Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile

Julie Saugstad, John (Mark) Kinzie, Michi M. Shinohara, Thomas P. Segerson, Gary Westbrook

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Abstract

The metabotropic glutamate receptor (mGluR) cDNAs were originally cloned from rat, except for the mouse cDNA clone encoding mGluR8. Mouse mGluR8 couples weakly to the inhibition of adenylate cyclase, thus hindering the characterization of its pharmacological properties. We isolated a rat mGluR8 cDNA that encodes a protein of 908 amino acids. In situ hybridization revealed prominent mGluR8 mRNA expression in olfactory bulb, pontine gray, lateral reticular nucleus of the thalamus, and piriform cortex. Less abundant expression was detected in cerebral cortex, hippocampus, cerebellum, and mammillary body. Glutamate evoked pertussis toxin-sensitive potassium currents in Xenopus laevis oocytes coexpressing mGluR8 and G protein-coupled inwardly rectifying potassium channels. mGluR8 was also activated by the group III-specific agonist L-2-amino-4-phosphonobutyric acid; (2(S),1'(S),2'(S)]-2-(carboxycyclopropyl)glycine, which has been frequently used as a selective group II agonist; and the nonselective agonist (1(S),3(R)]-1-aminocyclopentane-1,3-dicarboxylic acid but not by the group I- specific agonist 3,5-dihydroxyphenylglycine or the group II-specific agonist [2(S), 1'(R),2'(R),3'(R)]-2-(2,3-dicarboxycyclopropyl)glycine. The agonist profile in order of potency was [2(S),1'(S),2'(S)]-2- (carboxycyclopropyl)glycine ≃ L-2-amino-4-phosphonobutyric acid > glutamate >> [1(S),3(R)]-1-aminocyclopentane-1,3-dicarboxylic acid, with EC50 values of 0.63, 0.67, 2.5, and 47 μM, respectively. Both the group I/II-specific antagonist (R,S)-α-methyl-4-carboxyphenylglycine and the group III-specific antagonist α-methyl-amino-phosphonobutyrate inhibited mGluR8. The pharmacological profile of mGluR8 is distinct among mGluRs but closely matches that of presynaptic inhibition in some central nervous system pathways. Thus, cellular responses mediated by both group II and III agonists may in some cases reflect activation of mGluR8 rather than multiple mGluR subtypes.

Original languageEnglish (US)
Pages (from-to)119-125
Number of pages7
JournalMolecular Pharmacology
Volume51
Issue number1
StatePublished - Jan 1997

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Organism Cloning
Pharmacology
Metabotropic Glutamate Receptors
Complementary DNA
Glutamic Acid
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Mammillary Bodies
Lateral Thalamic Nuclei
metabotropic glutamate receptor 8
Olfactory Bulb
Pertussis Toxin
Xenopus laevis
Adenylyl Cyclases
Cerebral Cortex
Cerebellum
Oocytes
In Situ Hybridization
Hippocampus
Potassium
Central Nervous System

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile. / Saugstad, Julie; Kinzie, John (Mark); Shinohara, Michi M.; Segerson, Thomas P.; Westbrook, Gary.

In: Molecular Pharmacology, Vol. 51, No. 1, 01.1997, p. 119-125.

Research output: Contribution to journalArticle

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