title: A G protein gamma subunit-specific peptide inhibits muscarinic receptor signaling.
abstract: Muscarinic acetylcholine receptors modulate the function of a variety of effectors through heterotrimeric G proteins. A prenylated peptide specific to the G protein gamma5 subunit type inhibits G protein activation by the M2 muscarinic receptor in a reconstitution assay. Scrambling the amino acid sequence of the peptide significantly reduces the efficacy of the peptide. The peptide does not disrupt the G protein heterotrimer. In cultured sympathetic neurons, the gamma5 peptide inhibits modulation of Ca(2+) current by the M4 receptor. Peptide activity is specific, the scrambled peptide and peptides specific to two other members of the G protein gamma subunit family are significantly less effective. The gamma5 peptide has no effect on Ca(2+) current modulation by the alpha2-adrenergic and somatostatin receptors. In addition, the gamma5 peptide inhibits muscarinic receptor signaling in spinal cord slices with specificity. These results support a specific role for G protein gamma subunit types in signal transduction, most likely at the receptor-G protein interface.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: I
authors.initials: I
authors.lastname: Azpiazu
authors.forename: H
authors.initials: H
authors.lastname: Cruzblanca
authors.forename: P
authors.initials: P
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Linder
authors.forename: M
authors.initials: M
authors.lastname: Zhuo
authors.forename: N
authors.initials: N
authors.lastname: Gautam
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D006224:Cricetinae; D003593:Cytoplasm / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D066298:In Vitro Techniques; D019832:N-Methylscopolamine / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010095:Oxotremorine / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D043588:Receptor, Muscarinic M4; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000502:physiology*; D014162:Transfection
chemical_list: D015220:Calcium Channels; D010446:Peptide Fragments; D043588:Receptor, Muscarinic M4; D018341:Receptors, Adrenergic, alpha-2; D011976:Receptors, Muscarinic; D017481:Receptors, Somatostatin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010095:Oxotremorine; D002217:Carbachol; D020962:Heterotrimeric GTP-Binding Proteins; D003000:Clonidine; D002118:Calcium; D019832:N-Methylscopolamine