Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers

J. R. López, G. Cordovez, N. Linares, P. D. Allen

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca2+ concentration ([Ca2+](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca2+](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+](i) and prevented the cADPR-induced increase in [Ca2+](i). These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+](i).

Original languageEnglish (US)
Pages (from-to)236-242
Number of pages7
JournalPflugers Archiv European Journal of Physiology
Volume440
Issue number2
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Ca microelectrodes
  • cADP-ribose
  • Calcium
  • Dantrolene
  • Heparin
  • Malignant hyperthermia
  • Ruthenium red
  • Ryanodine
  • Skeletal muscle

ASJC Scopus subject areas

  • Physiology

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