Signal Transduction in Smooth Muscle: Selected Contribution: Effect of volatile anesthetics on cADP-ribose-induced Ca release system

Chini, Eduardo N. Selected Contribution: Effect of volatile anesthetics on cADP-ribose-induced Ca21 release system. J Appl Physiol 91: 516–521, 2001.— Volatile anesthetics have multiple actions on intracellular Ca21 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 Ca21 stores. Ca21 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 mM did not induce Ca21 release by itself in sea urchin egg homogenates. However, halothane potentiates the Ca21 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 Ca21 release was decreased about three times by addition of 800 mM 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 Ca21 homeostasis may involve modulation of the cADPR signaling system.