Extreme C terminus of G protein α-subunits contains a site that discriminates between G(i)-coupled metabotropic glutamate receptors

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Abstract

Metabotropic glutamate receptors (mGlu receptors), the Ca2+-sensing receptor, γ-aminobutyric acid type B receptors, and one group of pheromone receptors constitute a unique family (also called family 3) of heptahelical receptors. This original family shares no sequence similarity with any other G protein-coupled receptors. The identification and comparison of the molecular determinants of receptor/G protein coupling within the different receptor families may help identify genera] rules involved in this protein/protein interaction. In order to detect possible contact sites important for coupling selectivity between family 3 receptors and the G protein α-subunits, we examined the coupling of the cyclase-inhibiting mGlu2 and mGlu4 receptors to chimeric α(q)-subunits bearing the 5 extreme C- terminal amino acid residues of either Gα(i), Gα(o), or Gα(z). Whereas mGlu4 receptor activated all three chimeric G proteins, mGlu2 receptor activated Gα(qi) and Gα(qo) but not Gα(qz). The mutation of isoleucine-4 of Gα(qz) into cysteine was sufficient to recover coupling of the mutant G protein to mGlu2 receptor. Moreover, the mutation of cysteine -4 of Gα(qo) into isoleucine was sufficient to suppress the coupling to mGlu2 receptor. Mutations at positions -5 and -1 had an effect on coupling efficiency, but not selectivity. Our results emphasize the importance of the residue -4 of the α-subunits in their specific interaction to heptahelical receptors by extending this finding on the third family of G protein-coupled receptors.

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Blahos, J., Mary, S., Perroy, J., De Colle, C., Brabet, I., Bockaert, J., & Pin, J. P. (1998). Extreme C terminus of G protein α-subunits contains a site that discriminates between G(i)-coupled metabotropic glutamate receptors. Journal of Biological Chemistry, 273(40), 25765–25769. https://doi.org/10.1074/jbc.273.40.25765

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