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HCA3 receptor

Family: Hydroxycarboxylic acid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Functional Assays
Physiological Functions
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 387 12q24.31 HCAR3 hydroxycarboxylic acid receptor 3
Previous and Unofficial Names
HM74
NIACR2
GPR109B
Nic2
Low affinity nicotinic acid receptor
HCA3
G protein-coupled receptor 109B
Database Links
ChEMBL Target 100430 (Hs)
DrugBank Target 928 (Hs)
Ensembl ENSG00000255398 (Hs)
Entrez Gene 8843 (Hs)
GeneCards HCAR3 (Hs)
HomoloGene 55944 (Hs)
Human Protein Reference Database 06917 (Hs)
InterPro P49019 (Hs)
KEGG Gene hsa:8843 (Hs)
OMIM 606039 (Hs)
PharmGKB Gene PA164723918 (Hs)
Protein Ontology (PRO) PRO:000001630 (Hs)
RefSeq Nucleotide NM_006018 (Hs)
RefSeq Protein NP_006009 (Hs)
TreeFam ENSG00000255398 (Hs)
UniGene Hs. 458425 (Hs)
UniProt P49019 (Hs)
Wikipedia HCA3 receptor
Hydroxycarboxylic acid receptors
Search for 3D structures on the PDB
Search by keyword: Hydroxycarboxylic acid receptors HCA3 receptor Search by accession number: P49019
Natural/Endogenous Ligand(s)
3-hydroxyoctanoic acid
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 6o Hs Full agonist 8.52 pEC50 8
4-(n-propyl)amino-3-nitrobenzoic acid Hs Full agonist 7.52 pEC50 7
5-methyl-​5-(5-meth​ylthiophe​n-3-yl)-4​-oxo-4,5-​dihydrofu​ran-2-car​boxylic a​cid Hs Full agonist 6.7 pEC50 3
1-isopropylbenzotriazole-5-carboxylic acid Hs Full agonist 6.4 pEC50 6
D-kynurenine Hs Full agonist 5.58 pEC50 2
2-hydroxyoctanoic acid Hs Full agonist 5.4 pEC50 1
5-ethyl-4-oxo-5-phenyl-4,5-dihydro-furan-2-carboxylic acid Hs Full agonist 5.3 pEC50 3
nicotinic acid Hs Full agonist 4.0 – 6.52 pEC50 12
3-hydroxyoctanoic acid Hs Full agonist 5.1 pEC50 1
D-phenyalanine Hs Full agonist 5.04 pEC50 2
D-tryptophan Hs Full agonist 5.01 pEC50 2
acifran Hs Full agonist 4.7 – 5.2 pEC50 3,5,10,12
Agonist Comments
Nicotinic acid is capable of stimulating GPR109B at high concentrations only (>300μM), which precludes the determination of an EC50 value or the assessment of full verses partial agonism [12].
Antagonist Comments
Currently no antagonists are known for GPR109B.
Allosteric Regulator Comments
Currently no allosteric regulators are known for GPR109B.

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

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Other - See Comments
Comments:  GPR109B is also shown to activate the MAPK cascade (ERK1/ERK2) in a PTX-sensitive manner.
References:  3,5,10,12
Tissue Distribution
Monocytes.
Species:  Human
Technique:  RT-PCR.
References:  4
Adipose tissue, spleen, lung.
Species:  Human
Technique:  RT-PCR.
References:  9,12
Neutrophils.
Species:  Human
Technique:  RT-PCR.
References:  1-2
Intestinal epithelial cells.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR.
References:  11
Functional Assays
Measurement of GTPγS binding in HEK 293T cells transfected with the human GPR109B receptor and GTPαo1.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  Stimulation of GTPγS binding.
References:  12
Measurement of cAMP levels in whole CHO cells transfected with the human GPR109B receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  3,6
Measurement of ERK1/2 phosphorylation in whole CHO cells transfected with the human GPR109B receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Stimulation of ERK1/2 phosphorylation.
References:  5
Physiological Functions
Inhibition of lipolytic activity.
Species:  Human
Tissue:  Adipocytes.
References:  6
HCA3 mediates antilipolytic effects of the [beta]-oxidation intermediate 3-OH-octanoic acid. May be involved in negative feedback regulation of lipolysis in cases of increased [beta]-oxidation.
Species:  Human
Tissue:  Adipose tissue.
References:  1
HCA3 mediates the chemotactic activity of D-amino acids.
Species:  Human
Tissue:  Neutrophils.
References:  2
General Comments
There is no rodent analogue of GPR109B, but the gene has also been identified in the chimpanzee genome. GPR109B appears to be the product of gene duplication of GPR109A and is >95% identical to GPR109A.

REFERENCES

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1. Ahmed, K; Tunaru, S; Langhans, CD; Hanson, J; Michalski, CW; Kölker, S; Jones, PM; Okun, JG; Offermanns, S. (2009) Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis. J. Biol. Chem., 284 (33): 21928-33. [PMID:19561068]

2. Irukayama-Tomobe, Y; Tanaka, H; Yokomizo, T; Hashidate-Yoshida, T; Yanagisawa, M; Sakurai, T. (2009) Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B. Proc. Natl. Acad. Sci. U.S.A., 106 (10): 3930-4. [PMID:19237584]

3. Jung, J. K., Johnson, B. R., Duong, T., Decaire, M., Uy, J., Gharbaoui, T., Boatman, P. D., Sage, C. R., Chen, R., Richman, J. G., Connolly, D. T. and Semple, G. (2007) Analogues of acifran: agonists of the high and low affinity niacin receptors, GPR109a and GPR109b. J Med Chem, 50: 1445-1448. [PMID:17358052]

4. Knowles, H. J., te Poele, R. H., Te Poole, R., Workman, P. and Harris, A. L. (2006) Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways. Biochem Pharmacol, 71: 646-656. [PMID:16386710]

5. Mahboubi, K., Witman-Jones, T., Adamus, J. E., Letsinger, J. T., Whitehouse, D., Moorman, A. R., Sawicki, D., Bergenhem, N. and Ross, S. A. (2006) Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochem Biophys Res Commun, 340: 482-490. [PMID:16389067]

6. Semple, G., Skinner, P. J., Cherrier, M. C., Webb, P. J., Sage, C. R., Tamura, S. Y., Chen, R., Richman, J. G. and Connolly, D. T. (2006) 1-Alkyl-benzotriazole-5-carboxylic acids are highly selective agonists of the human orphan G-protein-coupled receptor GPR109b. J Med Chem, 49: 1227-1230. [PMID:16480258]

7. Skinner, PJ; Cherrier, MC; Webb, PJ; Sage, CR; Dang, HT; Pride, CC; Chen, R; Tamura, SY; Richman, JG; Connolly, DT; et al.. (2007) 3-Nitro-4-amino benzoic acids and 6-amino nicotinic acids are highly selective agonists of GPR109b. Bioorg. Med. Chem. Lett., 17 (23): 6619-22. [PMID:17931863]

8. Skinner, PJ; Webb, PJ; Sage, CR; Dang, TH; Pride, CC; Chen, R; Tamura, SY; Richman, JG; Connolly, DT; Semple, G. (2009) 5-N,N-Disubstituted 5-aminopyrazole-3-carboxylic acids are highly potent agonists of GPR109b. Bioorg. Med. Chem. Lett., 19 (15): 4207-9. [PMID:19524438]

9. Soga, T., Kamohara, M., Takasaki, J., Matsumoto, S., Saito, T., Ohishi, T., Hiyama, H., Matsuo, A., Matsushime, H. and Furuichi, K. (2003) Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun, 303: 364-369. [PMID:12646212]

10. Taggart, A. K., Kero, J., Gan, X., Cai, T. Q., Cheng, K., Ippolito, M., Ren, N., Kaplan, R., Wu, K., Wu, T. J., Jin, L., Liaw, C., Chen, R., Richman, J., Connolly, D., Offermanns, S., Wright, S. D. and Waters, M. G. (2005) (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem, 280: 26649-26652. [PMID:15929991]

11. Thangaraju, M; Cresci, GA; Liu, K; Ananth, S; Gnanaprakasam, JP; Browning, DD; Mellinger, JD; Smith, SB; Digby, GJ; Lambert, NA; et al.. (2009) GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res., 69 (7): 2826-32. [PMID:19276343]

12. 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]

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: HCA3 receptor. Last modified on 12/02/2013. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=313.


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