Modulation of cyclic AMP formation by putative metabotropic receptor agonists

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Abstract
1 The effects of various metabotropic glutamate receptor agonists on [3H]-cyclic AMP accumulation and phosphoinositide hydrolysis were investigated in guinea-pig cerebral cortical slices prelabelled with [3H]-adenine or [3H]-inositol. 2 1-Aminocyclopentane-1S,3R-dicarboxylate (1S,3R-ACPD), l-2-amino-4-phosphonobutanoate (l-AP4) and (2S,3S,4S)-α-(carboxycyclopropyl)glycine (l-CCG-I), elicited concentration-dependent inhibitions of forskolin-stimulated [3H]-cyclic AMP accumulation, with IC50 values of 2.1 ± 0.3, 71 ± 17 and 0.2 ± 0.1 μm respectively. 3 1S,3R-ACPD and l-CCG-I increased the cyclic AMP responses to histamine H2 receptor stimulation with EC50 values of 7 ± 2 μm and 19 ± 2 μm respectively. 1S,3R-ACPD (EC50 value 17 ± 2 μm) and l-CCG-I (EC50 value 15 ± 3 μm) potentiated the cyclic AMP responses to the adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA, 10 μm). This potentiating effect of l-CCG-I was reduced in the presence of a protein kinase C inhibitor, and also in the absence of extracellular calcium. In contrast, l-AP4 inhibited the NECA response in a concentration-dependent manner, with an IC50 value of 120 ± 20 μm. 4 l-AP4 (at concentrations up to 1 mM) failed to stimulate phosphoinositide hydrolysis in guinea-pig cerebral cortical slices, but both 1S,3R-ACPD (EC50 value 35 ± 6 μm) and l-CCG-I (approximately 160 μm) elicited concentration-dependent stimulations of phosphoinositide turnover. 5 These results confirm the existence of at least two distinct subtypes of metabotropic receptor in guinea-pig cortex. The data also substantiate previous studies indicating the importance of the agonist l-CCG-I as a pharmacological tool for distinguishing metabotropic receptor subtypes.