CHARACTERIZATION OF METABOTROPIC GLUTAMATE RECEPTOR-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN RAT CULTURED CEREBELLAR GRANULE CELLS

1 The pharmacology of excitatory amino acid (EAA)-stimulated phosphoin ositide (PI) hydrolysis, monitored via [H-3]-inositol monophosphate ac cumulation, was investigated in primary cultures of rat cerebellar gra nule cells. 2 EAA-stimulated PI hydrolysis peaked after 4-5 days in vi tro and subsequently declined. 3 The agonist order of potency was foun d to be (EC(50)): L-quisqualic acid (Quis) (2 mu M)]]L-glutamate (50 m u M)>(1S,3R)-1-aminocydopentane-1,3-dicarboxylic acid ((1S,SR)-ACPD) ( 102 mu M). L-Glutamate (E(max)=873% of basal activity) elicited the la rgest stimulation of PI hydrolysis, whereas Quis (E(max)=603%) and (1S ,3R)-ACPD (E(max)=306%) produced somewhat lower stimulations. 4 Severa l phenylglycine derivatives were found to be active in inhibiting 2 mu M Quis-stimulated PI hydrolysis, in order of potency (IC50): (S)-4-ca rboxy-3-hydroxyphenylglycine (41 mu M)greater than or equal to(S)-4-ca rboxyphenylglycine (51 mu M)]](+)-alpha-methyl-4-carboxyphenylglycine (243 mu M). 5 Cultured cerebellar granule cells of the rat appear to h ave Group I mGluR pharmacology similar to that reported for cloned mGl uR1 and provide an ideal system for investigating novel mGluR1 ligands in a native environment.