Control of cardiac Ca2+ levels: Inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel conductance

P. M. McDonough, K. Yasui, R. Betto, G. Salviati, C. C. Glembotski, P. T. Palade, R. A. Sabbadini

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

The naturally occurring second messenger sphingosine (SPH) was examined for its ability to influence cardiac myocyte Ca2+ regulation. SPH inhibited intracellular Ca2+ transients in adult and neonatal rat ventricular myocytes. The inhibition was steeply dose dependent, with complete blockage of the Ca2+ transients occurring in the 20- to 25-μmol/L range. Whole- cell patch clamping revealed substantial inhibition of the L-type Ca2+ channel current (I(Ca)) by SPH. The ability of SPH to block both the Ca2+ transients and I(Ca) was not dependent on protein kinases, since the general protein kinase inhibitor H7 failed to prevent the actions of SPH. The specificity of the effect of SPH was determined in experiments showing that SPH analogues did not produce comparable effects. Neither the naturally occurring ceramide, N-stearoyl SPH, nor the cell-permeant ceramide, N-acetyl SPH, had SPH-like actions on the Ca2+ transients or L-type channel conductances. Caffeine-induced Ca2+ transients were also inhibited by the actions of SPH on cardiac sarcoplasmic reticulum Ca2+ release, and the threshold for caffeine-induced Ca2+ release was raised. We conclude that SPH inhibits excitation-contraction coupling in cardiac myocytes by reducing the amount of entering 'trigger Ca2+' for Ca2+-induced Ca2+ release and by simultaneously raising the threshold of the ryanodine receptor for Ca2+- induced Ca2+ release. Consequently, we propose that sphingolipids produced by the sphingomyelin signal transduction pathway could be physiologically relevant regulators of cardiac [Ca2+](i) and therefore cardiac contractility.

Original languageEnglish (US)
Pages (from-to)981-989
Number of pages9
JournalCirculation research
Volume75
Issue number6
DOIs
StatePublished - 1994
Externally publishedYes

Keywords

  • L-type channel
  • cardiac myocytes
  • ceramide
  • ryanodine receptors
  • sphingosine

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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