| Title | Voltage-Gated Sodium Channel Modulation by Sigma Receptors in Cardiac Myocytes and Heterologous Systems. | | Author(s) | Johannessen MA, Ramachandran S, Riemer L, Ramos-Serrano A, Ruoho AE, Jackson MB | | Institution | University of Wisconsin. | | Source | Am J Physiol Cell Physiol 2009 Mar 11. | | 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 (Nav1.5) by sigma receptors. Sigma-1 receptor ligands (SKF10047 and (+)-pentazocine) and sigma-1/sigma-2 receptor ligands (haloperidol and ditolylguanidine) all reversibly inhibited Nav1.5 channels to varying degrees in HEK293 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 knock-out 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 HEK293 cells, but scarce in COS-7 cells. This difference was consistent with the greater efficacy of sigma-1 receptor specific ligands in HEK293 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 inhibition of Na(+) current had no voltage dependence, and produced no change in channel kinetics. Na(+) channels represent a new addition to the large number of voltage-gated ion channels inhibited 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. Key words: Sigma receptor, Heart muscle, Voltage-gated Na+ channels. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19279232 |
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