Molecular basis of G protein-coupled receptor function

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

SUMMARY Following their activation by extracellular ligands, most GPCRs causes rapid phosphorylation of the activated receptors by GPCR kinases (GRKs), leading to the recruitment of members of the arrestin protein family (beta-arrestin-1 and -2). Beta-arrestin-1/2 binding to the activated receptors disrupts receptor/G protein coupling and promotes GPCR internalization. However, during the past two decades, many studies have demonstrated that beta-arrestins can also act as signaling molecules in their own right. This finding is not only of theoretical interest but also of potential clinical relevance. For example, several studies have shown that ligands with preferential recruit G proteins over Numerous studies have described the development of ligands that selectively activate G proteins without recruiting beta-arrestins or, vice versa, of ligands that can recruit beta-arrestins but are unable to stimulate G protein signaling. Studies with many other GPCRs have shown that this approach may prove useful for the development of novel classes of drugs endowed with enhanced therapeutic efficacy and/or a more favorable side effect profile. Mutant M3 muscarinic receptors biased for G protein activation or recruitment of beta-arrestins During the past three decades, we used the M3 muscarinic acetylcholine receptor (M3R), a prototypic class A GPCR, to identify the molecular basis underlying ligand binding, G protein coupling selectivity, GPCR dimerization, and several other GPCR functions. Recent high-resolution structures of the M3R in complex with chemically diverse muscarinic ligands have created new opportunities for medicinal chemists to develop drugs that selectively target the M3R, in particular given the fact that the M3R regulates key functions of the CNS and many important peripheral effects, including the release of insulin from pancreatic beta-cells. M3R activation leads to the recruitment of G proteins of the Gq family, followed by the binding of beta-arrestins. Our goal is to explore to which extent the recruitment of beta-arrestins by activated M3Rs contributes to the physiological responses caused by M3R activation. Such knowledge may guide the development of so-called biased M3R ligands that preferentially promote either G protein signaling or beta-arrestin recruitment. We developed two biased mutant M3Rs with opposing functional properties. One of the mutant M3Rs selectively activates G proteins, while the other one preferentially recruits beta-arrestins. In a recent study (Biochemistry, Meister et al., 2025), we characterized these functionally biased mutant M3Rs in cultured cells. The future use of these new molecular tools for generating M3R knockin mice or for structural studies could guide the design of new classes of biased M3R ligands endowed with improved therapeutic efficacy. Report publication: Meister J, Wanka L, Perry-Hauser NA, Iverson TM, Gurevich VV, Beck-Sickinger AG, Kruse AC, Wess J. Development of mutant M3 muscarinic receptors biased for G protein activation or recruitment of b-arrestins. Biochemistry 64, 2727-2736, 2025.