Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Am J Physiol Cell Physiol. 2022 Aug 1;323(2):C478-C485. doi: 10.1152/ajpcell.00209.2022. Epub 2022 Jun 27.
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.
低钾周期性麻痹（HypoPP）是一种骨骼肌通道病，由钙通道 1.1（Ca1.1）的电压传感器域（通常在 S4 段的精氨酸处）或钠通道 1.4（Na1.4）的错义突变引起。主要临床表现为反复发作的无力，这是由于含有渗漏突变通道的异常去极化纤维兴奋性受损所致。尽管纤维兴奋丧失足以解释急性无力发作，但 Ca1.1 突变通道电压传感器功能的有害变化也可能损害兴奋-收缩偶联（EC 偶联）。我们使用低亲和力钙指示剂 Oregon Green 488 BAPTA-5N（OGB-5N）来评估电压依赖性钙释放作为我们 HypoPP 敲入突变小鼠模型的 EC 偶联的衡量标准。从 Ca1.1-R528H 小鼠中分离的纤维的峰值 Δ/约为 WT 小鼠观察到的幅度的三分之二；而在 Na1.4-R669H 小鼠的 HypoPP 纤维中，Δ/与 WT 无法区分。对于来自两种 HypoPP 小鼠模型的纤维，Δ/与 WT 的电压依赖性均无差异。由于与 Ca1.1 相关的 HypoPP 比与 Na1.4 相关的 HypoPP 发生晚期持续性肌无力更为严重，我们提出 Ca1.1-R528H 突变通道的钙释放减少可能会增加对固定肌病性无力的易感性。相比之下，Ca1.1 和 Na1.4 相关的 HypoPP 发作的短暂性无力相似，这与急性无力发作主要是由渗漏通道引起的观点一致，而不是钙释放减少的结果。
