Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

Johannessen M, Fontanilla D, Mavlyutov T, Ruoho AE, Jackson MB. Antagonist action of progesterone at sigma-receptors in the modulation of voltage-gated sodium channels. Am J Physiol Cell Physiol 300: C328-C337, 2011. First published November 17, 2010; doi: 10.1152/ajpcell.00383.2010.-sigma-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate sigma-receptors, but endogenous sigma-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a sigma-receptor agonist. Progesterone and other steroids bind sigma-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to sigma(1)-and sigma(2)-receptors and evaluated its effect on sigma-receptor-mediated modulation of voltage-gated Na+ channels. Progesterone binds both sigma-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na+ channel Na(v)1.5. Patch-clamp recording in this cell line tested Na+ current modulation by the sigma-receptor ligands ditolylguanidine, PB28, (+) SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by sigma(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of sigma(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of sigma(1)-receptors. Progesterone binding to sigma-receptors blocks sigma-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.