Electrophysiological and Pharmacological Analyses of Na v 1.9 Voltage-Gated Sodium Channel by Establishing a Heterologous Expression System.

Nav 1. 9 voltage-gated sodium channel is preferentially expressed in peripheral nociceptive neurons. Recent progresses have proved its role in pain sensation, but our understanding of Nav 1.9, in general, has lagged behind because of limitations in heterologous expression in mammal cells. In this work, functional expression of human Nav 1.9 (hNav 1.9) was achieved by fusing GFP to the C-terminal of hNav 1.9 in ND7/23 cells, which has been proved to be a reliable method to the electrophysiological and pharmacological studies of hNav 1.9. By using the hNav 1.9 expression system, we investigated the electrophysiological properties of four mutations of hNav 1.9 (K419N, A582T, A842P, and F1689L), whose electrophysiological functions have not been determined yet. The four mutations significantly caused positive shift of the steady-state fast inactivation and therefore increased hNav 1.9 activity, consistent with the phenotype of painful peripheral neuropathy. Meanwhile, the effects of inflammatory mediators on hNav 1.9 were also investigated. Impressively, histamine was found for the first time to enhance hNav 1.9 activity, indicating its vital role in hNav 1.9 modulating inflammatory pain. Taken together, our research provided a useful platform for hNav 1.9 studies and new insight into mechanism of hNav 1.9 linking to pain.