A G protein gamma subunit-specific peptide inhibits muscarinic receptor signaling

Muscarinic acetylcholine receptors modulate the function of a variety of ef fecters through heterotrimeric G proteins. A prenylated peptide specific to the G protein gamma 5 subunit type inhibits G protein activation by the M2 muscarinic receptor in a reconstitution assay. Scrambling the amino acid s equence of the peptide significantly reduces the efficacy of the peptide. T he peptide does not disrupt the G protein heterotrimer. In cultured sympath etic neurons, the gamma 5 peptide inhibits modulation of Ca2+ current by th e M4 receptor. Peptide activity is specific, the scrambled peptide and pept ides specific to two other members of the G protein gamma subunit family ar e significantly less effective. The gamma 5 peptide has no effect on Ca2+ c urrent modulation by the alpha 2-adrenergic and somatostatin receptors. In addition, the gamma 5 peptide inhibits muscarinic receptor signaling in spi nal cord slices with specificity. These results support a specific role for G protein gamma subunit types in signal transduction, most likely at the r eceptor-G protein interface.