Biological Roles and Therapeutic Potential of Hydroxy-Carboxylic Acid Receptors

Abstract

In the recent past, deorphanization studies have described intermediates of energy metabolism to activate G protein-coupled receptors and to thereby regulate metabolic functions. GPR81, GPR109A, and GPR109B, formerly known as the nicotinic acid receptor family, are encoded by clustered genes and share a high degree of sequence homology. Recently, hydroxy-carboxylic acids were identified as endogenous ligands of GPR81, GPR109A, and GPR109B, and therefore these receptors have been placed into a novel receptor family of hydroxy-carboxylic acid (HCA) receptors. The HCA1 receptor (GPR81) is activated by the glycolytic metabolite 2-hydroxy-propionic acid (lactate), the HCA2 receptor is activated by the ketone body 3-hydroxy-butyric acid, and the HCA3 receptor (GPR109B) is a receptor for the β-oxidation intermediate 3-hydroxy-octanoic acid. While HCA1 and HCA2 receptors are present in most mammalian species, the HCA3 receptor is exclusively found in humans and higher primates. HCA receptors are expressed in adipose tissue and mediate anti-lipolytic effects in adipocytes through Gi-type G protein-dependent inhibition of adenylyl cyclase. HCA2 and HCA3 inhibit lipolysis during conditions of increased β-oxidation such as prolonged fasting, whereas HCA1 mediates the anti-lipolytic effects of insulin in the fed state. As HCA2 is a receptor for the established anti-dyslipidemic drug nicotinic acid, HCA1 and HCA3 also represent promising drug targets and several synthetic ligands for HCA receptors have been developed. In this article, we will summarize the deorphanization and pharmacological characterization of HCA receptors. Moreover, we will discuss recent progress in elucidating the physiological and pathophysiological role to further evaluate the therapeutic potential of the HCA receptor family for the treatment of metabolic disease.

Blood clotting behavior is innately modulated in Ursus Americanus during early and late denning relative to summer months

“…Nevertheless, the ACT analyzer we employed performed an automated temperature correction, so it is likely that this part of the clotting cascade should not have been affected by their state of mild hypothermia. In addition to the effect on enzymatic activity, hypothermia can also induce an inhibition of platelet function (Ahmed, 2011;Polderman, 2012).…”

Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives

“…ßOHB is also a ligand for 2 G‐protein‐coupled receptors that bind short‐chain fatty acids: hydroxycarboxylic acid receptor 2 (HCAR2) and the free fatty acid receptor 3 (FFAR3 or GPR41). ßOHB has been identified as an endogenous agonist of HCAR2 . Its activation by βOHB increases β‐oxidation and thereby ketone body formation while simultaneously inhibiting lipolysis and restricting further supply of fatty acids for ketogenesis to maintain energy homeostasis.…”

Gpr81 Lactate Receptors in the Regulation of Cell Functional Activity

“…Иссле-дование влияния лактата на другие рецепторы этого же семейства (такие как HCA2, HCA3) показало, что стимуляция лактатом HCA2 и HCA3 рецепторов не вы-зывает их активацию, несмотря на высокую степень гомологии с НСА1. Следовательно, лактат является высокоспецифичным агонистом для HCA1 рецепторов [2,9,30]. GPR81 относится к G-белок-сопряженным ре-цепторам (GPCR) класса А/1 (родопсиновые рецепто-ры), подкласс А11, и впервые был найден в поисковой базе данных с использованием алгоритма BLAST [6,23].…”

“…Лактат активирует GPR81 в физиологических концентрациях в диапазоне 1 -20 мM [2,8,41]. ЕС50 лактата для активации GPCR составляет 5 mM, для ингибирования образования цАМФ в клетках раз-личной природы -от 2,1 до 4.2 мM [2,8,27].…”

“…ЕС50 лактата для активации GPCR составляет 5 mM, для ингибирования образования цАМФ в клетках раз-личной природы -от 2,1 до 4.2 мM [2,8,27]. L-лактат обладает в два раза более сильным эффектом, чем D-лактат [3,6].…”