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Coupling of metabotropic glutamate receptors to phosphoinositide mobilisation and inhibition of cyclic AMP generation in the guinea‐pig cerebellum
Author(s) -
Neil Karen E.,
Kendall David A.,
Alexander Stephen P.H.
Publication year - 1996
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.1476-5381.1996.tb15404.x
Subject(s) - metabotropic glutamate receptor , acpd , glutamate receptor , metabotropic receptor , forskolin , metabotropic glutamate receptor 5 , inositol phosphate , medicine , metabotropic glutamate receptor 6 , chemistry , endocrinology , biology , inositol , biochemistry , receptor
1 The effects of metabotropic glutamate receptor (mGluR) agonists on cyclic nucleotide and phosphoinositide turnover were investigated in adult guinea‐pig cerebellar slices by use of radioactive precursors. 2 L‐Glutamate, 1‐aminocyclopentane‐1S,3R‐dicarboxylate (1S,3R‐ACPD) and RS‐3,5‐dihydroxyphe‐nylglycine (DHPG) evoked concentration‐dependent increases in the accumulation of [ 3 H]‐inositol phosphates with pEC 50 values of 2.98±0.02, 4.45±0.06 and 4.47±0.07, respectively. Maximal responses to these agents were 43±8, 52±12 and 84±11% of the response to 1 mM histamine, respectively. 3 The phosphoinositide response to 1S,3R‐ACPD was antagonized in the presence of (+)‐α‐methyl‐4‐carboxyphenylglycine, with a calculated p K i value of 3.55±0.03. 4 Forskolin‐stimulated accumulation of [ 3 H]‐cyclic AMP was not significantly altered in the presence of 10 μ m DCG‐IV or 300 μ m 1S,3R‐ACPD. Similarly, 300 μ m 1S,3R‐ACPD failed to alter isoprenaline‐ (1 μ m ) or 2‐chloroadenosine (2‐CA, 30 μ m )‐stimulated accumulation of [ 3 H]‐cyclic AMP. 5 Forskolin‐stimulated accumulation of [ 3 H]‐cyclic AMP was concentration‐dependently inhibited in the presence of L‐glutamate and L‐serine‐O‐phosphate (L‐SOP) with pIC 50 values of 2.91±0.17 and 2.86±0.04 with maximal inhibitions of 47±2 and 92±3%, respectively. L‐2‐Amino‐4‐phosphonobutyrate (L‐AP4) inhibited the forskolin response without saturating, evoking an inhibition of 71±7% at 3 mM. 6 2‐CA‐evoked accumulation of [ 3 H]‐cyclic AMP was also inhibited by L‐glutamate and L‐SOP with pIC 50 values of 2.71±0.03 and 2.72±0.08 and maximal inhibitions of 51±5 and 99±0%, respectively. L‐AP4 inhibited the 2‐CA response without saturating, evoking an inhibition of 68±1% at 3 mM. 7 Isoprenaline‐evoked accumulation of [ 3 H]‐cyclic AMP was inhibited by L‐glutamate and L‐SOP with pIC 50 values of 3.21±0.01 and 2.96±0.08 and maximal inhibitions of 88±2 and 93±3%, respectively. 8 These results suggest that the guinea‐pig cerebellum expresses Group I and Group III mGluRs coupled to phosphoinositide turnover and inhibition of cyclic AMP generation, respectively.