),2'(R),3'(R))-2-(2,3-DICARBOXYCYCLOPROPYL)GLYCINE POSITIVELY MODULATES METABOTROPIC GLUTAMATE RECEPTORS COUPLED TO POLYPHOSPHOINOSITIDE HYDROLYSIS IN RAT HIPPOCAMPAL SLICES

In rat hippocampal slices, the novel metabotropic glutamate receptor ( mGluR) ligand, ),2'(R),3'(R))-2-(2,3-dicarboxycyclopropyl)glycine (DCG -IV) enhanced the stimulation of polyphosphoinositide (PPI) hydrolysis elicited by quisqualate or by submaximal concentrations of ibotenate or (1(S),3(R))-1-aminocyclopentane-1,3-dicarboxylic acid (1(S),3(R)-AC PD). The enhancing effect of DCG-IV was (i) specific for mGluR agonist s, (ii) restricted to hippocampal slice preparation, (iii) reversible, and (iv) not subject to homologous desensitization. in addition, DCG- IV did not interact with L-2-amino-4-phosphonobutanoate (AP4), a nonco mpetitive antagonist of mGluRs coupled to PPI hydrolysis in brain slic es [32]. The action of I)CG-IV on quisqualate-stimulated PPI hydrolysi s was insensitive to antagonists of ionotropic glutamate receptors and did not appear to be a consequence of a reduction in the intracellula r levels of cAMP [14]. When the stimulation of PPI hydrolysis was meas ured as a function of the incubation time, DCG-IV potentiated quisqual ate-stimulated PPI hydrolysis after 60 min of incubation, when quisqua late had already reached its maximal effect. Knowing that activation o f protein kinase C (PKC) limits the extent of mGluR agonist-stimulated PPI hydrolysis over time, we have studied the enhancing effect of DCG -IV in the presence of the PKC activator, 12-O-tetradecanoylphorbol-13 -acetate (TPA). As expected [9], TPA reduced quisqualate-stimulated PP I hydrolysis in control slices, but was inactive in slices incubated i n the presence of DCG-IV. Taken collectively, these results suggest th at DCG-IV positively modulates the activity of mGluRs coupled to PPI h ydrolysis through a mechanism, which involves PKC-mediated phosphoryla tion processes.