| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Neurodegenerative Disease Center, Department of Neurology
2 Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 28 May 2004;
accepted after revision 9 July 2004;
first published online 14 July 2004)
Corresponding author M. M. Rich: Neurodegenerative Disease Center, Department of Neurology, Emory University School of Medicine, 5th Floor Whitehead Building, Atlanta, GA 30322, USA. Email: mmrich{at}emory.edu
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Innervated adult skeletal muscle expresses only the Nav1.4 sodium channel isoform (Yang et al. 1991; Rich et al. 1999). In SD muscle, however, RNA for a second sodium channel isoform (Nav1.5) is expressed at high levels, suggesting Nav1.5 protein may be abundant (Rich et al. 1999). In vitro, heterologously expressed Nav1.5 channels gate at more negative potentials than Nav1.4 channels so the presence of Nav1.5 could shift the voltage dependence of sodium current in SD muscle (Wang et al. 1996; Zhang et al. 1999). Thus, one explanation for the shift in the voltage dependence of sodium channel inactivation in SD muscle is the presence of high levels of Nav1.5. However, a study of sodium channel gating in denervated muscle found that although Nav1.5 contributed less than 30% of total sodium conductance, there was a 10 mV shift of sodium channel activation and inactivation towards more hyperpolarized potentials (Pappone, 1980). This raises the possibility that the voltage dependence of Nav1.4 gating is altered following denervation. Since the animal model of critical illness myopathy that we use involves denervation of skeletal muscle, we also considered a second possibility: that altered Nav1.4 gating contributes to the hyperpolarized shift in sodium channel inactivation in SD muscle.
To determine whether expression of Nav1.5 causes the shift in gating of sodium current in SD muscle we selectively blocked Nav1.4 with tetrodotoxin (TTX) and µ-conotoxin GIIIB. We found that hyperpolarized shifts in the voltage dependence of sodium current gating did not correlate closely with the amount of Nav1.5 present. Instead, in more severely affected fibres, there was a hyperpolarized shift in the voltage dependence of fast inactivation of both Nav1.4 and Nav1.5. Our data suggest that modulation of the voltage dependence of inactivation of the Nav1.4 and Nav1.5 sodium channel isoforms plays an important role in loss of muscle fibre excitability in the animal model of critical illness myopathy.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Denervation, treatment of rats and viewing of muscle fibres were done as previously described (Rich et al. 1998; Rich & Pinter, 2001). Briefly, rat muscle was denervated by removing a 10-mm segment of the left sciatic nerve in anaesthetized (ketamine, 5 mg kg–1, and zylaxine, 15 mg kg–1, administered intraperitoneally) adult female Wistar rats (250–350 g body weight). Dexamethasone (5 mg kg–1) was injected daily intraperitoneally beginning on the day of denervation and continuing for 7–11 days. Rats were killed by carbon dioxide inhalation, the extensor digitorum longus (EDL) was dissected tendon to tendon and muscle fibres were labelled with 10 µM 4-(4-diethylaminostyrl)-N-methylpyridinium iodide (4-Di-2-ASP) and visualized using an upright epifluorescence microscope. For all experiments the recording chamber was continuously perfused with solution containing (mM): NaCl, 118; KCl, 3.5; CaCl2,1.5; MgSO4, 0.7; NaHCO3, 26.2; NaH2PO4, 1.7; glucose, 10.8 (pH 7.3–7.4, 20–22°C) equilibrated with 95% O2 and 5% CO2. All animal protocols were performed in accordance with Emory University IACUC guidelines.
Loose patch voltage clamp
Loose patch voltage recording and analysis was performed as previously described (Rich & Pinter, 2001, 2003). Briefly, patch electrodes were made from soft glass (catalogue no. 22-358739, Fisher Scientific) using a horizontal pipette puller (Flaming/Brown type) and were heat polished. Patch pipettes were filled with the normal external solution (see above) containing 1 ng ml–1 sulforhodamine. The seal factor (Rs/(Rs+Rp), where Rs is the shunt resistance and Rp is the patch pipette resistance) was kept greater than 0.4. The leak current was compensated manually by adjusting the compensation current (Stuhmer et al. 1983). Shunt resistance was measured on-line immediately before the application of each voltage step and used to adjust the step amplitude.
Fibres were not impaled to measure the resting potential prior to seal formation. Instead the resting potential was assumed (based on an average of 5–10 fibres) during voltage protocols and then measured after patch recordings were complete. The difference between the assumed and measured resting potential was then used to correct step voltages used during data acquisition. By impaling the muscle fibre after patch recordings were complete, potential problems related to issues of muscle damage and depolarization due to impalement were avoided.
Tetrodotoxin and µ-conotoxin GIIIB application
Tetrodotoxin in citrate (TTX) was purchased from Alomone Laboratories (Jerusalem). Prior to application of TTX we measured the voltage dependence of fast inactivation in several fibres in each muscle. We then applied 300 nM TTX to the bath and used suction to fill the pipette with the same TTX solution. We then reformed seals on the same muscle fibres and measured sodium currents. Muscle fibres were re-identified using pictures we had taken during the initial recording of sodium currents (Fig. 2). To help identify fibres we stained endplates by applying 5 µg ml–1 rhodamine-conjugated bungarotoxin (Molecular Probes, Eugene OR, USA) for 30 s. Sodium currents were recorded near (within 100–200 µm), but never over muscle fibre endplates. By assuming a Kd of 1.9 µM for Nav1.5 (White et al. 1991) and 5 nM for Nav1.4 (Trimmer et al. 1989; for review see Goldin, 2001) one can estimate that 300 nM TTX blocked 97% of Nav1.4 and 23% of Nav1.5 (Lupa et al. 1995). We then solved for the percentage of Nav1.4 and Nav1.5 using the following equations:
|
|
|
|
|
Measurement of Inactivation of Nav1.4 and Nav1.5
Measures of fast inactivation were performed as previously described and all data was fitted to a Boltzmann function (Rich & Pinter, 2003). Briefly, measurement of fast inactivation was performed using a 50 ms pre-pulse to the test potential followed by a 10 ms pulse to –20 mV. For calculation of Nav1.4 inactivation, fibres were analysed in one of two ways. In SD fibres in which sodium current remaining after application of TTX or µ-conotoxin GIIIB was less than 10% of the amplitude prior to application of toxin, it was assumed that current was carried entirely by Nav1.4 since the error introduced by the presence of Nav1.5 was minimal. In fibres in which more than 10% of the sodium current remained after application of toxin, the voltage dependence of the Nav1.4 gating was calculated as follows: sodium current remaining after application of toxin (TTX currents were corrected for amplitude using the equations given above) was subtracted from the sodium current prior to toxin application at each voltage step. The current amplitudes after subtraction of current carried by Nav1.5 were then fitted with Boltzmann distributions and analysed.
Statistics and generation of modelled Boltzmann curves
All data other than linear fits were compared using Student's t test to determine statistical significance. Bonforroni correction was applied in all instances where multiple comparisons were made between treatment groups. All means are given ± the S.E.M. Fitting of the data analysing correlations between parameters was performed using linear regression analysis. All fits (linear and Boltzmann) were performed using Origin software (OriginLab Corp., Northampton, MA, USA). Boltzmann curves for simulation of Nav1.4 and Nav1.5 gating were generated, scaled and added using Origin software. For example, to generate a curve made up of 75% Nav1.4, the values from the Nav1.4 curve were multiplied by 0.75 and added to the 0.25 times the values from the Nav1.5 curve. Curves generated by mixing various percentages of Nav1.4 and Nav1.5 were then fitted with Boltzmann curves to estimate the midpoint and slope of the sodium current carried by the mix of sodium channel isoforms.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
|
Based on published data, greater than 50% of sodium current would need to be carried by Nav1.5 in order to cause a shift of fast inactivation of greater than 10 mV (Fig. 1) (Wang et al. 1996; Zhang et al. 1999). It is estimated that a dose of 300 nM TTX blocks 97% of Nav1.4 current and 23% of Nav1.5 current (Lupa et al. 1995). We found that the majority of sodium current in most fibres was blocked by a dose of 300 nM TTX. An example of a fibre in which close to 30% of the current remained after TTX application is shown in Fig. 3. The voltage dependence of fast inactivation in the fibre prior to application of TTX was –72.7 mV with a slope of 4.6. These values are similar to those obtained from control muscle which has no Nav1.5, and suggest that, in the fibre shown, having more than a third of the sodium current carried by Nav1.5 was not sufficient to induce a hyperpolarized shift in fast inactivation of the total current.
|
|
Not all SD fibres have a hyperpolarized shift in the voltage dependence of inactivation (Rich & Pinter, 2001, 2003). The reason for the variation between fibres is unknown, but it provided a way to compare the voltage dependence of inactivation of Nav1.4 to that of Nav1.5 in both mildly and severely affected fibres. We found that the voltage dependence of inactivation of Nav1.4 and Nav1.5 were shifted in parallel in more severely affected SD fibres (Fig. 5, R= 0.68, P < 0.01). This suggests that the process underlying the shift in inactivation affects both Nav1.4 and Nav1.5.
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The role of Nav1.5 expression on excitability of SD muscle
We have previously demonstrated that loss of electrical excitability in patients with critical illness myopathy can be replicated by combining denervation and corticosteroid treatment in rat muscle in vivo (steroid-denervated; SD) (Rich et al. 1998; Rich & Pinter, 2001). In this model there are a number of factors that contribute to reduced excitability of muscle. Depolarization of the resting potential following denervation is one of the most important factors since it increases inactivation of sodium channels (Rich & Pinter, 2003). However, changes in the specific membrane resistance as well as a reduction in sodium current density are also contributing factors (Rich et al. 1998). Finally, there is a 10–15 mV hyperpolarized shift in the voltage dependence of fast inactivation that appears to play a central role in loss of excitability (Rich & Pinter, 2001, 2003). The current study was aimed at determining the cause of this shift.
In normal muscle fibres, only Nav1.4 is present (Yang et al. 1991). In SD muscle, however, mRNA for both the Nav1.4 and Nav1.5 is present at high levels (Rich et al. 1999). The voltage dependence in vitro of fast inactivation of the Nav1.5 has been found to be close to 20 mV more negative than for Nav1.4 (Wang et al. 1996; Zhang et al. 1999). Thus, it seemed reasonable to expect that higher levels of Nav1.5 might underlie the hyperpolarized shift in the voltage dependence of fast inactivation in affected SD fibres. However, we found that higher levels of Nav1.5 correlated only loosely with a more hyperpolarized voltage dependence of inactivation.
Comparison of the voltage dependence of inactivation of Nav1.4 to that of Nav1.5 in vivo revealed a similar voltage dependence of inactivation. These data suggest that the voltage dependence of inactivation of Nav1.5 may be different in vivo from what has been reported in vitro. One explanation for the difference is that most studies of the voltage dependence of Nav1.5 have used traditional gigaseal patch recording whereas we are using loose patch. It has been found that gigaseal patch recording shifts the voltage dependence of Nav1.5 in isolated cardiac myocytes by close to –20 mV whereas loose patch does not (Eickhorn et al. 1994). If Nav1.5 activates and inactivates at similar potentials to Nav1.4, its re-expression in denervated and SD muscle might be expected to have little effect on excitability. However, Nav1.5 has been found to be less susceptible to slow inactivation (Richmond et al. 1998; Vilin et al. 2001). Since both denervated and SD muscle fibres have relatively depolarized resting potentials, the resistance of Nav1.5 to slow inactivation may serve to increase excitability.
The finding that the voltage dependence of inactivation of Nav1.5 can be modified in a model of critical illness myopathy raises the question as to whether patients with critical illness myopathy may have cardiac problems caused by increased inactivation of Nav1.5. We previously found that severe sepsis can cause critical illness myopathy (Rich et al. 1997; Bird & Rich, 2002) as well as abnormalities on ECG that are consistent with a reduction in cardiac sodium current (Rich et al. 2002). Such a reduction in cardiac sodium current may contribute to the decrease in cardiac contractility that is found in sepsis (Parker et al. 1984; Ognibene et al. 1988). It is thus possible that an alteration in the voltage dependence of inactivation of Nav1.5 contributes to cardiac dysfunction in septic patients.
Possible factors modulating voltage dependence of inactivation of Nav1.4 and Nav1.5
There is evidence suggesting that gating of Nav1.4 is modulated in vivo from work studying the voltage dependence of sodium channel gating in different fibre types. It has been found that slow twitch fibres have a more positive voltage dependence of inactivation (Ruff & Whittlesey, 1993; Ruff, 1996). Since Nav1.4 is the only sodium channel present in adult muscle (Yang et al. 1991; Rich et al. 1999), this suggests that gating of Nav1.4 is different in fast and slow fibres. We used the extensor digitorum longus muscle in which the vast majority of fibres are fast twitch (Ruff et al. 1982). Thus, in our study the shift we see in fast inactivation is occurring in fibres that had a fast phenotype prior to denervation and steroid treatment.
A number of secondary modifications have been found to modulate sodium channel function in vitro. Phosphorylation by PKA and PKC has been shown to reduce peak sodium conductance (Cantrell & Catterall, 2001) through a process that is similar to slow inactivation (Carr et al. 2003). However, in general, phosphorylation does not cause major changes in the voltage dependence of fast inactivation (Cantrell & Catterall, 2001). Glycosylation shifts the voltage dependence of fast inactivation of both Nav1.4 and Nav1.5 toward hyperpolarized potentials through what appears to be a surface charge mechanism (Bennett et al. 1997; Zhang et al. 1999). However, the shift in the voltage dependence of fast inactivation caused by glycosylation appears modest. Nitric oxide has also been found to inhibit neuronal sodium currents through hyperpolarized shifts in both fast and slow inactivation (Li et al. 1998; Bielefeldt et al. 1999). It is not known whether nitric oxide can affect gating of Nav1.4 or Nav1.5. It has recently been found that calcium-dependent binding of calmodulin enhances slow inactivation of Nav1.5 sodium channels (Tan et al. 2002). Calmodulin binds Nav1.4 in a calcium-independent manner, but appears to have little effect on the voltage dependence of activation and fast inactivation (Herzog et al. 2003; see, however, Deschenes et al. 2002). Further studies in SD muscle will be necessary to determine whether any of these mechanisms are involved in the altered voltage dependence of Nav1.4 and Nav1.5 inactivation in this disorder.
Our work suggests that a hyperpolarized shift in the voltage dependence of inactivation of Nav1.4 and Nav1.5 contribute to muscle fibre inexcitability in the animal model of critical illness myopathy. Other situations in which abnormal regulation of excitability occurs in the setting of genetically normal sodium channels include neuropathic pain and neuronal response to demyelination (Waxman et al. 2000; Lai et al. 2003). However, in these situations it appears that regulation of sodium channel isoform expression may be the most important change. It thus appears that loss of muscle fibre excitability in critical illness myopathy represents a new kind of ion channel disease in which the defect is caused by neither a mutation in the channel nor a change in isoform expression.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Bielefeldt K, Whiteis CA, Chapleau MW & Abboud FM (1999). Nitric oxide enhances slow inactivation of voltage-dependent sodium currents in rat nodose neurons. Neurosci Lett 271, 159–162.[CrossRef][Medline]
Bird SJ & Rich MM (2002). Critical illness myopathy and polyneuropathy. Curr Neurol Neurosci Rep 2, 527–533.[Medline]
Cantrell AR & Catterall WA (2001). Neuromodulation of Na+ channels: an unexpected form of cellular plasticity. Nat Rev Neurosci 2, 397–407.[Medline]
Carr DB, Day M, Cantrell AR, Held J, Scheuer T, Catterall WA & Surmeier DJ (2003). Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity. Neuron 39, 793–806.[CrossRef][Medline]
Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D & Moczydlowski E (1985). Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J Biol Chem 260, 9280–9288.
Deschenes I, Neyroud N, D, Marban E, Yue DT & Tomaselli GF (2002). Isoform-specific modulation of voltage-gated Na+ channels by calmodulin. Circ Res 90, E49–E57.1161/01.RES.0000012502.92751.E6
Eickhorn R, Dragert C & Antoni H (1994). Influence of cell isolation and recording technique on the voltage dependence of the fast cardiac sodium current of the rat. J Mol Cell Cardiol 26, 1095–1108.1006/jmcc.1994.1129[CrossRef][Medline]
Goldin AL (2001). Resurgence of sodium channel research. Annu Rev Physiol 63, 871–894.1146/annurev.physiol.63.1.871[CrossRef][Medline]
Herzog RI, Liu C, Waxman SG & Cummins TR (2003). Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties. J Neurosci 23, 8261–8270.
Lai J, Hunter JC & Porreca F (2003). The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol 13, 291–297.1016/S0959-4388(03)00074-6[CrossRef][Medline]
Li Z, Chapleau MW, Bates JN, Bielefeldt K, Lee HC & Abboud FM (1998). Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons. Neuron 20, 1039–1049.1016/S0896-6273(00)80484-5[CrossRef][Medline]
Li RA, Ennis IL, Xue T, Nguyen HM, Tomaselli GF, Goldin AL & Marban E (2003). Molecular basis of isoform-specific micro-conotoxin block of cardiac, skeletal muscle, and brain Na+ channels. J Biol Chem 278, 8717–8724.1074/jbc.M210882200
Lupa MT, Krzemien DM, Schaller KL & Caldwell JH (1995). Expression and distribution of sodium channels in short- and long-term denervated rodent skeletal muscles. J Physiol 483, 109–118.
Ognibene FP, Parker MM, Natanson C, Shelhamer JH & Parrillo JE (1988). Depressed left ventricular performance. Response to volume infusion in patients with sepsis and septic shock. Chest 93, 903–910.
Pappone PA (1980). Voltage-clamp experiments in normal and denervated mammalian skeletal muscle fibres. J Physiol 306, 377–410.
Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA & Parrillo JE (1984). Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100, 483–490.[Medline]
Rich MM, Bird SJ, Raps EC, McCluskey LF & Teener JW (1997). Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 20, 665–673.1002/(SICI)1097-4598(199706)20:6\|[amp ]\|#60;665::AID-MUS2\|[gt ]\|3.3.CO;2-3[CrossRef][Medline]
Rich MM, Kraner SD & Barchi RL (1999). Altered gene expression in steroid-treated denervated muscle. Neurobiol Dis 6, 515–522.1006/nbdi.1999.0257[CrossRef][Medline]
Rich MM, McGarvey ML, Teener JW & Frame LH (2002). ECG changes during septic shock. Cardiology 97, 187–196.[Medline]
Rich MM & Pinter MJ (2001). Sodium channel inactivation in an animal model of acute quadriplegic myopathy. Ann Neurol 50, 26–33.1002/ana.1016[CrossRef][Medline]
Rich MM & Pinter MJ (2003). Crucial role of sodium channel fast inactivation in muscle fibre inexcitability in a rat model of critical illness myopathy. J Physiol 547, 555–566.1113/jphysiol.2002.035188
Rich MM, Pinter MJ, Kraner SD & Barchi RL (1998). Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol 43, 171–179.[CrossRef][Medline]
Rich MM, Teener JW, Raps EC, Schotland DL & Bird SJ (1996). Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 46, 731–736.
Richmond JE, Featherstone DE, Hartmann HA & Ruben PC (1998). Slow inactivation in human cardiac sodium channels. Biophys J 74, 2945–2952.
Ruff RL (1996). Sodium channel slow inactivation and the distribution of sodium channels on skeletal muscle fibres enable the performance properties of different skeletal muscle fibre types. Acta Physiol Scand 156, 159–168.1046/j.1365-201X.1996.189000.x[CrossRef][Medline]
Ruff RL, Martyn D & Gordon AM (1982). Glucocorticoid-induced atrophy is not due to impaired excitability of rat muscle. Am J Physiol 243, E512–E521.[Medline]
Ruff RL & Whittlesey D (1993). Na+ currents near and away from endplates on human fast and slow twitch muscle fibers. Muscle Nerve 16, 922–929.[CrossRef][Medline]
Stuhmer W, Roberts WM & Almers W (1983). The loose-patch clamp. In Single Channel Recording, ed. Sakmann B & Neher E. Plenum Press, pp. 123–132, New York.
Tan HL, Kupershmidt S, Zhang R, Stepanovic S, Roden DM, Wilde AA, Anderson ME & Balser JR (2002). A calcium sensor in the sodium channel modulates cardiac excitability. Nature 415, 442–447.1038/415442a[CrossRef][Medline]
Trimmer JS, Cooperman SS, Tomiko SA, Zhou JY, Crean SM, Boyle MB, Kallen RG, Sheng ZH, Barchi RL, Sigworth FJ, et al. (1989). Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron 3, 33–49.[CrossRef][Medline]
Vilin YY, Fujimoto E & Ruben PC (2001). A single residue differentiates between human cardiac and skeletal muscle Na+ channel slow inactivation. Biophys J 80, 2221–2230.
Wang DW, George AL Jr & Bennett PB (1996). Comparison of heterologously expressed human cardiac and skeletal muscle sodium channels. Biophys J 70, 238–245.
Waxman SG, Dib-Hajj S, Cummins TR & Black JA (2000). Sodium channels and their genes: dynamic expression in the normal nervous system, dysregulation in disease states (1). Brain Res 886, 5–14.1016/S0006-8993(00)02774-8[CrossRef][Medline]
White MM, Chen LQ, Kleinfield R, Kallen RG & Barchi RL (1991). SkM2, a Na+ channel cDNA clone from denervated skeletal muscle, encodes a tetrodotoxin-insensitive Na+ channel. Mol Pharmacol 39, 604–608.[Abstract]
Yang JS, Sladky JT, Kallen RG & Barchi RL (1991). TTX-sensitive and TTX-insensitive sodium channel mRNA transcripts are independently regulated in adult skeletal muscle after denervation. Neuron 7, 421–427.1016/0896-6273(91)90294-A[CrossRef][Medline]
Zhang Y, Hartmann HA & Satin J (1999). Glycosylation influences voltage-dependent gating of cardiac and skeletal muscle sodium channels. J Membr Biol 171, 195–207.1007/s002329900571[CrossRef][Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  E. Zebedin, M. Mille, M. Speiser, T. Zarrabi, W. Sandtner, B. Latzenhofer, H. Todt, and K. Hilber C2C12 skeletal muscle cells adopt cardiac-like sodium current properties in a cardiac cell environment Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H439 - H450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J-P Lefaucheur, T Nordine, P Rodriguez, and L Brochard Origin of ICU acquired paresis determined by direct muscle stimulation J. Neurol. Neurosurg. Psychiatry, April 1, 2006; 77(4): 500 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Filatov, M. J. Pinter, and M. M. Rich Resting Potential-dependent Regulation of the Voltage Sensitivity of Sodium Channel Gating in Rat Skeletal Muscle In Vivo J. Gen. Physiol., July 25, 2005; 126(2): 161 - 172. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
, data from fibres treated with µ-conotoxin GIIIB; 
, data from fibres treated with TTX.
