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HCA1 receptor

Family: Hydroxycarboxylic acid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 346 12q24.3 HCAR1 hydroxycarboxylic acid receptor 1
Mouse 7 351 5 F Gpr81 G protein-coupled receptor 81
Rat 7 351 12q15 Hcar1 hydroxycarboxylic acid receptor 1
Previous and Unofficial Names
TA-GPCR
LACR
FKSG80
G-protein coupled receptor 81
LACR1
G-protein coupled receptor 104
T-cell activation G protein-coupled receptor
lactate receptor 1
GPR81
GPR104
HCA1
G protein-coupled receptor 104
G protein-coupled receptor 81
LOC689936
similar to G protein-coupled receptor 81
Database Links
Ensembl ENSG00000196917 (Hs), ENSMUSG00000049241 (Mm), ENSRNOG00000026661 (Rn)
Entrez Gene 27198 (Hs), 363919 (Mm), 689936 (Rn)
GeneCards HCAR1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gpr81 (Mm)
HomoloGene 13060 (Hs)
Human Protein Reference Database 06083 (Hs)
InterPro Q9BXC0 (Hs), Q8C131 (Mm)
KEGG Gene hsa:27198 (Hs), mmu:363919 (Mm), rno:689936 (Rn)
OMIM 606923 (Hs)
PharmGKB Gene PA28925 (Hs)
PhosphoSitePlus Q9BXC0 (Hs)
Protein Ontology (PRO) PRO:000001649 (Hs)
RefSeq Nucleotide NM_032554 (Hs), NM_175520 (Mm), NM_001145334 (Rn)
RefSeq Protein NP_115943 (Hs), NP_780729 (Mm), NP_001138806 (Rn)
TreeFam ENSG00000196917 (Hs), ENSMUSG00000049241 (Mm), ENSRNOG00000026661 (Rn)
UniGene Hs. 610873 (Hs)
UniProt Q9BXC0 (Hs), Q8C131 (Mm)
Wikipedia HCA1 receptor
Hydroxycarboxylic acid receptors
Search for 3D structures on the PDB
Search by keyword: Hydroxycarboxylic acid receptors HCA1 receptor Search by accession number: Q9BXC0, Q8C131
Natural/Endogenous Ligand(s)
L-lactic acid
Comments: Proposed ligand, two publications
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
3,5-dihydroxybenzoic acid Mm Full agonist 3.76 pEC50 11
3,5-dihydroxybenzoic acid Hs Full agonist 3.72 pEC50 11
L-lactic acid Hs Full agonist 2.3 – 2.89 pEC50 1-2,10
D-lactic ​acid Hs Partial agonist 2.52 pEC50 2
L-lactic acid Mm Full agonist 2.17 – 2.82 pEC50 1,10
γ-hydroxybutyric acid Hs Full agonist 1.82 pEC50 10
nicotinic acid Hs Unknown - pEC50 15
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 [6,12-13], up to at least seven-fold increases in physiological lactic acid concentractions have been reported under certain conditions [3,5,8,14].

Nicotinic acid is capable of stimulating GPR81 at high concentrations only (10mM), which precludes the determination of an EC50 value or the assessment of full verses partial agonism [15].
Antagonist Comments
Currently no antagonists are known for GPR81.
Allosteric Regulator Comments
Currently no allosteric regulators are known for GPR81.

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
References: 
Tissue Distribution
Pituitary gland.
Species:  Human
Technique:  Northern blotting.
References:  9
Fetal liver, fetal heart.
Species:  Human
Technique:  RT-PCR.
References:  16
Adipose tissue- brown and white.
Species:  Human
Technique:  RT-PCR.
References:  10
Adipose tissue- brown and white.
Species:  Mouse
Technique:  Genetic reporter, RT-PCR.
References:  1,10
Adipose tissue- brown and white.
Species:  Rat
Technique:  RT-PCR.
References:  10
Expression Datasets

Click here to show/hide data

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
Measurement of GTPγS binding in HEK 293T cells transfected with the human GPR81 receptor and Gαo1.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  Stimulation of GTPγS binding.
References:  15
Physiological Functions
Mediation of inhibitory regulation of lipolysis by lactate.
Species:  Mouse
Tissue:  Adipose tissue.
References:  1-2,10
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
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
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

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 [7], whereas LPS decreases expression of HCA1 via TLR4 [4].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR81 (FKSG80) (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0330C2A
DiscoveRx PathHunter® eXpress GPR81 CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0330E2ACP1

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, T.Q., Ren, N., Jin, L., Cheng, K., Kash, S., Chen, R., Wright, S.D., Taggart, A.K. and Waters, M.G. (2008) Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun, 377 (3): 987-991. [PMID:18952058]

3. 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]

4. Feingold, KR; Moser, A; Shigenaga, JK; Grunfeld, C. (2011) Inflammation inhibits GPR81 expression in adipose tissue. Inflamm. Res., 60 (10): 991-5. [PMID:21751047]

5. 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]

6. 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]

7. 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]

8. Kreisberg, RA. (1980) Lactate homeostasis and lactic acidosis. Ann. Intern. Med., 92 (2 Pt 1): 227-37. [PMID:6766289]

9. Lee, D. K., Nguyen, T., Lynch, K. R., Cheng, R., Vanti, W. B., Arkhitko, O., Lewis, T., Evans, J. F., George, S. R. and O'Dowd, B. F. (2001) Discovery and mapping of ten novel G protein-coupled receptor genes. Gene, 275: 83-91. [PMID:11574155]

10. Liu, C., Wu, J., Zhu, J., Kuei, C., Yu, J., Shelton, J., Sutton, S.W., Li, X., Yun, S.J., Mirzadegan, T., Mazur, C., Kamme, F. and Lovenberg, T.W. (2009) Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81. J Biol Chem., 284 (5): 2811-2822. [PMID:19047060]

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. 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]

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

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

15. Wise, A., Foord, S. M., Fraser, N. J., Barnes, A. A., Elshourbagy, N., Eilert, M., Ignar, D. M., Murdock, P. R., Steplewski, K., Green, A., Brown, A. J., Dowell, S. J., Szekeres, P. G., Hassall, D. G., Marshall, F. H., Wilson, S. and Pike, N. B. (2003) Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem, 278: 9869-9874. [PMID:12522134]

16. Wu, F. M., Huang, H. G., Hu, M., Gao, Y. and Liu, Y. X. (2006) [Molecular cloning, tissue distribution and expression in engineered cells of human orphan receptor GPR81]. Sheng Wu Gong Cheng Xue Bao, 22: 408-412. [PMID:16755919]

To cite this database page, please use the following:

Stefan Offermanns, Steven L. Colletti, Adriaan P. Ijzerman, Timothy W. Lovenberg, Graeme Semple, Alan Wise.
Hydroxycarboxylic acid receptors: HCA1 receptor. Last modified on 12/02/2013. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=311.


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