REDUCTION OF RESTING K+ CURRENT BY METABOTROPIC GLUTAMATE AND MUSCARINIC RECEPTORS IN RAT CA3 CELLS - MEDIATION BY G-PROTEINS

1. Effects of 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) acting at metabotropic glutamate receptors (mGluRs), and methacholine (MCh), acting at cholinergic muscarinic receptors, were investigated in CA3 neurones in hippocampal slice cultures using the patch-clamp technique. 2. Both 1S,3R-ACPD (10 mu M) and MCh (0.5 mu M) activated an inward current associated with a decrease in membrane conductance. The current was observed when the slow calcium-dependent after-hyperpolarizing current (I-AHP) and the voltage-dependent current (I-M) were not activated, reversed close to the reversal potential for K+ (E(K)) (E(rev) = - 92.8 +/- 10.7 and - 89.2 +/- 8.6 mV for 1S,3R-ACPD and MCh, respectively), varied linearly with membrane potential, and thus corresponds to a leak K+ current. 3. The decrease in K+ conductance elicited with 1S,3R-ACPD (50 mu M) was substantially reduced (> 70 %) with bath application of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM), a selective mGluR antagonist and was not mimicked by the enantiomer 1R,3S-ACPD (100 mu M). 4. The effects of 1S,3R-ACPD and MCh were mediated by activation of G-proteins since no inward current could be elicited in GDP beta S-loaded cells (500 mu M). When cells were dialysed with GTP (100 mu M) or GTP gamma S (250 mu M), however, the amplitude of the current was significantly enhanced. 5. These findings provide evidence that G-proteins couple the activation of mGluRs and muscarinic receptors to a decrease in leak K+ conductance.