Role of the voltage sensor module in Na(v) domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

The segment 4 (S4) voltage sensor in voltage-gated sodium channels (Na(v)s) 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(v)s 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(v)s, 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.