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HCA1 receptor

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Target not currently curated in GtoImmuPdb

Target id: 311

Nomenclature: HCA1 receptor

Family: Hydroxycarboxylic acid receptors

Gene and Protein Information Click here for help
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 Click here for help
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 Click here for help
Specialist databases
GPCRDB hcar1_human (Hs), hcar1_mouse (Mm)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
L-lactic acid
Comments: Proposed ligand, two publications

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 2 [PMID: 24486398] Small molecule or natural product Hs Agonist 7.2 pEC50 17
pEC50 7.2 [17]
compound 2 [PMID: 31932225] Small molecule or natural product Hs Agonist 7.1 pEC50 3,19
pEC50 7.1 (EC50 7.4x10-8 M) [3,19]
3,5-dihydroxybenzoic acid Small molecule or natural product Ligand has a PDB structure Mm Full agonist 3.8 pEC50 11
pEC50 3.8 (EC50 1.72x10-4 M) [11]
3,5-dihydroxybenzoic acid Small molecule or natural product Ligand has a PDB structure Hs Full agonist 3.7 pEC50 11
pEC50 3.7 (EC50 1.91x10-4 M) [11]
D-lactic acid Small molecule or natural product Ligand has a PDB structure Hs Partial agonist 2.5 pEC50 2
pEC50 2.5 [2]
L-lactic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Mm Full agonist 2.2 – 2.8 pEC50 1,12
pEC50 2.2 – 2.8 [1,12]
L-lactic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 1.3 – 2.9 pEC50 1-2,12,18
pEC50 1.3 – 2.9 [1-2,12,18]
γ-hydroxybutyric acid Small molecule or natural product Approved drug Hs Full agonist 1.8 pEC50 12
pEC50 1.8 (EC50 1.53x10-2 M) [12]
nicotinic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 20
[20]
View species-specific agonist tables
Agonist Comments
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 [7,13,15], up to at least seven-fold increases in physiological lactic acid concentractions have been reported under certain conditions [4,6,9,16].

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 [20].
Antagonist Comments
Currently no antagonists are known for HCA1.
Allosteric Modulator Comments
Currently no allosteric regulators are known for HCA1.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
References: 
Tissue Distribution Click here for help
Fetal liver, fetal heart.
Species:  Human
Technique:  RT-PCR.
References:  21
Adipose tissue- brown and white.
Species:  Human
Technique:  RT-PCR.
References:  12
Pituitary gland.
Species:  Human
Technique:  Northern blotting.
References:  10
Pial fibroblast-like cells and pericyte-like cells of intracerebral microvessels.
Species:  Mouse
Technique:  Genetic reporter and immunohistochemistry.
References:  14
Adipose tissue- brown and white.
Species:  Mouse
Technique:  Genetic reporter, RT-PCR.
References:  1,12
Kidney microvasculature (mouse and dog).
Species:  Mouse
Technique:  In situ hybridization.
References:  19
Adipose tissue- brown and white.
Species:  Rat
Technique:  RT-PCR.
References:  12
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of GTPγS binding in HEK 293T cells transfected with the human HCA1 receptor and Gαo1.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  Stimulation of GTPγS binding.
References:  20
Physiological Functions Click here for help
Mediation of inhibitory regulation of lipolysis by lactate.
Species:  Mouse
Tissue:  Adipose tissue.
References:  1-2,12
Inhibition of lipolysis in response to insulin. Insulin increases formation and release of lactate in adipocytes. Lactate then acts in an auto-/paracrine manner through HCA1 on adipocytes.
Species:  Mouse
Tissue:  Adipocytes.
References:  1
Physiological Consequences of Altering Gene Expression Click here for help
Reduced insulin-induced antilipolysis: mice lacking HCA1 show reduced antilipolysis in response to insulin as well as a reduced weight gain under high fat diet.
Species:  Mouse
Tissue:  Adipose tissue.
Technique:  Gene knockouts.
References:  1
Loss of exercise-induced increase in capillary density in the cerebral cortex.
Species:  Mouse
Tissue:  Pial and intracerebral vessels.
Technique:  Gene knockout.
References:  14
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr81tm1Dgen Gpr81tm1Dgen/Gpr81tm1Dgen
B6.Cg-Gpr81
MGI:2441671  MP:0008033 impaired lipolysis PMID: 18952058 
General Comments
Thiazolidinediones increase the expression of HCA1 via PPARγ [8], whereas LPS decreases expression of HCA1 via TLR4 [5].

References

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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. 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]

14. 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]

15. Niessner H, Beutler E. (1973) Fluorometric analysts of glycolytic intermediates in human red blood cells. Biochem Med, 8 (1): 123-34. [PMID:4744313]

16. Osnes JB, Hermansen L. (1972) Acid-base balance after maximal exercise of short duration. J Appl Physiol, 32 (1): 59-63. [PMID:5007019]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

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