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Am J Physiol Cell Physiol 296: C1049-C1057, 2009. First published March 11, 2009; doi:10.1152/ajpcell.00431.2008
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RECEPTORS AND SIGNAL TRANSDUCTION

Voltage-gated sodium channel modulation by {sigma}-receptors in cardiac myocytes and heterologous systems

Molly Johannessen,1 Subramaniam Ramachandran,2 Logan Riemer,1 Andrea Ramos-Serrano,1 Arnold E. Ruoho,2 and Meyer B. Jackson1

Departments of 1Physiology and 2Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Submitted 21 August 2008 ; accepted in final form 5 March 2009

The {sigma}-receptor, a broadly distributed integral membrane protein with a novel structure, is known to modulate various voltage-gated K+ and Ca2+ channels through a mechanism that involves neither G proteins nor phosphorylation. The present study investigated the modulation of the heart voltage-gated Na+ channel (Nav1.5) by {sigma}-receptors. The {sigma}1-receptor ligands [SKF-10047 and (+)-pentazocine] and {sigma}1/{sigma}2-receptor ligands (haloperidol and ditolylguanidine) all reversibly inhibited Nav1.5 channels to varying degrees in human embryonic kidney 293 (HEK-293) cells and COS-7 cells, but the {sigma}1-receptor ligands were less effective in COS-7 cells. The same four ligands also inhibited Na+ current in neonatal mouse cardiac myocytes. In {sigma}1-receptor knockout myocytes, the {sigma}1-receptor-specific ligands were far less effective in modulating Na+ current, but the {sigma}1/{sigma}2-receptor ligands modulated Na+ channels as well as in wild type. Photolabeling with the {sigma}1-receptor photoprobe [125I]-iodoazidococaine demonstrated that {sigma}1-receptors were abundant in heart and HEK-293 cells, but scarce in COS-7 cells. This difference was consistent with the greater efficacy of {sigma}1-receptor-specific ligands in HEK-293 cells than in COS-7 cells. {sigma}-Receptors modulated Na+ channels despite the omission of GTP and ATP from the patch pipette solution. {sigma}-Receptor-mediated inhibition of Na+ current had little if any voltage dependence and produced no change in channel kinetics. Na+ channels represent a new addition to the large number of voltage-gated ion channels modulated by {sigma}-receptors. The modulation of Nav1.5 channels by {sigma}-receptors in the heart suggests an important pathway by which drugs can alter cardiac excitability and rhythmicity.

heart muscle; haloperidol


Address for reprint requests and other correspondence: M. B. Jackson, Dept. of Physiology, Univ. of Wisconsin School of Medicine and Public Health, 1300 Univ. Ave., Madison, WI 53706 (e-mail: mjackson{at}physiology.wisc.edu)






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