Intracellular Ca(2+)- and PKC-dependent upregulation of T-type Ca(2+) channels in LPC-stimulated cardiomyocytes

J Mol Cell Cardiol. 2010 Jan;48(1):131-9. doi: 10.1016/j.yjmcc.2009.08.032. Epub 2009 Sep 8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Animals, Newborn
  • Arrhythmias, Cardiac / chemically induced
  • Arrhythmias, Cardiac / metabolism
  • Calcium / metabolism*
  • Calcium Channels, T-Type / metabolism*
  • Cell Line
  • Cells, Cultured
  • Humans
  • Lysophosphatidylcholines / pharmacology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Protein Kinase C / metabolism*
  • Rats
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Calcium Channels, T-Type
  • Lysophosphatidylcholines
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
  • Calcium