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Identification of GPCR signaling pathways critical for regulating glucose and energy homeostasis

G protein-coupled receptors (GPCRs) are the target of about one third of drugs in current clinical use, indicative of the extraordinary clinical relevance of this protein family. Like other cell types, metabolically important cell types, such as hepatocytes, adipocytes, and endocrine cells of the pancreas, express dozens of GPCRs endowed with distinct G protein coupling properties. Heterotrimeric G proteins are grouped into four major subfamilies which activate or inhibit distinct intracellular pathways: Gs, Gi, Gq, and G12. Virtually all GPCRs are expressed in multiple tissues and cell types, making it difficult to asses the in vivo metabolic roles of a specific GPCR expressed by a particular cell type. To address this issue, our lab is using designer GPCRs known as DREADDs (Designer Receptors Exclusively Activated by a Designer Drug) to study the metabolic roles of activating specific classes of G proteins in distinct cell types in vivo. Most DREADDs represent mutant muscarinic acetylcholine receptors that are selectively linked to either Gs, Gi, Gq, or G12. These designer GPCRs can be effectively activated by certain clozapine derivates, such as clozapine-N-oxide (CNO) or deschloroclozapine (DCZ), but not by acetylcholine, the endogenous muscarinic receptor agonist. When used in the proper concentration/dose range, CNO and DCZ are pharmacologically inert. My lab has generated and analyzed many novel mouse strains that express specific DREADDs in distinct cell types that are critically involved in maintaining glucose and energy homeostasis. Systematic phenotypic analysis of these various mouse strains has led to many novel insights into the metabolic roles of specific GPCR/G protein signalling pathways. During my talk, I will focus on recent work involving the use of DREADD technology, complemented by gene knockout studies in mice, to identify novel targets for the treatment of type 2 diabetes and related metabolic disorders.

The 99th Annual Meeting of the Japanese Pharmacological Society

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[2-SL-05]Identification of GPCR signaling pathways critical for regulating glucose and energy homeostasis

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