The segment 4 (S4) voltage sensor in voltage-gated sodium channels (Na_vs) 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_v DIVS4 have position-specific functions in the fast inactivation process, and mutations in these residues are associated with diverse phenotypes of Na_v-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_v 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 Na_vs 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 Na_vs, 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.

电压门控钠通道（Na _v s）中的第4段（S4）电压传感器具有特定于域的功能，而域DIV（DIVS4）中的S4区段通过激活以下分子的耦合在激活和快速失活过程中起关键作用DIVS4中的精氨酸残基和DIVS1-3中的推定门电荷转移中心（pGCTC）残基。此外，Na _v DIVS4中的前四个精氨酸残基（R1-R4）在快速失活过程中具有特定位置的功能，并且这些残基中的突变与Na _v的不同表型相关相关疾病（钠通道病）。R1和R2突变通常表现出延迟的快速失活，从而导致功能获得，而R3和R4突变通常表现出从失活中恢复的延迟，以及依赖于使用的严重电流衰减，从而导致严重的功能丧失。相反，Na _v DIVS1-3中pGCTC残基的突变也可以改变快速失活。快速灭活的这种改变可能是由于DIVS4与DIVS1-3的相互作用被破坏而引起的。尽管Na _v快速失活s既发生在开放状态（open-state inactivation； OSI），也发生在关闭状态（closed-state inactivation； CSI），在钠通道病的病理生理学方面，CSI的变化所引起的关注远少于OSI。CSI可以通过DIVS4中精氨酸残基和Na _v s中pGCTC残基的突变而改变，并且改变的CSI可能是钠通道病的潜在主要生物物理缺陷。因此，CSI应该受到关注，以阐明钠通道病的病理生理。