Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers.
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 beta-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 microM) 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 microM), 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.
López
J R
JR
Centro de Biofísica y Bioquimica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela. jlopez@cbb.ivic.ve
Cordovez
G
G
Linares
N
N
Allen
P D
PD
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D036563:Cyclic ADP-Ribose; D003620:Dantrolene / Q000494:pharmacology; D004198:Disease Susceptibility; D005110:Extracellular Space / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008305:Malignant Hyperthermia / Q000209:etiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009994:Osmolar Concentration; D012016:Reference Values; D012430:Ruthenium Red / Q000494:pharmacology; D013552:Swine
D002121:Calcium Channel Blockers; D012430:Ruthenium Red; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D006493:Heparin; D003620:Dantrolene; D002118:Calcium