The voltage-gated Na+ channel Nav1.8 contains an ER-retention/retrieval signal antagonized by the β3 subunit

Abstract

Voltage-gated Na+ channel (Nav) 1.8 contributes to the majority of the Na+ current that underlies the depolarizing phase of action potentials. Nav1.8 is mainly distributed intracellularly and its current amplitude can be enhanced by the β3 subunit. However, little is known about the mechanisms underlying its intracellular retention and the effects mediated by the β3 subunit. Here, we show that the β3 subunit promotes surface expression of Nav1.8 by masking its endoplasmic reticulum (ER)-retention/retrieval signal. The RRR motif in the first intracellular loop of Nav1.8 is responsible for retaining Nav1.8 in the ER and restricting its surface expression. The β3 subunit facilitates surface expression of Nav1.8. The intracellular C-terminus of the β3 subunit interacts with the first intracellular loop of Nav1.8 and masks the ER-retention/retrieval signal. Mutation of the RRR motif results in a significant increase in surface expression of Nav1.8 and abolishes the β3-subunit-mediated effects. Thus, the β3 subunit regulates surface expression of Nav1.8 by antagonizing its ER-retention/retrieval signal. These results reveal a novel mechanism for the effect of the Na+ channel β subunits on the α subunits.