EFFECTS OF ETHANOL AND ANESTHETICS ON TYPE-1 AND TYPE-5 METABOTROPIC GLUTAMATE RECEPTORS EXPRESSED IN XENOPUS-LAEVIS OOCYTES

Previous studies have demonstrated that ethanol and volatile anestheti cs inhibit the function of some metabotropic (G protein-coupled) recep tors, including the 5-hydroxytryptamine(2), and muscarinic cholinergic receptors. The metabotropic glutamate receptors (mGluRs) show little sequence homology with most other metabotropic receptors and are impor tant modulators of synaptic transmission in the mammalian central nerv ous system. It was of interest to determine drug actions on these rece ptors, and we investigated the effects of ethanol, halothane, the anes thetic compound F3 (I-chloro-l,2,2-trifluorocyclobutane), and the nona nesthetics F6 (1,2-dichlorohexafluorocyclobutane) and F8 (2,3-chlorooc tafluorobutane) on the function of mGluR1 and mGluR5 expressed in Xeno pus laevis oocytes. Halothane, F3, and ethanol inhibited mGluR5-induce d Ca2+-dependent Cl- currents, yet pharmacologically relevant concentr ations of these compounds had little effect on the glutamate-induced c urrents in the oocytes expressing mGluR1. F6 had inhibitory effects on both receptors, and F8 did not affect either mGluR1 or mGluR5 functio n. The protein kinase C (PKC) inhibitor GF109203X enhanced the glutama te-induced current, and the PKC activator phorbol-12-myristate-13-acet ate inhibited this current in the oocytes expressing mGluR5, but these compounds had little effect on mGluR1 function. GF109203X abolished t he inhibitory effects of halothane, F3, and ethanol on mGluR5s. Conver sely, the phosphatase inhibitor calyculin A prolonged the action of ha lothane and ethanol. Furthermore, mutation of a PKC consensus site (Se r890) of mGluR5 abolished the inhibitory effects of halothane, F3, and ethanol. These results suggest that ethanol and volatile anesthetics inhibit mGluR5 because they promote PKC-mediated phosphorylation.