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  • br Discovery of GPR A The murine

    2022-01-19


    Discovery of GPR109A The murine niacin receptor, protein upregulated in macrophages by interferon-γ (PUMA-G), was identified as a G-protein-coupled receptor (GPCR) expressed in adipocytes and spleen [22], [23]. This finding suggested a role of this receptor in macrophage function [24]. In 2003, the high- and low-affinity niacin receptors, G-protein-coupled receptor 109A (GPR109A, also known as HM74A) and G-protein-coupled receptor 109B (GPR109B, also known as HM74) respectively, were reported as Gi-coupled orphan GPCRs [25], [26], [27], [28]. Despite the high homology (95%) between these two receptors, niacin showed over 1000-fold higher binding affinity and functional activity against GPR109A over GPR109B. In addition, GPR109A is expressed primarily on adipocytes, spleen, and immune cells. It was soon discovered that β-hydroxybutyrate, a ketone body-derived fatty acid, activates GPR109A and PUMA-G receptors in transfected Chinese hamster ovary (CHO) L-745,870 trihydrochloride with half-maximal effect at 0.7–0.8mmol/L [29]. Indeed, the physiological concentration of β-hydroxybutyrate approaches 0.2–0.4mmol/L after an overnight fast, and 1–2mmol/L after 2–3 days of fasting. Furthermore, infusion of β-hydroxybutyrate successfully suppressed lipolysis. These observations strongly support the hypothesis that β-hydroxybutyrate may serve as an endogenous ligand for GPR109A. On the other hand, niacin, albeit more potent with a half-maximal effect of 100nmol/L, does not achieve endogenous levels sufficient to provide GPR109A-mediated pharmacological effects. While the precise mechanism regarding the pharmacological action of niacin remains elusive, it is known that niacin binds to GPR109A on adipocytes and decreases the hydrolysis of adipocyte TG, thereby resulting in a transient reduction of plasma concentrations of free fatty acids (FFA). It has been hypothesized that the reduction of FFA decreases the availability of FFA in the liver, thereby reducing TG synthesis and their subsequent packaging into VLDL-C. The reduction of TG-rich VLDL-C may lead to decreased HDL-C metabolism via limiting the cholesterol ester transfer protein (CETP)-mediated exchange of cholesterol from HDL-C to VLDL-C and of TG from VLDL to HDL [30]. It is also postulated that niacin may inhibit the uptake and removal of Apo-AI-containing HDL-C in hepatocytes and augment reverse cholesterol transport [31], [32]. This allows efflux of more cholesterol from the vascular wall. In addition, activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) in a monocytoid cell line was reported as a result of treatment of 1mmol/L of niacin, thereby increasing the efflux-related receptors including CD36 and ATP-binding cassette protein A1 [33]. Moreover, since GPR109A is also expressed on immune cells, it is possible that some of its antiatherosclerotic effects are derived from modulation of vascular inflammation. With respect to vasodilation, niacin-elicited vasodilation requires the activation of GPR109A in skin Langerhans cells [34], [35], which then triggers the release of arachidonic acid from membrane phospholipids and its subsequent metabolism to PGD2. The production of PGD2 then activates DP1 receptors in dermal blood vessels to cause vasodilation [36].
    Modeling A modeling study of the GPR109A niacin-binding site was first reported in 2005 [37]. A site-directed mutagenesis study coupled with generation of chimeric receptors comprising GPR109A and GPR109B led to the identification of putative niacin-binding pocket. This model was based on the bovine rhodopsin crystal structure template 1HZX. It was determined that Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) were critical for binding of niacin. In this binding pocket, the carboxylate group of niacin forms a salt bridge with Arg111 at TMH3. In addition, Phe276/Tyr284 at TMH7 and Trp91 at the junction TMH2/ECL1 may contribute to the binding of niacin via π–π interactions. Lastly, the pyridine nitrogen atom appears to form a hydrogen bond with Ser187 at ECL2. Thus, the niacin-binding pocket in GPR109A is apparently distinct from most other rhodopsin family receptors.