MPI for Heart and Lung Research
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Project leaders: Dr. Sorin Tunaru, Dr. Sarah Tonack, Dr. Remy Bonnavion, Dr. M. Wessam Alnouri

PhD Students: Isabell Brandenburger, Alan LeMercier

Technical Assistant: Kathrin Adolph

human non-olfactory GPCRs

Human non-olfactory G-pro­tein-coupled receptors (GPCRs). Established drug targets are in red, orphan GPCRs are in green.

G-protein-coupled receptors (GPCRs) are the largest receptor family in mammals, with about 800 receptors encoded in the human genome. Almost half of the receptors are olfactory receptors, whereas the remaining receptors respond to a wide spectrum of different ligands. For about 150 GPCRs no ligand has so far been described, making them “orphan GPCRs”. Every cell of the body expresses at least 15 to 20 GPCRs, which are involved in the regulation of all body functions. Their high ligand selectivity and their central and specific role in the modulation of physiological and pathophysiological processes make GPCRs ideal drug targets, and about a third of all approved drugs act through GPCRs.

In the past, we have identified new receptors activated by metabolites such as lactate, ketone bodies and free fatty acids (Tunaru et al., 2003; Ahmed et al., 2010; Offermanns, 2014; Blad et al., 2012). Using complex mouse genetics, we have been able to elucidate the role of several of these receptors in the pharmacological effects of drugs (Hanson et al., 2010; Lukasova et al., 2011), in the regulation of insulin secretion (Tang et al., 2015) as well as in endothelial flow sensing and blood pressure regulation (Wang et al., 2015). Using siRNA-based approaches, we have identified new ligand receptor pairs (Tunaru et al., 2012). Current work mainly focuses on orphan GPCRs and aims at the identification of new physiological GPCR ligands mainly in the areas of the cardiovascular system, metabolism and cancer.

Literature

Wang S, Iring A, Strilic B, Albarrán Juárez J, Kaur H, Troidl K, Tonack S, Burbiel JC, Müller CE, Fleming I, Lundberg JO, Wettschureck N, Offermanns S (2015). P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction. J. Clin. Invest. 125: 3077-3086

Offermanns S (2014). Free Fatty Acid (FFA) and Hydroxy Carboxylic Acid (HCA) Receptors. Annu. Rev. Pharmacol. Toxicol. 54: 407-434

Tunaru S, Althoff TF, Nusing RM, Diener M, Offermanns S (2012). Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP3 receptors. Proc. Natl. Acad. Sci. U. S. A. 109: 9179-9184

Blad CC, Tang C, Offermanns S (2012). G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat. Rev. Drug. Discov. 11: 601-619

Lukasova M, Malaval C, Gille A, Kero J, Offermanns S (2011). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J. Clin. Invest. 121: 1163-1173

Ahmed K, Tunaru S, Tang C, Müller M, Gille A, Sassmann A, Hanson J, and Offermanns S (2010). An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab. 11: 311-319

Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, Tunaru S, Wirth A, Offermanns S (2010). Keratinocytes express GPR109A and mediate epidermal effects of nicotinic acid and mono-Methyl fumarate via COX-2-dependent prostanoid formation J. Clin. Invest. 120: 2910-2919

Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. 2003. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat. Med. 9: 352-355