MULTIPLE PATHWAYS FOR REGULATION OF THE KCL-INDUCED [H-3]-GABA RELEASE BY METABOTROPIC GLUTAMATE RECEPTORS, IN PRIMARY RAT CORTICAL CULTURES

In rat cortical primary cultures, group II- and III-metabotropic gluta mate receptor-selective agonists concentration-dependently reduced KCl -induced [H-3]GABA release, with IC50 values of 11 nM for LY354740, 80 nM for L(+)-2-amino-4-phosphonobutyric acid (L-AP4), 180 nM for DCG-I V, and 330 nM for L-SOP. The group II antagonists, LY341495 and EGLU, reversed the effect of LY354740, and the group III antagonist MTPG rev ersed the effect of L-AP4. In the presence of omega-conotoxin GVIA, LY 354740 inhibited the remaining [H-3]GABA release, whereas L-AP4 was in active. In contrast, in the presence of nifedipine, L-AP4 inhibited th e remaining [H-3]GABA release, but LY354740 was no longer active. The PKA inhibitor, H89, blocked the effects of both L-AP4 and LY354740, wh ereas the PKC inhibitor Ro 31-8220 blocked only the effect of LY354740 . Both Ro 31-8220 and H89 reduced the [H-3]GABA release to 60% of cont rol. In whole-cell, voltage-clamp experiments, LY354740 and L-AP4 inhi bited voltage-gated calcium channel currents with IC50 values of 28 nM and 22 mu M, respectively. The results suggest that, in these cells, KCl-induced [H-3]GABA release is modulated by two different mechanisms , one involving group II receptors and a direct control of the Ca2+ ch annel activity, and the other mediated by group III receptors and poss ibly involving a regulation located downstream of the Ca2+ channel act ivation. (C) 1998 Elsevier Science B.V.