Disease relevance of GPR109A

• The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia [1].
• Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells [2].

High impact information on GPR109A

• Our data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE(2) and PGD(2), most likely from immune cells of the skin [3].
• GPR109A has been proven to be the molecular target for the actions of nicotinic acid on adipose tissue, and in this issue of the JCI, Benyó et al. have confirmed the involvement of GPR109A in the nicotinic acid-induced flushing response, a common side effect [4].
• The recent discovery of a nicotinic acid receptor that is a G-protein-coupled receptor has led to a renewed interest in the pharmacological effects of nicotinic acid [5].
• The recent discovery and characterization of a membrane-bound nicotinic acid receptor (HM74) explains niacin's acute inhibition of adipocyte lipolysis, but the role of HM74 in lowering triglycerides is unclear [6].
• We then describe the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptor for nicotinic acid and other compounds with related pharmacology [1].

Biological context of GPR109A

• Here we show that many of the nonsynonymous SNPs listed in public databases for HM74 and HM74A are artifacts resulting from extensive homology between these two genes [7].
• Nicotinic acid receptor (GPR109A) gene expression was assessed in various tissues and cell lines [8].
• Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways [9].
• Our data suggest that the A431 cell line may serve as a cellular model for further investigation of niacin/HM74a-mediated signal transduction in modulating metabolism [10].
• WHERE NEXT: Research on signalling through the nicotinic acid receptor might give rise to novel and more effective methods to interfere with fatty-acid metabolism, with insulin resistance, hyperlipidaemia, and atherosclerosis as target diseases [11].

Anatomical context of GPR109A

• HM74b mRNA is found in human, murine, and rat adipose tissues [12].
• The responsive cells were localized to the epidermis, and immunocytochemical studies revealed the presence of GPR109A on epidermal Langerhans cells [8].
• IFNgamma treatment increased both mRNA and plasma membrane expression of GPR109A [8].
• Niacin also induced PPARgamma transcriptional activity in HM74 and HM74a CHO cell transfectants, although not in vector-only control cells [9].
• An HM74a-specific real time PCR probe set was designed and the mRNA levels of HM74a in A431 and 32 other cultured cell lines were measured quantitatively [10].

Associations of GPR109A with chemical compounds

• Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors [13].
• This receptor responds to both nicotinic acid and the ketone body beta-hydroxybutyrate, the latter thought to be the more probable endogenous ligand for HM74A [14].
• Nicotinic acid and Acipimox inhibit forskolin-stimulated intracellular cAMP accumulation in human HM74b-expressing cells and activate GTP gamma S binding in a dose-dependent manner [12].
• Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74 [15].
• HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation [9].

Regulatory relationships of GPR109A

• The very recent discovery of a nicotinic acid receptor and the finding that the drug stimulates the expression of the ABCA 1 membrane cholesterol transporter have paved the way for exciting and promising new 50 years in the history of nicotinic acid [16].

Other interactions of GPR109A

• Since nicotinic acid is one of the few available medicines that raise HDL ("good cholesterol") levels, HM74A and HM74 appear promising targets for future pharmacotherapy [14].
• Remarkably, its putative mechanism of action has only been recently elucidated, particularly because of the cloning of a G protein-coupled receptor (HM74A or GPR109A) [14].

Analytical, diagnostic and therapeutic context of GPR109A

• To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid [13].

References