Turning G proteins on and off using peptide ligands.
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.
Ja
William W
WW
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Wiser
Ofer
O
Austin
Ryan J
RJ
Jan
Lily Y
LY
Roberts
Richard W
RW
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
D018076:DNA, Complementary; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008024:Ligands; D010455:Peptides; D019204:GTP-Binding Proteins