a Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine , Maebashi , Gunma , Japan.
Channels (Austin). 2019 Dec;13(1):331-343. doi: 10.1080/19336950.2019.1649521.
The segment 4 (S4) voltage sensor in voltage-gated sodium channels (Nas) have domain-specific functions, and the S4 segment in domain DIV (DIVS4) plays a key role in the activation and fast inactivation processes through the coupling of arginine residues in DIVS4 with residues of putative gating charge transfer center (pGCTC) in DIVS1-3. In addition, the first four arginine residues (R1-R4) in Na DIVS4 have position-specific functions in the fast inactivation process, and mutations in these residues are associated with diverse phenotypes of Na-related diseases (sodium channelopathies). R1 and R2 mutations commonly display a delayed fast inactivation, causing a gain-of-function, whereas R3 and R4 mutations commonly display a delayed recovery from inactivation and profound use-dependent current attenuation, causing a severe loss-of-function. In contrast, mutations of residues of pGCTC in Na DIVS1-3 can also alter fast inactivation. Such alterations in fast inactivation may be caused by disrupted interactions of DIVS4 with DIVS1-3. Despite fast inactivation of Nas occurs from both the open-state (open-state inactivation; OSI) and closed state (closed-state inactivation; CSI), changes in CSI have received considerably less attention than those in OSI in the pathophysiology of sodium channelopathies. CSI can be altered by mutations of arginine residues in DIVS4 and residues of pGCTC in Nas, and altered CSI can be an underlying primary biophysical defect of sodium channelopathies. Therefore, CSI should receive focus in order to clarify the pathophysiology of sodium channelopathies.
电压门控钠离子通道（Nas）的 S4 电压传感器具有域特异性功能，而 DIV 域中的 S4 段（DIVS4）通过将 DIVS4 中的精氨酸残基与 DIVS1-3 中的假定门控电荷转移中心（pGCTC）的残基偶联，在激活和快速失活过程中发挥关键作用。此外，Na DIVS4 中的前四个精氨酸残基（R1-R4）在快速失活过程中具有位置特异性功能，这些残基的突变与各种 Na 相关疾病（钠通道病）的表型相关。R1 和 R2 突变通常表现为快速失活延迟，导致功能获得，而 R3 和 R4 突变通常表现为失活后恢复延迟和严重的使用依赖性电流衰减，导致严重的功能丧失。相比之下，Na DIVS1-3 中 pGCTC 残基的突变也可以改变快速失活。这种快速失活的改变可能是由于 DIVS4 与 DIVS1-3 之间的相互作用被破坏所致。尽管 Nas 的快速失活既来自开放状态（开放状态失活；OSI）又来自关闭状态（关闭状态失活；CSI），但在钠通道病的病理生理学中，CSI 的改变受到的关注远不如 OSI 那么多。CSI 可以通过 DIVS4 中的精氨酸残基和 Nas 中的 pGCTC 残基的突变而改变，改变的 CSI 可能是钠通道病的潜在原发性生物物理缺陷。因此，为了阐明钠通道病的病理生理学，CSI 应该受到关注。
