TYPE 4A METABOTROPIC GLUTAMATE-RECEPTOR - IDENTIFICATION OF NEW POTENT AGONISTS AND DIFFERENTIATION FROM THE L-(-2-AMINO-4-PHOSPHONOBUTANOIC ACID-SENSITIVE RECEPTOR IN THE LATERAL PERFORANT PATHWAY IN RATS())

Before the discovery of the metabotropic glutamate receptors (mGluRs), the glutamate analogue L-2-amino-4-phosphonobutanoic acid (L-AP4) was identified as a potent presynaptic inhibitor of evoked synaptic trans mission in the lateral perforant pathway in rats. The localization and L-AP4 sensitivity of the mGluR4a subtype of mGluRs were consistent wi th the hypothesis that this receptor mediates the synaptic depressant effects of L-AP4 in the lateral perforant pathway. In the present stud y, the pharmacology of mGluR4a expressed in baby hamster kidney 570 ce lls was characterized and compared with that previously reported for t he lateral perforant pathway responses. The endogenous excitatory amin o acid L-aspartate was inactive at mGluR4a, whereas L-homocysteic acid was only 5-fold less potent than L-glutamate. These data suggest that L-homocysteic acid may be an endogenous agonist at mGluR4a. Of the 30 L-AP4 analogues examined, several compounds were identified as agonis ts at mGluR4a. The cyclopropyl-AP4 analogue (Z)-(+/-)-2-amino-2,3-meth ano-4-phosphonobutanoic acid inhibited forskolin-stimulated cAMP produ ction with an EC(50) of 0.58 mu M, which is comparable to that of L-AP 4 (EC(50) = 0.43 mu M). Two other cyclic analogues of L-AP4 were appro ximately 10-fold less potent as agonists at mGluR4a, i.e., -amino-3-(p hosphonomethylene)cyclobutanecarboxylic acid (EC(50) = 4.4 mu M) and ( E)-(+/-)-2-amino-2,3-methano-4-phosphonobutanoic acid (EC(50) = 7.9 mu M). Comparison of the potencies of the compounds for activation of mG luR4a with their potencies for inhibition of lateral perforant pathway responses demonstrates that some compounds have comparable activities in the two systems, whereas several compounds are at least 10-fold mo re potent in one of the systems. In addition, although the mGluR antag onist (+)-alpha-methyl-4-carboxyphenylglycine blocked the effects of L -AP4 in the lateral perforant pathway, it did not block the effects of L-AP4 at the cloned receptor. These data provide evidence that mGluR4 a does not mediate the effects of L-AP4 in the lateral perforant pathw ay, they provide new tools to identify the function of these receptors in the mammalian central nervous system, and they indicate that the e ffects of L-AP4 in the lateral perforant pathway are mediated by a (+) -alpha-methyl-4-carboxyphenylglycine-sensitive receptor.