EFFECTS OF QUISQUALIC ACID ANALOGS ON METABOTROPIC GLUTAMATE RECEPTORS COUPLED TO PHOSPHOINOSITIDE HYDROLYSIS IN RAT HIPPOCAMPUS

L-Glutamic acid (L-Glu) and L-aspartic acid (L-Asp) activate several r eceptor subtypes, including metabotropic Glu receptors coupled to phos phoinositide (PI) hydrolysis. Quisqualic acid (Quis) is the most poten t agonist of these receptors. There is evidence that activation of the se receptors may cause a long lasting sensitization of neurons to depo larization, a phenomenon called the Quis effect. The purpose of the cu rrent studies was to use Quis analogs and the recently identified meta botropic receptor antagonist, (+)-alpha-methyl-4-carboxy-phenylglycine (( +)-MCPG), to define the structural properties required for interact ion with the metabotropic receptors coupled to PI hydrolysis and to de termine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or prese nce of the metabotropic receptor-specific agonist ISR,3RS-1-amino-1,3- cyclopentanedicarboxylic acid (ISR,3RS-ACPD) in neonatal rat hippocamp us. Some of the compounds that induce the Quis effect also stimulate P I hydrolysis, including Quis itself and 9 (homoquisqualic acid). Not a ll of the Quis analogs that stimulate PI hydrolysis, however, induce t he Quis effect, including 7A (EC(50) = 750 +/- 150 mu M) and (RS)-4-br omohomoibotenic acid (BrHI) (EC(50) = 130 +/- 40 mu M) Although (+)-MC PG blocked PI hydrolysis stimulated by Quis (IC50 = 370 +/- 70 mu M), it had no effect on the induction of the Quis effect. Other Quis analo gs did not stimulate PI hydrolysis but rather blocked the effects of 1 SR,3RS-ACPD. The IC50 values were 240 +/- 70 mu M for 2, 250 +/- 90 mu M for 3, and 640 +/- 200 mu M for 4. Data for inhibition by 2 and 3 w ere consistent with non-competitive mechanisms of action. These studie s provide new information about the structural features of Quis requir ed for interaction with metabotropic receptors coupled to PI hydrolysi s and provide evidence that the Quis effect is not mediated by (+)-MCP G sensitive subtypes of these receptors.