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Am J Physiol Cell Physiol. 2011 Feb;300(2):C328-37. doi: 10.1152/ajpcell.00383.2010. Epub 2010 Nov 17.

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

Author information

1
Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. mjackson@physiology.wisc.edu

Erratum in

  • Am J Physiol Cell Physiol. 2013 Nov 1;305(9):C997.

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.

PMID:
21084640
PMCID:
PMC3043630
DOI:
10.1152/ajpcell.00383.2010
[Indexed for MEDLINE]
Free PMC Article

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