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Modulation of cyclic AMP formation by putative metabotropic receptor agonists
Author(s) -
Cartmell Jayne,
Kemp John A.,
Alexander Stephen P.H.,
Shinozaki Haruhiko,
Kendall David A.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14069.x
Subject(s) - metabotropic receptor , agonist , inositol phosphate , metabotropic glutamate receptor , medicine , endocrinology , adenosine , biology , chemistry , receptor , biophysics , biochemistry , inositol
1 The effects of various metabotropic glutamate receptor agonists on [ 3 H]‐cyclic AMP accumulation and phosphoinositide hydrolysis were investigated in guinea‐pig cerebral cortical slices prelabelled with [ 3 H]‐adenine or [ 3 H]‐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 [ 3 H]‐cyclic AMP accumulation, with IC 50 values of 2.1 ± 0.3, 71 ± 17 and 0.2 ± 0.1 μ m respectively. 3 1S,3R‐ACPD and l ‐CCG‐I increased the cyclic AMP responses to histamine H 2 receptor stimulation with EC 50 values of 7 ± 2 μ m and 19 ± 2 μ m respectively. 1S,3R‐ACPD (EC 50 value 17 ± 2 μ m ) and l ‐CCG‐I (EC 50 value 15 ± 3 μ m ) potentiated the cyclic AMP responses to the adenosine receptor agonist 5′‐N‐ethylcarboxamidoadenosine (NECA, 10 μ m ). 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 IC 50 value of 120 ± 20 μ m . 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 (EC 50 value 35 ± 6 μ m ) and l ‐CCG‐I (approximately 160 μ m ) 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.