Modulation of cyclic AMP formation by putative metabotropic receptor agonists.
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)-alpha-(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 microM 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 microM and 19 +/- 2 microM respectively. 1S,3R-ACPD (EC50 values 17 +/- 2 microM) and L-CCG-I (EC50 value 15 +/- 3 microM) potentiated the cyclic AMP responses to the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 10 microM). 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 microM. 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 microM) and L-CCG-I (approximately 160 microM) 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.
Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre.
J
J
Cartmell
J A
JA
Kemp
S P
SP
Alexander
H
H
Shinozaki
D A
DA
Kendall
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006868:Hydrolysis; D066298:In Vitro Techniques; D010716:Phosphatidylinositols / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism
D000600:Amino Acids, Dicarboxylic; D000613:Aminobutyrates; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; C035261:(alpha-carboxycyclopropyl)glycine; D019830:Adenosine-5'-(N-ethylcarboxamide); D000242:Cyclic AMP; C012729:2-amino-4-phosphonobutyric acid; D000241:Adenosine