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

Johannessen M, Ramachandran S, Riemer L, Ramos-Serrano A, Ruoho AE, Jackson MB. Voltage-gated sodium channel modulation by -receptors in cardiac myocytes and heterologous systems. Am J Physiol Cell Physiol 296: C1049–C1057, 2009. First published March 11, 2009; doi:10.1152/ajpcell.00431.2008.—The -receptor, a broadly distributed integral membrane protein with a novel structure, is known to modulate various voltage-gated K and Ca 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 -receptors. The 1-receptor ligands [SKF-10047 and ( )-pentazocine] and 1/ 2-receptor ligands (haloperidol and ditolylguanidine) all reversibly inhibited Nav1.5 channels to varying degrees in human embryonic kidney 293 (HEK293) cells and COS-7 cells, but the 1-receptor ligands were less effective in COS-7 cells. The same four ligands also inhibited Na current in neonatal mouse cardiac myocytes. In 1-receptor knockout myocytes, the 1-receptor-specific ligands were far less effective in modulating Na current, but the 1/ 2-receptor ligands modulated Na channels as well as in wild type. Photolabeling with the 1receptor photoprobe [I]-iodoazidococaine demonstrated that 1receptors were abundant in heart and HEK-293 cells, but scarce in COS-7 cells. This difference was consistent with the greater efficacy of 1-receptor-specific ligands in HEK-293 cells than in COS-7 cells. -Receptors modulated Na channels despite the omission of GTP and ATP from the patch pipette solution. -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 -receptors. The modulation of Nav1.5 channels by -receptors in the heart suggests an important pathway by which drugs can alter cardiac excitability and rhythmicity.