G protein γ subunit interaction with a receptor regulates receptor-stimulated nucleotide exchange

The surfaces of heterotrimeric G proteins (alpha beta gamma) 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 gamma subunit blocks muscarinic receptor-stimulated G protein activation in a sequence-dependent fashion. A G protein mutated at the same site on the gamma subunit shows enhanced receptor stimulated nucleotide exchange without affecting G protein hetero-trimerization. Ineffective contact between the gamma subunit and receptor increases the rate of receptor-stimulated nucleotide exchange. Specific interaction of the G protein gamma subunit with the receptor thus helps the beta gamma complex to act at a distance and control guanine nucleotide exchange in the a subunit.