Anesthetic effects on muscarinic signal transduction.
A wealth of pharmacological and physiological evidence has established that anesthetics disrupt synaptic transmission at muscarinic and other synapses. The sequence of molecular events precipitated by agonist binding to the receptors is under intense scrutiny. It appears that at the majority of synapses G proteins serve to mediate the transfer of information from receptors to intracellular mechanisms. The major exception to this scheme is the situation in which an ion channel is incorporated directly in the receptor structure. Binding of an agonist to these receptors produces a conformational change in the receptors which opens an intrinsic ion channel. This situation occurs in nicotinic acetylcholine gamma-amino butyric acid type A (GABAA, and 5-hydroxytryptamine type 3 (5-HT3) receptors). Assays have been developed to evaluate several steps in the cascade of events involved in synaptic signal transduction, and these assays have been employed to determine the step at which anesthetics act to disrupt synaptic transmission. We have demonstrated that several volatile anesthetics alter the interaction of muscarinic receptors with transducer G proteins. Ligand-binding experiments suggest that receptor-G protein complexes are stabilized, thereby disrupting G protein GTPase activity and muscarinic control of cellular activity. This "stabilization" does not appear to involve an inhibition of guanine nucleotide binding, the proximal event in receptor-G protein dissociation. Two possibilities warrant further consideration: (1) that GDP release from inactive G protein trimers, which is normally catalyzed by the receptor, is inhibited, and (2) that receptor-G protein complexes fail to dissociate even in response to GTP binding. We are currently examining these possibilities using purified G proteins and receptors in reconstituted systems.
Aronstam
R S
RS
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912.
Dennison
R L
RL
D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D000777:Anesthetics; D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins