Pharmacological kinetics of BmK AS, a sodium channel site 4-specific modulator on Nav1.3.

Objective: In this study, the pharmacological kinetics of Buthus martensi Karsch (BmK) AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Na(v)1.3 expressed in Xenopus oocytes.

Methods: Two-electrode voltage clamp was used to record the whole-cell sodium current.

Results: The peak currents of Na(v)1.3 were depressed by BmK AS over a wide range of concentrations (10, 100, and 500 nmol/L). Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Na(v)1.3 at all concentrations.

Conclusion: This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Na(v)1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Na(v)1.3-targeted pathology.