Voltage-gated sodium channel modulation by σ-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.

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

“…Taken together, these data suggest that CM764 induces a sigma-2-modulated stimulation of cellular glycolysis under normoxia. This is a novel function of the sigma-2 receptor that is more consistent with observations of sigma-2 receptor expression in rapidly proliferating noncancerous cells such as HEK (Johannessen et al, 2009;Xu et al, 2011) and COS (Monassier et al, 2007;Johannessen et al, 2009) cells, as well as in tumor cells since it may offer protection against damage from ROS. Consistent with this hypothesis, CM764 induced an increase in MTT reduction that matched the increase induced in SK-N-SH neuroblastoma cells when dosed in human embryonic kidney cells and human osteosarcoma cells, indicating that this effect is present across a variety of tumor and noncancerous cell types.…”

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

“…In the absence of agonist, the s-1R is bound to binding immunoglobulin protein (BiP) Hayashi and Fujimoto, 2010), a major ER chaperone protein (Rao and Bredesen, 2004). Upon ligand activation, the s-1R dissociates from BiP and can modulate the activity of a number of ion channels in the ER (Hayashi and Su, 2007a) and at the plasma membrane (PM) (Aydar et al, 2002;Zhang and Cuevas, 2002;Tchedre et al, 2008;Johannessen et al, 2009;Crottès et al, 2011;Gao et al, 2012). In particular, the s-1R has been coimmunoprecipitated with K 1 channels such as K v 1.2, K v 1.3, and K v 1.4, suggesting that the s-1R is acting as a ligand-regulated auxiliary K 1 channel subunit (Aydar et al, 2002;Kinoshita et al, 2012;Kourrich et al, 2013).…”

Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats

“…-1 Receptor ligands, including neurosteroids, regulate this receptor-chaperone activity in an agonist/antagonist fashion Hayashi et al, 2009). In addition, -1 receptors were recently found to bind the psychedelic drug N,N-dimethyltryptamine and eventually produce a blockade of sodium channels, possibly through translocation of -1 receptors from the ER to the plasma membrane region (Fontanilla et al, 2009;Johannessen et al, 2009;Su et al, 2009).…”