Intracellular Ca(2+)- and PKC-dependent upregulation of T-type Ca(2+) channels in LPC-stimulated cardiomyocytes.
Lysophosphatidylcholine (LPC) accumulation in intracellular and/or interstitial space in cardiomyocytes may underlie as a mechanism for tachycardia and various arrhythmias during cardiac ischemia, which is usually accompanied by elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)). The present study was therefore designed to investigate possible mechanisms responsible for [Ca(2+)](i) elevation by LPC focusing on T-type Ca(2+) channel current (I(Ca.T)). LPC as well as phorbol 12-myristate 13-acetate (PMA) significantly accelerated the beating rates of neonatal rat cardiomyocytes. Augmentation of I(Ca.T) by LPC was dependent on the intracellular Ca(2+) concentration: an increase of I(Ca.T) was significantly larger in high [Ca(2+)](i) condition (pCa=7) than those in low [Ca(2+)](i) condition (pCa=11). In heterologous expression system by use of human cardiac Ca(V)3.1 and Ca(V)3.2 channels expressed in HEK293 cells, LPC augmented Ca(V)3.2 channel current (I(Cav3.2)) in a concentration-dependent manner but not Ca(V)3.1 channel current (I(Cav3.1)). Augmentation of I(Cav3.2) by LPC was highly [Ca(2+)](i) dependent: I(Cav3.2) was unchanged when pCa was 11 but was markedly increased when [Ca(2+)](i) was higher than 10(-10) M (pCa<or=10) by LPC application (10-50 microM). A specific inhibitor of protein kinase Calpha (Ro-32-0432) attenuated the increase of I(Cav3.2) by LPC. LPC stimulates I(Ca.T) in a [Ca(2+)](i)-dependent manner via PKCalpha activation, which may play a role in triggering arrhythmias in pathophysiological conditions of the heart.
Zheng
Mingqi
M
Heart Center, the First Hospital of Hebei Medical University, Shijiazhuang, China.
Wang
Yan
Y
Kang
Lin
L
Shimaoka
Toru
T
Marni
Farzana
F
Ono
Katsushige
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D020747:Calcium Channels, T-Type; D008244:Lysophosphatidylcholines; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium