Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs

Wang, Lei; Zhu, Lu; Meister, Jaroslawna; Bone, Derek B J; Pydi, Sai Prasad; Rossi, Mario; Wess, Jürgen

doi:10.1146/annurev-pharmtox-030220-121042

Cited by 30 publications

(27 citation statements)

References 112 publications

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“…Originally, beta-arrestins were identified as regulators of GPCR internalization and desensitization [22]; however, more recent studies have shown that beta-arrestins can also act as signaling molecules on their own, mediating G protein-independent signaling [23][24][25][26][27][28][29][30]. GPCRs modulate a very large number of metabolic functions including glucose production, glucose uptake, insulin action, insulin secretion, and differentiation and expansion of various cell types [5,[31][32][33][34][35][36][37]. Thus, it is not surprising that GPCRs have emerged as prime drug targets for the treatment of metabolic diseases such as obesity and T2D.…”

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Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

et al. 2021

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The incidence of obesity and type 2 diabetes (T2D) has been increasing steadily worldwide. It is estimated that by 2045 more than 800 million people will be suffering from diabetes. Despite the advancements in modern medicine, more effective therapies for treating obesity and T2D are needed. G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity, T2D, and liver diseases. During the past two decades, many laboratories worldwide focused on understanding the role of GPCR signaling in regulating glucose metabolism and energy homeostasis. The information gained from these studies can guide the development of novel therapeutic agents. In this review, we summarize recent studies providing insights into the role of GPCR signaling in peripheral, metabolically important tissues such as pancreas, liver, skeletal muscle, and adipose tissue, focusing primarily on the use of mutant animal models and human data.

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Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

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“…In most cases, CNO treatment of the various DREADD mutant mice resulted in robust metabolic phenotypes. In many cases, the observed phenotypic changes were more pronounced when mice were maintained on a high-fat (obesogenic) diet which causes impaired glucose tolerance and insulin sensitivity, two hallmarks of type 2 diabetes (T2D) (8,12). To demonstrate that DREADD-mediated responses do not diminish over time, several studies also examined the metabolic effects of chronic CNO treatment [e.g (13)(14)(15)].…”

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“…Activated G protein α-subunits stimulate or inhibit distinct intracellular effector enzymes or ion channels. This figure represents a modified version of Figure 1 published in ( 8 ). Epac, exchange protein activated by cAMP; GIRK, G-protein-regulated inward-rectifier potassium channel; LARG, Leukemia-Associated RhoGEF; PLCβ, phospholipase Cβ; PKA, protein kinase A; PKC, protein kinase C; RhoGEF, Rho guanine nucleotide exchange factor; ROCK, Rho-associated coiled-coil-containing protein kinase; VDCC, voltage-dependent Ca 2+- channel.…”

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“…During the past decade, we and other laboratories generated many mutant mouse strains that express different DREADDs in distinct cell types that are critical for maintaining glucose and energy homeostasis [for recent reviews, see ( 8 , 12 )]. These include β- and α-cells of the endocrine pancreas, adipocytes, hepatocytes, skeletal muscle cells, and distinct neuronal subpopulations of the hypothalamus.…”

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“…The metabolic phenotypes observed after CNO treatment of the different DREADD mutant mouse lines led to the identification of several distinct GPCR signaling pathways critical for the maintenance of glucose and/or energy homeostasis ( 8 , 12 ). For example, studies with DREADD mutant mice suggest that agents able to disrupt hepatocyte G q , G s , or G i signaling may prove useful to restore euglycemia under pathophysiological conditions associated with enhanced hepatic glucose production (e.g.…”

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Designer GPCRs as Novel Tools to Identify Metabolically Important Signaling Pathways

Wess

2021

Front. Endocrinol.

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G-protein coupled-receptors (GPCRs) form a very large family of cell surface receptors that respond to an extraordinary variety of extracellular ligands and sensory stimuli (1). The human genome codes for~800 distinct GPCR genes, representing~3-4% of all human genes (2). Approximately 1/3 of all FDA-approved drugs act on one or more GPCRs, indicative of the enormous clinical relevance of this class of receptors (3). Upon binding of extracellular ligands, GPCRs activate distinct classes of heterotrimeric G proteins, which are composed of four major subfamilies, G s , G i , G q , and G 12 (heterotrimeric G proteins are named after the a-subunits present in the heterotrimeric complex) (4). The receptor-activated a-subunits then modulate the activity of distinct intracellular signaling pathways (4) (also see Figure 1).Like all other cells, metabolically relevant cell types express dozens of different GPCRs (9). However, each individual GPCR is expressed by many other cell types and tissues (9). Moreover, agonist and/or antagonist ligands with high selectivity for a particular GPCR are not available in many cases. For these reasons, it has been very challenging to elucidate the in vivo metabolic roles of specific GPCR/G protein signaling pathways operative in a particular cell type.To circumvent these obstacles, my lab, as well as other research groups, started to employ a chemogenetic approach involving the use of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) (5). Structurally, the most commonly used DREADDs are mutant muscarinic acetylcholine receptors which, due to the presence of two point mutations in the transmembrane core, show little or no activity in the presence of acetylcholine, the endogenous muscarinic receptor agonist (Figure 1). However, muscarinic receptor-based DREADDs can be efficiently activated by a synthetic compound called clozapine-N-oxide (CNO) (5, 6). CNO is otherwise pharmacologically inert, at least when used in the proper dose or concentration range. More recently, CNO derivatives with increased metabolic stability and improved pharmacokinetic properties have been described (10,11). During the past 15 years,

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The dawn has come for new therapeutics to treat atherosclerosis: Targeting neuroimmune cardiovascular interfaces in artery brain circuits

Mohanta

Weber

Yin

et al. 2022

Clinical & Translational Med

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Atherosclerosis is the leading cause of mortality worldwide. However, regrettably, there are no treatment options that target the root causes of the disease, as its pathogenic mechanisms largely remain to be defined. Atherosclerosis has been viewed as a chronic inflammatory and unresolvable condition of all three arterial wall layers: Plaques develop in the inner intima layer of arteries leading to lumen narrowing and reduction of blood flow to downstream tissues, and when critical thresholds are breached, they cause heart attacks and strokes; smooth muscle cells in the media layer transdifferentiate into a synthetic and migratory phenotype and participate in artery remodelling by changing their transcriptome profile and secreting cytokines; and immune cells accumulate in the outer connective tissue coat of arteries, that is, the adventitia, andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs

Cited by 30 publications

References 112 publications

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

Designer GPCRs as Novel Tools to Identify Metabolically Important Signaling Pathways

The dawn has come for new therapeutics to treat atherosclerosis: Targeting neuroimmune cardiovascular interfaces in artery brain circuits

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