| Autor: |
Johannessen, Molly, Ramachandran, Subrananiam, Riemer, Logan, Ramos-Serrano, Andrea, Ruoho, Arnold E., Jackson, Meyer B. |
| Předmět: |
|
| Zdroj: |
American Journal of Physiology: Cell Physiology; May2009, Vol. 296 Issue 5, pC1049-C1057, 9p, 6 Graphs |
| Abstrakt: |
The σ-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 σ-rece ligands [SKF-10047 and (+)-pentazocine] and σ1/σ2-receptorligands (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 σ1-receptor ligands were less effective in COS-7 cells. The same four ligands also inhibited Na+ current in neonatal mouse cardiac myocytes. In σ1-receptor knockout myocytes, the σ1-receptor-specific ligands were far less effective in modulating Na+ current, but the σ1/σ2-receptor ligands modulated Na+ channels as well as in wild type. Photolabeling with the σ1-receptor photoprobe [125I]-iodoazidococaine demonstrated that σ1-receptors were abundant in heart and HEK-293 cells, but scarce in COS-7 cells. This difference was consistent with the greater efficacy of σ1-receptor-specific ligands in HEK-293 cells than in COS-7 cells. σ1-Receptors modulated Na+ channels despite the omission of GTP and ATP from the patch pipette solution. σ-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 σ-receptors. The modulation of Nav1.5 channels by σ-receptors in the heart suggests an important pathway by which drugs can alter cardiac excitability and rhythmicity. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
