis confirms the presence of a 5·4 kb BdNa1 transcript in B. candida tissue. The information provided by analysis of the BdNa1 sequence offers insight into the physiology of platyhelminth sodium currents.
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Negulyaev, Y. A., E. A. Vedernikova, and A. V. Maximov. "Disruption of actin filaments increases the activity of sodium-conducting channels in human myeloid leukemia cells." Molecular Biology of the Cell 7, no. 12 (December 1996): 1857–64. http://dx.doi.org/10.1091/mbc.7.12.1857.
Full textAbstract:
With the use of the patch clamp technique, the role of cytoskeleton in the regulation of ion channels in plasma membrane of leukemic K562 cells was examined. Single-channel measurements have indicated that disruption of actin filaments with cytochalasin D (CD) resulted in a considerable increase of the activity of non-voltage-gated sodium-permeable channels of 12 pS unitary conductance. Background activity of these channels was low; open probability (po) did not exceed 0.01-0.02. After CD, po grew at least 10-20 times. Cell-attached and whole-cell recordings showed that activation of sodium channels was elicited within 1-3 min after the addition of 10-20 micrograms/ml CD to the bath extracellular solution or in the presence of 5 micrograms/ml CD in the intracellular pipette solution. Preincubation of K562 cells with CD during 1 h also increased drastically the activity of 12 pS sodium channels. Whole-cell measurements confirmed that CD-activated channels were permeable to monovalent cations (preferentially to Na+ and Li+), but not to bivalent cations (Ca2+, Ba2+). Colchicine (1 microM), which affect microtubules, did not alter background channel activity. Our data indicate that actin filaments organization plays an important role in the regulation of sodium-permeable channels which may participate in providing passive Na+ influx in red blood cells.
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Patlak, J. B., and M. Ortiz. "Slow currents through single sodium channels of the adult rat heart." Journal of General Physiology 86, no. 1 (July 1, 1985): 89–104. http://dx.doi.org/10.1085/jgp.86.1.89.
Full textAbstract:
The currents through single Na+ channels from the sarcolemma of ventricular cells dissociated from adult rat hearts were studied using the patch-clamp technique. All patches had several Na+ channels; most had 5-10, while some had up to 50 channels. At 10 degrees C, the conductance of the channel was 9.8 pS. The mean current for sets of many identical pulses inactivated exponentially with a time constant of 1.7 +/- 0.6 ms at -40 mV. Careful examination of the mean currents revealed a small, slow component of inactivation at pulse potentials ranging from -60 to -30 mV. The time constant of the slow component was between 8 and 14 ms. The channels that caused the slow component had the same conductance and reversal potential as the fast Na+ currents and were blocked by tetrodotoxin. The slow currents appear to have been caused by repeated openings of one or more channels. The holding potential influenced the frequency with which such channel reopening occurred. The slow component was prominent during pulses from a holding potential of -100 mV, while it was very small during pulses from -140 mV. Ultraslow currents through the Na+ channel were observed occasionally in patches that had large numbers of channels. They consisted of bursts of 10 or more sequential openings of a single channel and lasted for up to 150 ms. We conclude that the single channel data cannot be explained by standard models, even those that have two inactivated states or two open states of the channel. Our results suggest that Na+ channels can function in several different "modes," each with a different inactivation rate.
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Behrens, M. I., A. Oberhauser, F. Bezanilla, and R. Latorre. "Batrachotoxin-modified sodium channels from squid optic nerve in planar bilayers. Ion conduction and gating properties." Journal of General Physiology 93, no. 1 (January 1, 1989): 23–41. http://dx.doi.org/10.1085/jgp.93.1.23.
Full textAbstract:
Squid optic nerve sodium channels were characterized in planar bilayers in the presence of batrachotoxin (BTX). The channel exhibits a conductance of 20 pS in symmetrical 200 mM NaCl and behaves as a sodium electrode. The single-channel conductance saturates with increasing the concentration of sodium and the channel conductance vs. sodium concentration relation is well described by a simple rectangular hyperbola. The apparent dissociation constant of the channel for sodium is 11 mM and the maximal conductance is 23 pS. The selectivity determined from reversal potentials obtained in mixed ionic conditions is Na+ approximately Li+ greater than K+ greater than Rb+ greater than Cs+. Calcium blocks the channel in a voltage-dependent manner. Analysis of single-channel membranes showed that the probability of being open (Po) vs. voltage relation is sigmoidal with a value of 0.5 between -90 and -100 mV. The fitting of Po requires at least two closed and one open state. The apparent gating charge required to move through the whole transmembrane voltage during the closed-open transition is four to five electronic charges per channel. Distribution of open and closed times are well described by single exponentials in most of the voltage range tested and mean open and mean closed times are voltage dependent. The number of charges associated with channel closing is 1.6 electronic charges per channel. Tetrodotoxin blocked the BTX-modified channel being the blockade favored by negative voltages. The apparent dissociation constant at zero potential is 16 nM. We concluded that sodium channels from the squid optic nerve are similar to other BTX-modified channels reconstituted in bilayers and to the BTX-modified sodium channel detected in the squid giant axon.