Hydroxycarboxylic acid receptor 1 explained

Hydroxycarboxylic acid receptor 1 (HCA₁), formerly known as G protein-coupled receptor 81 (GPR81), is a protein that in humans is encoded by the HCAR1 gene.^{[1] [2]} HCA₁, like the other hydroxycarboxylic acid receptors HCA₂ and HCA₃, is a G protein-coupled receptor (GPCR). The primary endogenous agonist of HCA₁ is lactic acid (and its conjugate base, lactate).^{[3] [4]} More recently, 3,5-dihydroxybenzoic acid has been reported to activate HCA₁.^[5]

Lactate was initially found to activate HCA₁ on fat cells and thereby to inhibit these cells lipolysis i.e., break-down of their fats into free fatty acids and glycerol.^{[6] [7]} Subsequent studies have found that in addition to fat cells, HCA₁ is expressed on cells in the brain, skeletal muscle, lymphoid tissue, uterus, kidney, liver, and pancreas as well as on immune cells such as macrophages and antigen-presenting cells. In the brain, HCA₁ acts to dampen neuron excitation and may also function to promote neurogenesis (i.e., production of neurons from neural stem cells) and angiogenesis, i.e., formation of new blood vessels from pre-existing blood vessels). The functions of HCA₁ in non-fat and non-neural tissues have not been fully defined but in many cases appear to involve promoting the survival of cells, including various types of cancer cells.^[8]

Further reading

• Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S . Identification of G protein-coupled receptor genes from the human genome sequence . FEBS Letters . 520 . 1–3 . 97–101 . June 2002 . 12044878 . 10.1016/S0014-5793(02)02775-8 . 7116392 . free .
• Mao M, Biery MC, Kobayashi SV, Ward T, Schimmack G, Burchard J, Schelter JM, Dai H, He YD, Linsley PS . T lymphocyte activation gene identification by coregulated expression on DNA microarrays . Genomics . 83 . 6 . 989–99 . June 2004 . 15177553 . 10.1016/j.ygeno.2003.12.019 .
• Madaan A, Nadeau-Vallée M, Rivera JC, Obari D, Hou X, Sierra EM, Girard S, Olson DM, Chemtob S . Lactate produced during labor modulates uterine inflammation via GPR81 (HCA1) . American Journal of Obstetrics and Gynecology . September 2016 . 216 . 1 . 60.e1–60.e17 . 27615440 . 10.1016/j.ajog.2016.09.072 . free .

Notes and References

1. Web site: Entrez Gene: GPR81 G protein-coupled receptor 81.
2. Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF . Discovery and mapping of ten novel G protein-coupled receptor genes . Gene . 275 . 1 . 83–91 . September 2001 . 11574155 . 10.1016/S0378-1119(01)00651-5 .
3. Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP . International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B) . Pharmacological Reviews . 63 . 2 . 269–90 . June 2011 . 21454438 . 10.1124/pr.110.003301 . free .
4. Web site: 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 . 13 July 2018.
5. Wagner W, Sobierajska K, Pułaski Ł, Stasiak A, Ciszewski WM . Whole grain metabolite 3,5-dihydroxybenzoic acid is a beneficial nutritional molecule with the feature of a double-edged sword in human health: a critical review and dietary considerations . Critical Reviews in Food Science and Nutrition . 1–19 . April 2023 . 37096487 . 10.1080/10408398.2023.2203762 . 258310985 .
6. Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ, Mirzadegan T, Mazur C, Kamme F, Lovenberg TW . Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81 . The Journal of Biological Chemistry . 284 . 5 . 2811–22 . January 2009 . 19047060 . 10.1074/jbc.M806409200 . free .
7. Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AK, Waters MG . Role of GPR81 in lactate-mediated reduction of adipose lipolysis . Biochemical and Biophysical Research Communications . 377 . 3 . 987–91 . December 2008 . 18952058 . 10.1016/j.bbrc.2008.10.088 .
8. Colucci AC, Tassinari ID, Loss ED, de Fraga LS . History and Function of the Lactate Receptor GPR81/HCAR1 in the Brain: A Putative Therapeutic Target for the Treatment of Cerebral Ischemia . Neuroscience . 526 . 144–163 . June 2023 . 37391123 . 10.1016/j.neuroscience.2023.06.022 . 259279124 .