G Protein γ Subunit Interaction with a Receptor Regulates Receptor-stimulated Nucleotide Exchange

The surfaces of heterotrimeric G proteins (αβγ) in contact with receptors and the molecular events at these sites, which lead to G protein activation, are largely unknown. We show here that a peptide from the C terminus of a G protein γ subunit blocks muscarinic receptor-stimulated G protein activation in a sequence-dependent fashion. A G protein mutated at the same site on the γ subunit shows enhanced receptor stimulated nucleotide exchange without affecting G protein heterotrimerization. Ineffective contact between the γ subunit and receptor increases the rate of receptor-stimulated nucleotide exchange. Specific interaction of the G protein γ subunit with the receptor thus helps the βγ complex to act at a distance and control guanine nucleotide exchange in the α subunit.