Key result
The L689I mutation in NaV1.4 removes an intermediate component of slow inactivation (~10 s) and impedes immobilization of DI and DII sensors over the same time domain.
The L689I mutation in NaV1.4 channels disrupts slow inactivation by impeding the immobilization of DI and DII voltage sensors, providing a mechanistic link for hyperkalemic periodic paralysis.
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Highlights NaV1.4 gating defects in paralysis models; leaves open in vivo validation and therapeutic translation.
In skeletal muscle, slow inactivation (SI) of Na(V)1.4 voltage-gated sodium channels prevents spontaneous depolarization and fatigue. Inherited mutations in Na(V)1.4 that impair SI disrupt activity-induced regulation of channel availability and predispose patients to hyperkalemic periodic paralysis. In our companion paper in this issue (Silva and Goldstein. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210909), the four voltage sensors in Na(V)1.4 responsible for activation of channels over microseconds are shown to slowly immobilize over 1-160 s as SI develops and to regain mobility on recovery from SI. Individual sensor movements assessed via attached fluorescent probes are nonidentical in their voltage dependence, time course, and magnitude: DI and DII track SI onset, and DIII appears to reflect SI recovery. A causal link was inferred by tetrodotoxin (TTX) suppression of both SI onset and immobilization of DI and DII sensors. Here, the association of slow sensor immobilization and SI is verified by study of Na(V)1.4 channels with a hyperkalemic periodic paralysis mutation; L689I produces complex changes in SI, and these are found to manifest directly in altered sensor movements. L689I removes a component of SI with an intermediate time constant (~10 s); the mutation also impedes immobilization of the DI and DII sensors over the same time domain in support of direct mechanistic linkage. A model that recapitulates SI attributes responsibility for intermediate SI to DI and DII (10 s) and a slow component to DIII (100 s), which accounts for residual SI, not impeded by L689I or TTX.
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Silva et al. (2013) studied Hyperkalemic periodic paralysis. L689I mutation in NaV1.4 was evaluated on Slow inactivation and voltage-sensor immobilization. The L689I mutation in NaV1.4 removes an intermediate component of slow inactivation (~10 s) and impedes immobilization of DI and DII sensors over the same time domain.
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