Na+ channels must deactivate to recover from inactivation

Kuo, Chung‐Chin; Bean, Bruce P.

doi:10.1016/0896-6273(94)90335-2

Cited by 279 publications

(397 citation statements)

References 34 publications

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“…This view is supported by the fact that R1448C has a much greater effect, at -20 mV, on inactivation from an open state than from closed states (Chahine et al, 1994). Our data also suggest that D4/$3 could be partly responsible for the fact that sodium channels tend not to open while they recover from inactivation (Kuo and Bean, 1994), but rather recover directly into closed states. This is consistent with a "first in, last out" principle.…”

Section: D4/$3 and D4/$4 Effects On Inactivation Segregate With Voltagesupporting

confidence: 73%

“…7 and 8). It has been suggested that the delay in recovery is a consequence of the fact that deactivation (i.e., closing of activation gates) must precede recovery (Kuo and Bean, 1994). A similar delay precedes the onset of inactivation, and also may be due to the coupling of inactivation to activation .…”

Section: Relationship Between Deactivation and Recovery From Inactivamentioning

confidence: 99%

“…One mechanism that might contribute to the observation that the double mutation resembles L1433R rather than R1448C in recovery from inactivation and steady state inactivation would be that D4/$3 plays a critical role in the deactivation of the channel and this must precede the recovery process (Patlak, 1991;Kuo and Bean, 1994). If we hypothesize that sodium channels must deactivate before recovery (Kuo and Bean, 1994), mutations in the D4/$3 could influence the rate of recovery by altering the kinetics of deactivation.…”

Section: Effects Of L1433r R1448c and Double Mutation On Deactivationmentioning

confidence: 99%

“…If we hypothesize that sodium channels must deactivate before recovery (Kuo and Bean, 1994), mutations in the D4/$3 could influence the rate of recovery by altering the kinetics of deactivation. If this were true, deactivation would be more affected by the L1433R and double mutations than by the R1448C mutation.…”

Section: Effects Of L1433r R1448c and Double Mutation On Deactivationmentioning

confidence: 99%

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Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

George

Horn

et al. 1996

The Journal of General Physiology

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Mutations in the gene encoding the voltage-gated sodium channel of skeletal muscle (SkM1) have been identified in a group of autosomal dominant diseases, characterized by abnormalities of the sarcolemmal excitability, that include paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HYPP). We previously reported that PC mutations cause in common a slowing of inactivation in the human SkM1 sodium channel. In this investigation, we examined the molecular mechanisms responsible for the effects of L1433R, located in D4/$3, on channel gating by creating a series of additional mutations at the 1433 site. Unlike the R1448C mutation, found in D4/$4, which produces its effects largely due to the loss of the positive charge, change of the hydropathy of the side chain rather than charge is the primary factor mediating the effects of L1433R. These two mutations also differ in their effects on recovery from inactivation, conditioned inactivation, and steady state inactivation of the hSkM1 channels. We constructed a double mutation containing both L1433R and R1448C. The double mutation closely resembled R1448C with respect to alterations in the kinetics of inactivation during depolarization and voltage dependence, but was indistinguishable from L1433R in the kinetics of recovery from inactivation and steady state inactivation. No additive effects were seen, suggesting that these two segments interact during gating. In addition, we found that these mutations have different effects on the delay of recovery from inactivation and the kinetics of the tail currents, raising a question whether this delay is a reflection of the deactivation process. These results suggest that the $3 and $4 segments play distinct roles in different processes of hSkM1 channel gating: D4/$4 is critical for the deactivation and inactivation of the open channel while D4/$3 has a dominant role in the recovery of inactivated channels. However, these two segments interact during the entry to, and exit from, inactivation states.

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Section: D4/$3 and D4/$4 Effects On Inactivation Segregate With Voltagesupporting

confidence: 73%

Section: Relationship Between Deactivation and Recovery From Inactivamentioning

confidence: 99%

Section: Effects Of L1433r R1448c and Double Mutation On Deactivationmentioning

confidence: 99%

Section: Effects Of L1433r R1448c and Double Mutation On Deactivationmentioning

confidence: 99%

See 2 more Smart Citations

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

George

Horn

et al. 1996

The Journal of General Physiology

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“…Thus, a 10 mV hyperpolarization produced an approximately sixfold increase in conductance. This increase is likely to result in part from the greater maximal availability at more negative potentials and in part from the increase of recovery rate with hyperpolarization (Hodgkin and Huxley, 1952;Kuo and Bean, 1994).…”

Section: Ttx-sensitive Sodium Currentsmentioning

confidence: 99%

Ionic Currents and Spontaneous Firing in Neurons Isolated from the Cerebellar Nuclei

2000

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Neurons of the cerebellar nuclei fire spontaneous action potentials both in vitro, with synaptic transmission blocked, and in vivo, in resting animals, despite ongoing inhibition from spontaneously active Purkinje neurons. We have studied the intrinsic currents of cerebellar nuclear neurons isolated from the mouse, with an interest in understanding how these currents generate spontaneous activity in the absence of synaptic input as well as how they allow firing to continue during basal levels of inhibition. Current-clamped isolated neurons fired regularly (ϳ20 Hz), with shallow interspike hyperpolarizations (approximately Ϫ60 mV), much like neurons in more intact preparations. The spontaneous firing frequency lay in the middle of the dynamic range of the neurons and could be modulated up or down with small current injections.During step or action potential waveform voltage-clamp commands, the primary current active at interspike potentials was a tetrodotoxin-insensitive (TTX), cesium-insensitive, voltageindependent, cationic flux carried mainly by sodium ions. Although small, this cation current could depolarize neurons above threshold voltages. Voltage-and current-clamp recordings suggested a high level of inactivation of the TTX-sensitive transient sodium currents that supported action potentials. Blocking calcium currents terminated firing by preventing repolarization to normal interspike potentials, suggesting a significant role for K(Ca) currents. Potassium currents that flowed during action potential waveform voltage commands had high activation thresholds and were sensitive to 1 mM TEA. We propose that, after the decay of high-threshold potassium currents, the tonic cation current contributes strongly to the depolarization of neurons above threshold, thus maintaining the cycle of firing.

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Sodium Channels

Lampert

Stühmer

Waxman

2015

Encyclopedia of Life Sciences

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Excitable cells, such as neurons or cardiomyocytes, communicate with each other via action potentials. This fast change in membrane voltage is initiated by the rapid opening of voltage‐gated sodium selective channels, of which to date nine subtypes are known (Nav1.1–Nav1.9). These large membrane spanning proteins undergo gating changes on a timescale ranging from milliseconds to minutes. Depolarization past threshold leads to activation and sodium ions flow into the cell. Within milliseconds the inactivation particle blocks the pore, current flow is interrupted and the channel is fast inactivated. Channels need to recover from fast inactivation at negative potentials to be able to reopen anew. Recent data on crystal structures shape our 3D picture of sodium channels and mutagenesis studies help understanding their structure–function relation. Sodium channels are major regulators of membrane excitability and play an important role in pain, arrhythmias and muscle diseases, and subtype‐specific blockers have been currently developed. Key Concepts The fast upstroke of the action potential (AP) is initiated by the opening of voltage‐gated sodium channels (Navs). Navs are large transmembrane proteins consisting of four homologous domains (DI–DIV). Each domain consists of six transmembrane segments S1–S6, which form a voltage sensor (S1–S4) and parts of the pore module (S5–S6). The domains are connected by intracellular linkers. The DIII–DIV linker contains the inactivation particle. Upon depolarization, Navs open quickly, sodium ions flow into the cell, and within milliseconds, fast inactivation occurs. Slow inactivation happens on a much slower timescale (seconds to minutes) and involves other parts of the channel protein. Recently, crystal structures of bacterial sodium channels have helped explicate the changes in 3D structure that accompany gating. Navs are involved in the generation of pain, arrhythmias and myopathies (among others).

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Na+ channels must deactivate to recover from inactivation

Cited by 279 publications

References 34 publications

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

Ionic Currents and Spontaneous Firing in Neurons Isolated from the Cerebellar Nuclei

Sodium Channels

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