title: 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.
authors.affiliation: Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. mjackson@physiology.wisc.edu
authors.forename: Molly
authors.initials: M
authors.lastname: Johannessen
authors.forename: Dominique
authors.initials: D
authors.lastname: Fontanilla
authors.forename: Timur
authors.initials: T
authors.lastname: Mavlyutov
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
authors.forename: Meyer B
authors.initials: MB
authors.lastname: Jackson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects; D004130:N,N-Dimethyltryptamine / Q000494:pharmacology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D006146:Guanidines; D004130:N,N-Dimethyltryptamine; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010620:Phenazocine; D010879:Piperazines; D011374:Progesterone; D034741:RNA, Small Interfering; D017480:Receptors, sigma; D015222:Sodium Channels; D000097605:Sigma-1 Receptor; C513937:PB28 compound; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; C106107:sigma-2 receptor; C012134:SK&F 10047; C050232:1,3-ditolylguanidine