title: Voltage-gated sodium channel modulation by sigma-receptors in cardiac myocytes and heterologous systems.
abstract: The sigma-receptor, a broadly distributed integral membrane protein with a novel structure, is known to modulate various voltage-gated K(+) and Ca(2+) channels through a mechanism that involves neither G proteins nor phosphorylation. The present study investigated the modulation of the heart voltage-gated Na(+) channel (Na(v)1.5) 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 Na(v)1.5 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 [(125)I]-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 Na(v)1.5 channels by sigma-receptors in the heart suggests an important pathway by which drugs can alter cardiac excitability and rhythmicity.
authors.affiliation: Dept. of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Johannessen
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Logan
authors.initials: L
authors.lastname: Riemer
authors.forename: Andrea
authors.initials: A
authors.lastname: Ramos-Serrano
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
authors.forename: Meyer B
authors.initials: MB
authors.lastname: Jackson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006160:Guanosine Triphosphate / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009294:Narcotics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010423:Pentazocine / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D034741:RNA, Small Interfering; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009294:Narcotics; D034741:RNA, Small Interfering; D017480:Receptors, sigma; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; C012134:SK&F 10047; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D012964:Sodium; D010620:Phenazocine; D006220:Haloperidol; D010423:Pentazocine