Intracellular Ca2+- and PKC-dependent upregulation of T-type Ca2+ 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 Ca2+ concentration ([Ca2+]i). The present study was therefore designed to investigate possible mechanisms responsible for [Ca2+]i elevation by LPC focusing on T-type Ca2+ channel current (ICa.T). LPC as well as phorbol 12-myristate 13-acetate (PMA) significantly accelerated the beating rates of neonatal rat cardiomyocytes. Augmentation of ICa.T by LPC was dependent on the intracellular Ca2+ concentration: an increase of ICa.T was significantly larger in high [Ca2+]i condition (pCa = 7) than those in low [Ca2+]i condition (pCa = 11). In heterologous expression system by use of human cardiac CaV3.1 and CaV3.2 channels expressed in HEK293 cells, LPC augmented CaV3.2 channel current (ICav3.2) in a concentration-dependent manner but not CaV3.1 channel current (ICav3.1). Augmentation of ICav3.2 by LPC was highly [Ca2+]i dependent: ICav3.2 was unchanged when pCa was 11 but was markedly increased when [Ca2+]i was higher than 10−10 M (pCa ≤ 10) by LPC application (10–50 μM). A specific inhibitor of protein kinase Cα (Ro-32-0432) attenuated the increase of ICav3.2 by LPC. LPC stimulates ICa.T in a [Ca2+]i-dependent manner via PKCα activation, which may play a role in triggering arrhythmias in pathophysiological conditions of the heart.