Lysophosphatidylcholine modulates cardiac I(Na) via multiple protein kinase pathways.
Lysophosphatidylcholine (LPC) is a naturally occurring intracellular phospholipid metabolite that has been implicated in arrhythmogenesis during ischemia. LPC has been shown to affect the cardiac Na+ current (I(Na)), but the mechanism of modulation remains undescribed. Recently, low concentrations of LPC have been shown to activate protein kinase C (PKC) independent of the receptor-delineated pathway. The purposes of this study were to describe the effects of intracellularly introduced LPC on I(Na) and to determine if these effects were mediated by kinases. Modulation of I(Na) was studied in ventricular cells with LPC (1 nmol/L to 1 micromol/L) internally applied using whole-cell patch-clamp techniques. Intracellular LPC caused a dose-dependent depolarizing shift of steady state inactivation that was accompanied by a change in slope factor. The development of resting inactivation from closed states was delayed 40%, whereas the recovery from inactivation was significantly accelerated. These results were mimicked by another bioactive lipid, lysophosphatidylethanolamine, or by a peptide analogue of PKC, which is a potent stimulator of endogenous PKC activity. Maximal recruitable current was significantly increased by LPC but not by PKC activation. Some of the effects of LPC on I(Na) could be partially inhibited by the specific PKC inhibitor chelerythrine chloride or by downregulation of PKC with phorbol ester pretreatment. However, genistein, a specific tyrosine kinase inhibitor, completely inhibited all the modulation of I(Na) caused by LPC. These data suggest that LPC modulates I(Na) in cardiac myocytes by a pathway that involves both PKC-dependent and tyrosine kinase- dependent phosphorylation.
Watson
C L
CL
Department of Medicine, University of Maryland, Baltimore, USA.
Gold
M R
MR
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D015222:Sodium Channels; D011493:Protein Kinase C