THE METABOTROPIC GLUTAMATE-RECEPTOR TYPES-2 3 INHIBIT L-TYPE CALCIUM CHANNELS VIA A PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN IN CULTURED CEREBELLAR GRANULE CELLS/

Modulation of Ca2+ channels by metabotropic glutamate receptors (mGluR s) was investigated in cerebellar granule cells using the cell-attache d configuration of the patch-clamp technique. Experiments were perform ed in the absence of external Ca2+ and Ba2+ was used as charge carrier . Bath applied glutamate or (1S,3R) trans-1-aminocyclopentane-1,3-dica rboxylic acid (1S,3R t-ACPD) inhibited Ca2+ channels activated by depo larizing pulses. These channels were sensitive to dihydropyridines and displayed a 23 pS conductance. This effect was mimicked by (2S,1'S,2' S)-2-(carboxycyclopropyl)glycine (L-CCG-I), a selective agonist of mGl uR2/R3 receptors, but not by quisqualate at a concentration that stimu lated inositol phosphate (InsP) synthesis, showing that mGluR1 and mGl uR5 did not participate to this mechanism. The phosphodiesterase inhib itor, isobutylmethylxanthine (IBMX), did not alter the action of the m GluR agonists and biochemical measurements showed that 1S,3R t-ACPD, i n the presence of IBMX, decreased cAMP formation in such a small amoun t that this change could not explain the almost complete inhibition of the channel activity observed under similar experimental conditions. Moreover, whole-cell recorded L-type Ca2+ currents were inhibited by L -CCG-I, in the presence of 1 mM intracellular cAMP. These observations were consistent with the hypothesis that cyclic nucleotide second mes sengers were not involved in this effect. Neither the protein kinase C activator phorbol-12,13-dibutyrate (PDBU) nor the phosphatase inhibit or okadaic acid affected the action of 1S,3R t-ACPD. The inhibitory ac tion of 1S,3R t-ACPD was abolished by pertussis toxin (PTX). These res ults suggest that mGluR2 or mGluR3 receptors suppress the activity of L-type Ca2+ channels by a mechanism involving G(i) or G(o) proteins. A likely direct effect of G-proteins on the channels is discussed.