Voltage-Dependent Ca²⁺ Release Is Impaired in Hypokalemic Periodic Paralysis Caused by Ca_V1.1-R528H but not by Na_V1.4-R669H

ABSTRACT Hypokalemic periodic paralysis (HypoPP) is a channelopathy of skeletal muscle caused by missense mutations in the voltage sensor domains (usually at an arginine of the S4 segment) of the Ca V 1.1 calcium channel or of the Na V 1.4 sodium channel. The primary clinical manifestation is recurrent attacks of weakness, resulting from impaired excitability of anomalously depolarized fibers containing leaky mutant channels. While the ictal loss of fiber excitability is sufficient to explain the acute episodes of weakness, a deleterious change in voltage sensor function for Ca V 1.1 mutant channels may also compromise excitation-contraction coupling (EC-coupling). We used the low-affinity Ca 2+ indicator OGN-5 to assess voltage-dependent Ca 2+ -release as a measure of EC-coupling for our knock-in mutant mouse models of HypoPP. The peak Δ F/F 0 in fibers isolated from Ca V 1.1-R528H mice was about two-thirds of the amplitude observed in WT mice; whereas in HypoPP fibers from Na V 1.4-R669H mice the Δ F/F 0 was indistinguishable from WT. No difference in the voltage dependence of Δ F/F 0 from WT was observed for fibers from either HypoPP mouse model. Because late-onset permanent muscle weakness is more severe for Ca V 1.1-associated HypoPP than for Na V 1.4, we propose the reduced Ca 2+ -release for Ca V 1.1-R528H mutant channels may increase the susceptibility to fixed myopathic weakness. In contrast the episodes of transient weakness are similar for Ca V 1.1- and Na V 1.4-associated HypoPP, consistent with the notion that acute attacks of weakness are primarily caused by leaky channels and are not a consequence of reduced Ca 2+ -release.