Voltage-dependent Ca release is impaired in hypokalemic periodic paralysis caused by Ca1.1-R528H but not by Na1.4-R669H.

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 Ca1.1 calcium channel or of the Na1.4 sodium channel. The primary clinical manifestation is recurrent attacks of weakness, resulting from impaired excitability of anomalously depolarized fibers containing leaky mutant channels. Although the ictal loss of fiber excitability is sufficient to explain the acute episodes of weakness, a deleterious change in voltage sensor function for Ca1.1 mutant channels may also compromise excitation-contraction coupling (EC-coupling). We used the low-affinity Ca indicator Oregon Green 488 BAPTA-5N (OGB-5N) to assess voltage-dependent Ca-release as a measure of EC-coupling for our knock-in mutant mouse models of HypoPP. The peak Δ/ in fibers isolated from Ca1.1-R528H mice was about two-thirds of the amplitude observed in WT mice; whereas in HypoPP fibers from Na1.4-R669H mice the Δ/ was indistinguishable from WT. No difference in the voltage dependence of Δ/ from WT was observed for fibers from either HypoPP mouse model. Because late-onset permanent muscle weakness is more severe for Ca1.1-associated HypoPP than for Na1.4, we propose that the reduced Ca-release for Ca1.1-R528H mutant channels may increase the susceptibility to fixed myopathic weakness. In contrast, the episodes of transient weakness are similar for Ca1.1- and Na1.4-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-release.