G-PROTEIN-MEDIATED DESENSITIZATION OF METABOTROPIC GLUTAMATERGIC AND MUSCARINIC RESPONSES IN CA3 CELLS IN RAT HIPPOCAMPUS

1. Desensitization of a metabotropic response was investigated in CA3 pyramidal neurons in hippocampal slice cultures using the patch-clamp technique. 2. 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) , an agonist at metabotropic glutamate receptors (mGluRs), and methach oline (MCh), an agonist at muscarinic receptors, induced a cationic cu rrent that appears to be activated through a G-protein-independent tra nsduction process, as previously shown. Prolonged or repetitive bath a pplication of agonists led to rapid desensitization of the cationic cu rrent with a time constant of similar to 20 s. 3. Complete recovery fr om desensitization was observed within 6 min. 4. These responses media ted by mGluRs and muscarinic receptors cross-desensitized. 5. Preventi ng the activation of G-proteins by loading cells with GDP beta S stron gly reduced or suppressed desensitization, and resulted in a sustained inward cationic current. When cells were filled with GTP gamma S to i rreversibly activate G-proteins, the desensitization process was enhan ced such that a first application of agonist caused a markedly reduced response. 6. These results show that a cationic current induced by me tabotropic agonists in hippocampal pyramidal cells undergoes apparent desensitization and suggests that this process occurs through a G-prot ein-mediated inhibition of the underlying membrane conductance.