Turning G Proteins On and Off Using Peptide Ligands
Intracellular Gα 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 Gα. Using messenger RNA display, we have identified unique peptide sequences that bind Gα_(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.
Additional Information© 2006 American Chemical Society. Received 8 September 2006. Date accepted 18 September 2006. Published online 20 October 2006. Published in print 1 October 2006. We thank D. S. Waugh (National Cancer Institute at Frederick) for providing the original pDW363 vector and P. J. Bjorkman for the use of the Biacore 2000 instrument. This work was supported by funding from the National Institutes of Health (GM60416) and the Beckman Foundation (R.W.R.), the Howard Hughes Medical Institute and National Institute of Mental Health (MH63981) (L.Y.J., in the Silvio Conte Center of Neuroscience at the University of California-San Francisco), the European Molecular Biology Organization (O.W.), and a Department of Defense National Defense Science and Engineering Graduate Fellowship (W.W.J.).
Accepted Version - nihms159574.pdf
Supplemental Material - cb600345ksi061020_000000.doc