EFFECTS OF VOLATILE ANESTHETICS ON THE G-PROTEIN-REGULATED MUSCARINICPOTASSIUM CHANNEL

The muscarinic-activated K+ channel K-(ACh), a prototype of channels r egulated by neuroendocrine agonists via G proteins, was used to invest igate the mode of action of isoflurane and halothane on G protein-coup led signal transduction processes. The evolution of the muscarinic cur rent I-K(ACh) was characterized through rapid agonist application and washout. At physiologically relevant concentrations, halothane and iso flurane reduced the rate of I-K(ACh) activation without comparable eff ects on deactivation. Furthermore, both anesthetics reduced or elimina ted the spontaneous decay (rapid desensitization) typical of the musca rinic response. In contrast to these similarities of anesthetic action on the time course of the response, the magnitude of I-K(ACh) was slo wly reduced by isoflurane but rapidly augmented by halothane, Neither halothane nor isoflurane altered the conductance of single I-K(ACh) ch annels, indicating that these volatile anesthetics act on channel open -close kinetics. The reduced I-K(ACh) activation rates suggest that im paired receptor/G protein interactions are induced by both anesthetics . For halothane, the increased amplitude of the response, also seen fo r I-K(ACh) activated in a receptor-independent manner by guanosine-5'- O-(3-thio)triphosphate, suggests a direct action on the channel. Alter ation of signal transduction processes by halothane and isoflurane may underlie some anesthetic actions of these compounds as well as second ary effects on the cardiovascular system.