Nomenclature: HCA3 receptor

Family: Hydroxycarboxylic acid receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

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
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
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 [PMID:19524438] Hs Full agonist 8.52 pEC50 8
pEC50 8.52 (EC50 3x10-9 M) [8]
4-(n-propyl)amino-3-nitrobenzoic acid Hs Full agonist 7.52 pEC50 7
pEC50 7.52 (EC50 3x10-8 M) [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
pEC50 6.7 [3]
1-isopropylbenzotriazole-5-carboxylic acid Hs Full agonist 6.4 pEC50 6
pEC50 6.4 [6]
D-kynurenine Hs Full agonist 5.58 pEC50 2
pEC50 5.58 (EC50 2.61x10-6 M) [2]
2-hydroxyoctanoic acid Hs Full agonist 5.4 pEC50 1
pEC50 5.4 (EC50 4x10-6 M) [1]
5-ethyl-4-oxo-5-phenyl-4,5-dihydro-furan-2-carboxylic acid Hs Full agonist 5.3 pEC50 3
pEC50 5.3 [3]
nicotinic acid Hs Full agonist 4.0 – 6.52 pEC50 12
pEC50 4.0 – 6.52 [12]
3-hydroxyoctanoic acid Hs Full agonist 5.1 pEC50 1
pEC50 5.1 (EC50 8x10-6 M) [1]
D-phenylalanine Hs Full agonist 5.04 pEC50 2
pEC50 5.04 (EC50 9.02x10-6 M) [2]
D-tryptophan Hs Full agonist 5.01 pEC50 2
pEC50 5.01 (EC50 9.72x10-6 M) [2]
acifran Hs Full agonist 4.7 – 5.2 pEC50 3,5,10,12
pEC50 4.7 – 5.2 [3,5,10,12]
Agonist Comments
Nicotinic acid is capable of stimulating HCA3 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 HCA3.
Allosteric Regulator Comments
Currently no allosteric regulators are known for HCA3.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Other - See Comments
Comments:  HCA3 is also shown to activate the MAPK cascade (ERK1/ERK2) in a PTX-sensitive manner.
References:  3,5,10,12
Tissue Distribution
Adipose tissue, spleen, lung.
Species:  Human
Technique:  RT-PCR.
References:  9,12
Monocytes.
Species:  Human
Technique:  RT-PCR.
References:  4
Neutrophils.
Species:  Human
Technique:  RT-PCR.
References:  1-2
Intestinal epithelial cells.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR.
References:  11
Functional Assays
Measurement of cAMP levels in whole CHO cells transfected with the human HCA3 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 HCA3 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Stimulation of ERK1/2 phosphorylation.
References:  5
Measurement of GTPγS binding in HEK 293T cells transfected with the human HCA3 receptor and GTPαo1.
Species:  Human
Tissue:  HEK 293T cells.
Response measured:  Stimulation of GTPγS binding.
References:  12
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 HCA3, but the gene has also been identified in the chimpanzee genome. HCAR3 appears to be the product of gene duplication of HCAR2 and is >95% identical to HCAR2.
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR109B β-Arrestin Cell Line (Cat no. 93-0791C2)
PathHunter® eXpress GPR109B CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0791E2CP2M)
more info

REFERENCES

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 JK, Johnson BR, Duong T, Decaire M, Uy J, Gharbaoui T, Boatman PD, Sage CR, Chen R, Richman JG, Connolly DT, Semple G. (2007) Analogues of acifran: agonists of the high and low affinity niacin receptors, GPR109a and GPR109b. J Med Chem50: 1445-1448. [PMID:17358052]

4. Knowles HJ, te Poele RH, Te Poole R, Workman P, Harris AL. (2006) Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways. Biochem Pharmacol71: 646-656. [PMID:16386710]

5. Mahboubi K, Witman-Jones T, Adamus JE, Letsinger JT, Whitehouse D, Moorman AR, Sawicki D, Bergenhem N, Ross SA. (2006) Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74. Biochem Biophys Res Commun340: 482-490. [PMID:16389067]

6. Semple G, Skinner PJ, Cherrier MC, Webb PJ, Sage CR, Tamura SY, Chen R, Richman JG, Connolly DT. (2006) 1-Alkyl-benzotriazole-5-carboxylic acids are highly selective agonists of the human orphan G-protein-coupled receptor GPR109b. J Med Chem49: 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, Furuichi K. (2003) Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun303: 364-369. [PMID:12646212]

10. Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ, Jin L, Liaw C, Chen R, Richman J, Connolly D, Offermanns S, Wright SD, Waters MG. (2005) (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem280: 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 SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB. (2003) Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem278: 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 12/12/2013. Accessed on 23/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=313.

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