Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2gene and in rodents by the Hcar2 gene.[5][6][7][8] The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31).[9] Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells.[5][10] HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid).[7][8] β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.[11]
β-Hydroxybutyric acid, butyric acid, and niacin have actions that are independent of HCA2. For example: 1) β-hydroxybutyric acid activates free fatty acid receptor 3[12] and inhibits some histone deacetylases that regulate the expression of various genes, increase mitochondrialadenosine triphosphate production, and promote antioxidant defenses;[13]2) butyric acid activates free fatty acid receptor 2 and like β-hydroxybutyric acid activates free fatty acid receptor 3[14] and inhibits some histone deacetylases;[15] and 3) niacin is an NAD+ precursor (see nicotinamide adenine dinucleotide) which when converted to NAD+ can alter over 500 enzymatic reactions that play key roles in regulating inflammation, mitochondrion functions, autophagy, and apoptosis.[13] Consequently, studies examining the functions of HCA2 based on the actions of butyric acid, β-hydroxybutyric acid, niacin, or other HCA2 activators need to provide data indicating that they actually do so by activating HCA2. One commonly used way to do this is to show that the activators have no or reduced effects on Hca2gene knockout cells or animals (i.e., cells or animals that had their HCa2 genes removed or inactivated) or gene knockdown cells or animals (i.e., cells or animals that had their HCa2 genes ability to express HCA2 greatly reduced).[16] The studies reported here on HCA2 activators focus on those that included experiments in Hca2 gene knockout and/or knockdown cells and animals.
^S Offermanns, SL Colletti, AP IJzerman, TW Lovenberg, G Semple, A Wise, MG Waters. "Hydroxycarboxylic acid receptors". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 13 July 2018.{{cite web}}: CS1 maint: multiple names: authors list (link)
^Straß S, Geiger J, Cloos N, Späth N, Geiger S, Schwamborn A, De Oliveira da Cunha L, Martorelli M, Guse JH, Sandri TL, Burnet M, Laufer S (June 2023). "Immune cell targeted fumaric esters support a role of GPR109A as a primary target of monomethyl fumarate in vivo". Inflammopharmacology. 31 (3): 1223–1239. doi:10.1007/s10787-023-01186-0. PMID37004600. S2CID257912134.
