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Vollum Institute for Advanced Biomedical Research (J.A.S., J.M.K.,
M.M.S., G.L.W.) and Departments of
Medicine (T.P.S.) and
Neurology
(G.L.W.), Oregon Health Sciences University, Portland, Oregon 97201
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)-
-methyl-4-carboxyphenylglycine and the group III-specific antagonist
-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.
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