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Not curated in GtoImmuPdb
Target id: 311
Nomenclature: HCA1 receptor
Family: Hydroxycarboxylic acid receptors
Annotation status:
Annotated and reviewed, awaiting update
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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 346 | 12q24.31 | HCAR1 | hydroxycarboxylic acid receptor 1 | |
| Mouse | 7 | 343 | 12q15 | Hcar1 | hydrocarboxylic acid receptor 1 | |
| Rat | 7 | 351 | 12q15 | Hcar1 | hydroxycarboxylic acid receptor 1 | |
| Previous and Unofficial Names |
| FKSG80 | LACR1 | lactate receptor 1 | T-cell activation G protein-coupled receptor | G protein-coupled receptor 104 | G protein-coupled receptor 81 | Gpr81 |
| Database Links |
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| Specialist databases | |
| GPCRdb | hcar1_human (Hs), hcar1_mouse (Mm) |
| Other databases | |
| Alphafold | Q9BXC0 (Hs), Q8C131 (Mm) |
| ChEMBL Target | CHEMBL1075101 (Hs), CHEMBL2146354 (Mm) |
| Ensembl Gene | ENSG00000196917 (Hs), ENSMUSG00000049241 (Mm), ENSRNOG00000026661 (Rn) |
| Entrez Gene | 27198 (Hs), 243270 (Mm), 689936 (Rn) |
| Human Protein Atlas | ENSG00000196917 (Hs) |
| KEGG Gene | hsa:27198 (Hs), mmu:243270 (Mm), rno:689936 (Rn) |
| OMIM | 606923 (Hs) |
| Pharos | Q9BXC0 (Hs) |
| RefSeq Nucleotide | NM_032554 (Hs), NM_175520 (Mm), NM_001145334 (Rn) |
| RefSeq Protein | NP_115943 (Hs), NP_780729 (Mm), NP_001138806 (Rn) |
| UniProtKB | Q9BXC0 (Hs), Q8C131 (Mm) |
| Wikipedia | HCAR1 (Hs) |
| Natural/Endogenous Ligands |
| L-lactic acid |
| Comments: Proposed ligand, two publications |
Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Of all naturally occurring agonists only L-lactic acid reaches levels sufficient to activate the receptor. Although the basal plasma concentrations of L-lactate are in the range of 0.5 and 2 mM [7,14,16], up to at least seven-fold increases in physiological lactic acid concentractions have been reported under certain conditions [4,6,9,17]. Nicotinic acid is capable of stimulating HCA1 at high concentrations only (10mM), which precludes the determination of an EC50 value or the assessment of full verses partial agonism [21]. |
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| Antagonist Comments | ||
| Currently no antagonists are known for HCA1. |
| Allosteric Modulator Comments | ||
| Currently no allosteric regulators are known for HCA1. |
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||
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| General Comments |
| Thiazolidinediones increase the expression of HCA1 via PPARγ [8], whereas LPS decreases expression of HCA1 via TLR4 [5]. Lactate drives tumour-induced cachexia via HCA1 activation [13]. |
1. Ahmed K, Tunaru S, Tang C, Müller M, Gille A, Sassmann A, Hanson J, Offermanns S. (2010) An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab, 11 (4): 311-9. [PMID:20374963]
2. Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AK, Waters MG. (2008) Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun, 377 (3): 987-91. [PMID:18952058]
3. Davidsson Ö, Nilsson K, Brånalt J, Andersson T, Berggren K, Chen Y, Fjellström O, Gradén H, Gustafsson L, Hermansson NO et al.. (2020) Identification of novel GPR81 agonist lead series for target biology evaluation. Bioorg Med Chem Lett, 30 (4): 126953. [PMID:31932225]
4. DiGirolamo M, Newby FD, Lovejoy J. (1992) Lactate production in adipose tissue: a regulated function with extra-adipose implications. FASEB J, 6 (7): 2405-12. [PMID:1563593]
5. Feingold KR, Moser A, Shigenaga JK, Grunfeld C. (2011) Inflammation inhibits GPR81 expression in adipose tissue. Inflamm Res, 60 (10): 991-5. [PMID:21751047]
6. Hagström-Toft E, Enoksson S, Moberg E, Bolinder J, Arner P. (1997) Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood. Am J Physiol, 273 (3 Pt 1): E584-92. [PMID:9316449]
7. HUCKABEE WE. (1958) Relationships of pyruvate and lactate during anaerobic metabolism. I. Effects of infusion of pyruvate or glucose and of hyperventilation. J Clin Invest, 37 (2): 244-54. [PMID:13513755]
8. Jeninga EH, Bugge A, Nielsen R, Kersten S, Hamers N, Dani C, Wabitsch M, Berger R, Stunnenberg HG, Mandrup S et al.. (2009) Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81). J Biol Chem, 284 (39): 26385-93. [PMID:19633298]
9. Kreisberg RA. (1980) Lactate homeostasis and lactic acidosis. Ann Intern Med, 92 (2 Pt 1): 227-37. [PMID:6766289]
10. Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF. (2001) Discovery and mapping of ten novel G protein-coupled receptor genes. Gene, 275 (1): 83-91. [PMID:11574155]
11. Liu C, Kuei C, Zhu J, Yu J, Zhang L, Shih A, Mirzadegan T, Shelton J, Sutton S, Connelly MA et al.. (2012) 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. J Pharmacol Exp Ther, 341 (3): 794-801. [PMID:22434674]
12. Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ, Mirzadegan T et al.. (2009) Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem, 284 (5): 2811-22. [PMID:19047060]
13. Liu X, Li S, Cui Q, Guo B, Ding W, Liu J, Quan L, Li X, Xie P, Jin L et al.. (2024) Activation of GPR81 by lactate drives tumour-induced cachexia. Nat Metab, 6 (4): 708-723. [PMID:38499763]
14. Marbach EP, Weil MH. (1967) Rapid enzymatic measurement of blood lactate and pyruvate. Use and significance of metaphosphoric acid as a common precipitant. Clin Chem, 13 (4): 314-25. [PMID:6036716]
15. Morland C, Andersson KA, Haugen ØP, Hadzic A, Kleppa L, Gille A, Rinholm JE, Palibrk V, Diget EH, Kennedy LH et al.. (2017) Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun, 8: 15557. [PMID:28534495]
16. Niessner H, Beutler E. (1973) Fluorometric analysts of glycolytic intermediates in human red blood cells. Biochem Med, 8 (1): 123-34. [PMID:4744313]
17. Osnes JB, Hermansen L. (1972) Acid-base balance after maximal exercise of short duration. J Appl Physiol, 32 (1): 59-63. [PMID:5007019]
18. Sakurai T, Davenport R, Stafford S, Grosse J, Ogawa K, Cameron J, Parton L, Sykes A, Mack S, Bousba S et al.. (2014) Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing. Eur J Pharmacol, 727: 1-7. [PMID:24486398]
19. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]
20. Wallenius K, Thalén P, Björkman JA, Johannesson P, Wiseman J, Böttcher G, Fjellström O, Oakes ND. (2017) Involvement of the metabolic sensor GPR81 in cardiovascular control. JCI Insight, 2 (19). [PMID:28978803]
21. Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A et al.. (2003) Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem, 278 (11): 9869-74. [PMID:12522134]
22. Wu FM, Huang HG, Hu M, Gao Y, Liu YX. (2006) [Molecular cloning, tissue distribution and expression in engineered cells of human orphan receptor GPR81]. Sheng Wu Gong Cheng Xue Bao, 22 (3): 408-12. [PMID:16755919]
