COUPLING OF METABOTROPIC GLUTAMATE RECEPTOR-2 AND RECEPTOR-4 TO G(ALPHA-15), G(ALPHA-16), AND CHIMERIC G(ALPHA-Q I) PROTEINS - CHARACTERIZATION OF NEW ANTAGONISTS/
J. Gomeza et al., COUPLING OF METABOTROPIC GLUTAMATE RECEPTOR-2 AND RECEPTOR-4 TO G(ALPHA-15), G(ALPHA-16), AND CHIMERIC G(ALPHA-Q I) PROTEINS - CHARACTERIZATION OF NEW ANTAGONISTS/, Molecular pharmacology, 50(4), 1996, pp. 923-930
Together with the calcium-sensing receptor, the metabotropic glutamate
receptors (mGluRs) share no sequence homology with the other G protei
n-coupled receptors (GPCRs) and therefore constitute a new family of r
eceptors. Recently, it was reported that G(alpha 15) and G(alpha 16) s
ubunits allow many GPCRs to activate phospholipase C (PLC). Furthermor
e, the exchange of a few carboxyl-terminal residues of G(alpha q) by t
hose of G(alpha i2) of G(alpha o) allows the resulting chimeric G(alph
a) subunits (G(alpha qi) and G(alpha qo), respectively) to couple G(i)
-coupled receptors to PLC. We report that mGluR2 and mGluR4, two recep
tors negatively coupled to adenylyl cyclase, activate PLC when coexpre
ssed with G(alpha 15), G(alpha qi), or G(alpha qo). This indicates tha
t the carboxyl-terminal end of the G(alpha) subunit also plays an impo
rtant role in the specific interaction between mGluRs and the G protei
ns. In addition, the measurement of PLC activation by G(i)-coupled mGl
uRs coexpressed with these G(alpha>) subunits constitutes an easy func
tional assay for the pharmacological characterization of these recepto
rs, The rank order of potency of antagonists was found to be (2S,3S,4S
)-2-methyl-2-(carboxycyclopropyl)glycine approximate to (R,S)-alpha-me
thyl-4-phosphonophenylglycine > (R,S)-alpha-methyl-4-sulfonophenylglyc
ine > (R,S)-alpha-methyl-4-tetrazolylphenylglycine = (S)-2-amino-2-met
hyl-4-phosphonobutyrate for mGluR2 and to be (R,S)-alpha-methyl-4-phos
phonophenylglycine greater than or equal to (S)-2-amino-2-methyl-4-pho
sphonobutyrate >> (R,S)-alpha-methyl-4-sulfonophenylglycine [(R,S)-alp
ha-methyl-4-tetrazolylphenylglycine and (2S,3S,4S)-2-methyl-2-(carboxy
cyclopropyl)glycine being inactive at 1 mM] for mGluR4. Using this fun
ctional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found t
o have a similar K-B value for mGluR2 and mGluR4.