Coupling of metabotropic glutamate receptors to phosphoinositide mobilisation and inhibition of cyclic AMP generation in the guinea‐pig cerebellum

• Published in: British journal of pharmacology Vol. 118; no. 2; pp. 311 - 316
• Main Authors: Neil, Karen E., Kendall, David A., Alexander, Stephen P.H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.1996
• Subjects: 2-Chloroadenosine - pharmacology; Animals; Cerebellum - drug effects; Cerebellum - metabolism; Colforsin - pharmacology; cyclic AMP; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Cycloleucine - analogs & derivatives; Cycloleucine - pharmacology; Female; Glutamic Acid - pharmacology; Glycine - analogs & derivatives; Glycine - pharmacology; Guinea Pigs; guinea‐pig cerebellum; In Vitro Techniques; Isoproterenol - pharmacology; Male; Metabotropic glutamate receptors; Phosphatidylinositols - metabolism; phosphoinositide turnover; Receptors, Metabotropic Glutamate - metabolism; Resorcinols - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15404.x

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 [3H]‐inositol phosphates with pEC50 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 pKi value of 3.55±0.03. 4 Forskolin‐stimulated accumulation of [3H]‐cyclic AMP was not significantly altered in the presence of 10 μm DCG‐IV or 300 μm 1S,3R‐ACPD. Similarly, 300 μm 1S,3R‐ACPD failed to alter isoprenaline‐ (1 μm) or 2‐chloroadenosine (2‐CA, 30 μm)‐stimulated accumulation of [3H]‐cyclic AMP. 5 Forskolin‐stimulated accumulation of [3H]‐cyclic AMP was concentration‐dependently inhibited in the presence of L‐glutamate and L‐serine‐O‐phosphate (L‐SOP) with pIC50 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 [3H]‐cyclic AMP was also inhibited by L‐glutamate and L‐SOP with pIC50 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 [3H]‐cyclic AMP was inhibited by L‐glutamate and L‐SOP with pIC50 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.