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

The surfaces of heterotrimeric G proteins (alpha beta gamma) in contact wit h receptors and the molecular events at these sites, which lead to G protei n activation, are largely unknown. We show here that a peptide from the C t erminus of a G protein gamma subunit blocks muscarinic receptor-stimulated G protein activation in a sequence-dependent fashion. A G protein mutated a t the same site on the gamma subunit shows enhanced receptor stimulated nuc leotide exchange without affecting G protein hetero-trimerization. Ineffect ive contact between the gamma subunit and receptor increases the rate of re ceptor-stimulated nucleotide exchange. Specific interaction of the G protei n 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.