Thursday, March 13, 2025
3/13/2025
PROJECT SUMMARY/ABSTRACT G protein-coupled receptors (GPCRs) are important targets of hormones, neurotransmitters and approximately one-third of FDA-approved drugs. These receptors signal by coupling to transducer proteins from four families of heterotrimeric G proteins and a family of four arrestins. Recent structural and functional studies have defined a conventional allosteric mechanism whereby ligand binding to receptors promotes activation of G proteins and arrestins. However, there is extensive functional diversity across hundreds of GPCRs and sixteen G proteins, and many examples of physiology and pharmacology do not conform to the conventional model. For example, we have found significant variability in the mechanism whereby GPCRs select appropriate G proteins, and some receptors that recognize unconventional G protein determinants for selectivity. We have also found some receptors that paradoxically inhibit G protein signaling instead of the usual activation, a type of GPCR-G protein coupling that is unproductive. Finally, we have found receptors that associate with G proteins prior to ligand binding and on average release G proteins after activation, a type of inverse coupling that can explain the unusal pharmacology of such receptors. A complete understanding of GPCR-mediated signaling will require a better understanding of these unconventional GPCR-G protein coupling mechanisms. In addition, it will be necessary to translate molecular studies carried out with overexpressed molecules in model cells to endogenously-expressed GPCRs and G proteins in their native context, where expression levels, stoichiometry and subcellular compartmentalization more closely match the in vivo situation. Accordingly, we will carry out studies to map unconventional selectivity determinants, determine the prevalence and physiological significance of unproductive and inverse GPCR-G protein coupling, and to better understand the conformational dynamics of GPCRs in cell membranes, and how this conformational landscape changes as receptors bind ligands and interact with transducer molecules.
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