Effects of volatile anesthetics on the G protein-regulated muscarinic potassium channel.
The muscarinic-activated K+ channel K(ACh), a prototype of channels regulated by neuroendocrine agonists via G proteins, was used to investigate the mode of action of isoflurane and halothane on G protein-coupled signal transduction processes. The evolution of the muscarinic current I(K(ACh)) was characterized through rapid agonist application and washout. At physiologically relevant concentrations, halothane and isoflurane reduced the rate of I(K(ACh)) activation without comparable effects on deactivation. Furthermore, both anesthetics reduced or eliminated the spontaneous decay (rapid desensitization) typical of the muscarinic response. In contrast to these similarities of anesthetic action on the time course of the response, the magnitude of I(K(ACh)) was slowly reduced by isoflurane but rapidly augmented by halothane. Neither halothane nor isoflurane altered the conductance of single I(K(ACh)) channels, indicating that these volatile anesthetics act on channel open-close kinetics. The reduced I(K(ACh)) activation rates suggest that impaired receptor/G protein interactions are induced by both anesthetics. For halothane, the increased amplitude of the response, also seen for I(K(ACh)) activated in a receptor-independent manner by guanosine-5'-O-(3-thio)triphosphate, suggests a direct action on the channel. Alteration of signal transduction processes by halothane and isoflurane may underlie some anesthetic actions of these compounds as well as secondary effects on the cardiovascular system.
Magyar
J
J
Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville 22908, USA.
Szabo
G
G
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011892:Rana catesbeiana; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013943:Thymol / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D013943:Thymol; D007530:Isoflurane; D019204:GTP-Binding Proteins; D006221:Halothane