Selected contribution: effect of volatile anesthetics on cADP-ribose-induced Ca(2+) release system.
Volatile anesthetics have multiple actions on intracellular Ca(2+) homeostasis, including activation of the ryanodine channel (RyR) and sensitization of this channel to agonists such as caffeine and ryanodine. Recently it has been described that the nucleotide cADP-ribose (cADPR) is the endogenous regulator of the RyR in many mammalian cells, and cADPR has been proposed to be a second messenger in many signaling pathways. I investigated the effect of volatile anesthetics on the cADPR signaling system, using sea urchin egg homogenates as a model of intracellular Ca(2+) stores. Ca(2+) uptake and release were monitored in sea urchin egg homogenates by using the fluo-3 fluorescence technique. Activity of the ADP-ribosyl cyclase was monitored by using a fluorometric method using nicotinamide guanine dinucleotide as a substrate. Halothane in concentrations up to 800 microM did not induce Ca(2+) release by itself in sea urchin egg homogenates. However, halothane potentiates the Ca(2+) release mediated by agonists of the ryanodine channel, such as ryanodine. Furthermore, other volatile anesthetics such as isoflurane and sevoflurane had no effect. Halothane also potentiated the activation of the ryanodine channel mediated by the endogenous nucleotide cADPR. The half-maximal concentration for cADPR-induced Ca(2+) release was decreased about three times by addition of 800 microM halothane. The reverse was also true: addition of subthreshold concentrations of cADPR sensitized the homogenates to halothane. In contrast, all the volatile anesthetics used had no effect on the activity of the enzyme that synthesizes cADPR. I propose that the complex effect of volatile anesthetics on intracellular Ca(2+) homeostasis may involve modulation of the cADPR signaling system.
Chini
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Department of Anesthesia, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. chini.eduardo@mayo.edu
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose; D006221:Halothane / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology
D018685:Anesthetics, Inhalation; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D002118:Calcium; D006221:Halothane