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

Abstract

σ-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 σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ(1)- and σ(2)-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na(+) channels. Progesterone binds both σ-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 σ-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 σ(1)-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ(2)-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ(1)-receptors. Progesterone binding to σ-receptors blocks σ-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.

A Direct Interaction between the Sigma-1 Receptor and the hERG Voltage-gated K+ Channel Revealed by Atomic Force Microscopy and Homogeneous Time-resolved Fluorescence (HTRF®)

“…The sigma-1 receptor is promiscuous in its modulation of ion channels, affecting voltage-gated (25)(26)(27)(28)(29)(30), ligand-gated (31)(32)(33), volume-regulated (14), and acid-sensing (34) ion channels. A sigma-1 receptor⅐K v 1.4 interaction was shown to be independent of second messenger generation or phosphorylation, implying a direct interaction (35).…”

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…It has been established by many researchers that sigma-1 receptors are able to modulate ion channels in a variety of cell types (Aydar et al 2002;Lupardus et al 2000;Johannessen et al 2011). In particular, the sigma-1 receptor was found to regulate the current density of VGSCs in MDA-MB-231 cells (Balasuriya et al 2012).…”

“…Modulation of the heart voltagegated Na + channel (Na v 1.5) by sigma-receptors was demonstrated and this could be an important pathway through which drugs could alter cardiac excitability and rhythmicity (Johannessen et al 2011). This was further corroborated by atomic force microscopy imaging of complexes between sigma-1 receptors and Na v 1.5 channels revealing a fourfold symmetry (Balasuriya et al 2012).…”

“…Sigma-1 receptors have been demonstrated to modulate Na v 1.5 channels in cardiomyocyes or when heterologously coexpressed in HEK-293 cells (Johannessen et al 2011). In an initial attempt to determine whether the effect of sigma-1 receptor drugs on the adhesion of MDA-MB-231 and MDA-MB-468 cells involved VGSC activity, we performed a number of experiments with a combination of treatments with SKF10047 and the polyclonal antibody to nNa v 1.5 which is known to be a channel blocker .…”

Role of Sigma Receptor and Neurosteroids in Pain Sensation

“…10,11 신경스테로이드는 종류에 따라 다양한 형태로 시그마-1 수용체의 활성을 조절하며, 특 히 progesterone은 시그마-1 수용체에 대해 길항 효능을 가 지지만 DHEA는 효현제(agonist)로서 작용한다고 알려져 있다. 12,13 시그마 수용체는 해부 조직학적으로 말초 기관 뿐만 아니라 hippocampus, hypothalamus, olfactory bulb, pons 등과 같은 중추신경계의 다양한 부위에서 발견되며, 특히 통증 조 절과 관련되는 periaqueductal gray (PAG) 및 locus coeruleus에서도 관찰된다. 14 또한 통증전달 경로의 첫 번째 관 문인 척수에서도 유해한 자극에 반응하는 superficial dorsal horn의 lamina I과 II에서 관찰되어 통증 전달에 중추적인 역할을 담당할 가능성을 제시한다.…”