Heterotrimeric G proteins play a critical role in communicating extracellular signals to intracellular signal transduction pathways through transmembrane-spanning G protein-coupled receptors. Using mRNA display, we have recently isolated a number of new peptides that bind the G protein Gi alpha 1. The effects of these peptides on G protein signaling in vivo was observed by electrophysiology, using cell lines expressing GIRK channels-potassium channels that are activated by released G subunits. Peptides were identified that enhance or repress basal levels of signaling, indicating the ability to directly turn G proteins on and off. In vitro binding studies show that the peptides are able to disrupt or stabilize G protein heterotrimers, in accord with the observed in vivo activities. Hence, we have identified ligands that act as direct activators, inhibitors, and attenuators of G protein signaling. These peptide modulators should be useful as tools for probing G protein function and as leads for developing novel molecules with new selectivities and/or functions. Overall our work demonstrates the utility of mRNA display for peptide ligand discovery.

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