Hydroxycarboxylic acid receptors: Introduction

G-protein-coupled receptors of the hydroxy-carboxylic acid (HCA) receptor family share significant sequence homology and form a small group of receptors which are encoded by clustered genes. In recent years, endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acids. The HCA1 receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA2 receptor (GPR109A) is a receptor for the ketone body 2-hydroxy-butyric acid, and the HCA3 receptor (GPR109B) is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. HCA1 and HCA2 are found in most mammalian species, whereas HCA3 is only present in higher primates. All three receptors have in common that they are expressed in adipocytes and are coupled to Gi-type G-proteins mediating anti-lipolytic effects in fat cells. The lactate receptor HCA1 appears to be involved in the anabolic effects of insulin in adipocytes, whereas HCA2 and HCA3 are under physiological conditions activated in cases of increased β-oxidation rates and ketone body production and most likely mediate a negative feedback regulation. HCA2 and HCA3 are also expressed in a variety of immune cells, including monocytes, macrophages, neutrophils and Langerhans cells. While the physiological role of this expression is rather unclear, there is evidence that these receptors can mediate anti-inflammatory effects. HCA2 is a receptor for the anti-dyslipidemic drug nicotinic acid (niacin) as well as for the anti-psoriatic drug monomethyl-fumarate. There is an increasing number of synthetic ligands targeting HCA receptors, and their full pharmacological potential is currently evaluated. [1]


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1. Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. (2011) International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev, 63 (2): 269-90. [PMID:21454438]

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