MODULATION BY IONOTROPIC EXCITATORY AMINO-ACIDS AND POTASSIUM OF (+ -)-1-AMINOCYCLOPENTANE-TRANS-1,3-DICARBOXYLIC ACID-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN MOUSE CEREBELLAR GRANULE CELLS/

The effect of ionotropic excitatory amino acids and potassium on the f ormation of inositol phosphates elicited by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic aci d (trans-ACPD) was studied in mouse cerebellar granule cells. In Mg2+- containing buffers, NMDA (50-100 mu M), alpha-amino-3-hydroxy-5-methyl -4-isoxazole propionate (AMPA; 10-1,000 mu M), and high potassium (10- 30 mM) enhanced synergistically the response to a maximally effective concentration of 500 mu M trans-ACPD. Potentiation of the trans-ACPD r esponse was blocked by higher concentrations of NMDA (>500 mu M) and p otassium (>35 mM) but not by AMPA (up to 1 mM). The potentiation by NM DA of the trans-ACPD-stimulated phosphoinositide hydrolysis was blocke d by D,L-2-amino-5-phosphonopentanoic acid (APV), a competitive NMDA-r eceptor antagonist, Under Mg2+-free conditions, the accumulation of in ositol phosphates in the presence of trans-ACPD alone was equal to tha t attained by trans-ACPD in Mg2+-containing buffers when costimulated with maximally enhancing concentrations of NMDA (50 mu M). trans-ACPD potentiated synergistically the NMDA-evoked increases in cytosolic fre e-Ca2+ levels in Mg2+-containing but not in Mg2+-free solutions, and m oreover did not enhance the AM PA-evoked increases in cytosolic free-C a2+ levels. The calcium ionophore A23187 caused a dose-dependent incre ase in inositol phosphate accumulation but did not enhance the respons e stimulated by trans-ACPD alone. These results demonstrate the existe nce of cross talk between metabotropic and ionotropic glutamate recept ors in cerebellar granule cells. The exact mechanism remains unclear b ut appears to involve interplay of G protein-coupled phospholipase C a ctivation and regulated elevation of cytosolic free-Ca2+ levels. This study may provide a framework for future investigations at the cellula r and molecular level that clarify the functional relevance and molecu lar mechanisms that are described.