Sodium channelopathies of skeletal muscle result from gain or loss of function

Abstract

Five hereditary sodium channelopathies of skeletal muscle have been identified. Prominent symptoms are either myotonia or weakness caused by an increase or decrease of muscle fiber excitability. The voltage-gated sodium channel NaV1.4, initiator of the muscle action potential, is mutated in all five disorders. Pathogenetically, both loss and gain of function mutations have been described, the latter being the more frequent mechanism and involving not just the ion-conducting pore, but aberrant pores as well. The type of channel malfunction is decisive for therapy which consists either of exerting a direct effect on the sodium channel, i.e., by blocking the pore, or of restoring skeletal muscle membrane potential to reduce the fraction of inactivated channels.

Domain III S4 in closed-state fast inactivation: Insights from a periodic paralysis mutation

“…2 However, these and other gating defects do not completely explain the phenotype of reduced membrane excitability in response to a drop in serum potassium. The majority of hypokalemic periodic paralysis mutations discovered to date in sodium or calcium channels involve reduction of charge in the voltage sensing S4 segments.…”

“…1,2 In sodium channels, charge-reducing mutations of the outer S4 arginines R1 or R2 in domains I to III produce an inwardly rectifying proton or cation current observed with hyperpolarization of membrane potential as experienced with a drop in serum potassium. [3][4][5][6] Present models of hypokalemic periodic paralysis incorporate this leak or "omega" current as a contributing factor in the pathogenesis of the disorder (for a review see refs).…”

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

“…2B and Table 1) by ranolazine of both WT and R1448 mutant channels was observed when the HP was changed to -90 mV, which is close to the resting membrane potential of a normal muscle fiber. 23,25 Interestingly, when the HP of HEK293 cells was changed to -70 mV to mimic the resting membrane potential of an injured skeletal muscle fiber, 23 the potency of ranolazine increased further (IC 50 of 0.94-6.3 μM, Table 1). In summary, the UDB of peak I Na by ranolazine increased with the stimulating frequency (10 to 30 Hz) and with depolarization of the resting membrane potential (from -140 mV to -90 mV at 10 Hz).…”

A hot topic

“…With intensive cooling, the myotonia can give way to periodic paralysis of the muscles. 24,31 PMC is caused by mutations in the skeletal muscle sodium channel isoform Na V 1.4. Most PMC mutations impair channel inactivation, leading to persistent I Na and subsequent reduction of membrane excitability responsible for the periodic paralysis phenotype, while others increase membrane excitability resulting in muscle stiffness.…”

“…Most PMC mutations impair channel inactivation, leading to persistent I Na and subsequent reduction of membrane excitability responsible for the periodic paralysis phenotype, while others increase membrane excitability resulting in muscle stiffness. 26,31,32 This may seem counterintuitive, but a gradient exists between severity of inactivation impairment and resulting phenotype. Minor impairments to fast inactivation (between 8-20% non-inactivating channel population) result in a late I Na that depolarizes the membrane just enough to bring it closer to action potential threshold, thus increasing the probability of action potential firing and muscle stiffness.…”