High impact information on GPR109B

• 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 [1].
• 1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a low-affinity receptor for the HDL-raising drug niacin [2].
• Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARgamma protein and enhanced PPARgamma transcriptional activity [3].
• Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways [3].
• Thus, three of the newly identified proteins probably belong to a 'leukocyte chemotactic peptide receptor family'. HM74 differs from the other clones with respect to the amino acid homology, suggesting that this may be the receptor for a different type of ligand [4].

Biological context of GPR109B

• All polypeptides encoded by the cloned cDNAs share common features with the G protein-coupled receptor superfamily, such as seven putative hydrophobic transmembrane domains and, except for HM74, N-linked glycosylation sites near the N-terminus [4].
• Amino acid sequence comparison reveals that the best match in the protein databases is with the human orphan GPCR called HM74 (33% identity) [5].
• 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 [6].
• Moreover, using haplotype analysis, a nearly significant haplotypic association was observed at the HM74 gene [7].

Associations of GPR109B with chemical compounds

• 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 [8].

Other interactions of GPR109B

• 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 [9].

References