A prenylated peptide specific to the C terminal tail of a G protein gamma subunit type, gamma 5, inhibits activation of a G protein by the M2 muscarinic receptor. The gamma 5 peptide was tested for direct effects on the M2 receptor's properties. The wild type 75 peptide reduced the affinity of M2 for the agonist, carbachol, more than 5-fold in an antagonist displacement assay. The peptide was inactive when its amino acid sequence was scrambled or when it was unprenylated. Although the wild type peptide reduced the affinity of M2 for the antagonist QNB, it had no effect on the antagonists NMS or atropine. These results suggest that in the presence of the peptide the M2 receptor adopts a novel conformational state that affects the ligand binding surface. The results also suggest that the G protein gamma 5 subunit tail interacts with a receptor. (c) 2006 Elsevier Inc. All rights reserved.