Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

Abstract

The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672→His and →Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel α subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672→Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel α subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

“…Although these data do not rule out contributions of VSDI-III or other regions to macroscopic fast or slow inactivation (19,(37)(38)(39), they do suggest a prominent role for VSDIV in slow inactivation, especially because this process can be promoted (ICA) or inhibited (Hm1a) through pharmacologic agents that target this particular voltage sensor domain. Notably, the concept that slow inactivation is tied to a VSDIV transition subsequent to activation supports previous models proposing that Na v channel voltage sensor immobilization and slow inactivation are coupled (1,(15)(16)(17)(18)36).…”

Non-Equilibrium Gating in Cardiac Na + Channels

“…Nonetheless, the combination of theoretical prediction and experimental verification has led to the identification of a novel mechanism through which altered Na ϩ channel activity can account for prolonged QT intervals in mutation carriers. Although the waveform of the cardiac action potential and the electrical properties that define its plateau phase are unique, this integrative approach is applicable to understanding the molecular basis of other congenital diseases, such as myotonia and epilepsy, in which subtle changes in Na ϩ channel gating may increase the contribution of channel reopenings to myotonic discharge (myotonias) [25][26][27][28] or bursts of neural activity (epilepsy and seizure disorders). 5,29 …”

Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

“…Point mutations in CACNA1S or SCN4A, which encode the skeletal muscle voltage-gated calcium and sodium channels, associate with HypoPP. [1][2][3][4][5][6][7][8][9][10] However, in most studies at least 20% of cases remain genetically undefined. 8,11,12 Sodium and calcium channels have homologous pore-forming ␣ subunits, each containing four domains containing six transmembrane segments.…”