title: Turning G proteins on and off using peptide ligands.
abstract: Intracellular Galpha subunits represent potential therapeutic targets for a number of diseases. Here we describe three classes of new molecules that modulate G protein signaling by direct targeting of Galpha. Using messenger RNA display, we have identified unique peptide sequences that bind Galpha i1 . Functionally, individual peptides were found that either enhance or repress basal levels of G protein-activated inwardly rectifying potassium (GIRK) channel signaling, a downstream effector of G protein activation, indicating that the peptides directly turn G proteins on or off in vivo . A third functional class acts as a signaling attenuator; basal GIRK channel activity is unaffected but responses to repeated G protein activation are reduced. These data demonstrate that G protein-directed ligands can achieve physiological effects similar to those resulting from classical receptor targeting and may serve as leads for developing new classes of therapeutics.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Ja
authors.forename: Ofer
authors.initials: O
authors.lastname: Wiser
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Austin
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Jan
authors.forename: Richard W
authors.initials: RW
authors.lastname: Roberts
mesh_terms: D000595:Amino Acid Sequence; D001671:Biochemistry / Q000379:methods; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D018076:DNA, Complementary; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008024:Ligands; D010455:Peptides; D019204:GTP-Binding Proteins