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HCA3 receptor

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Not curated in GtoImmuPdb

Target id: 313

Nomenclature: HCA3 receptor

Family: Hydroxycarboxylic acid receptors

Annotation status:  image of a blue circle Annotated and reviewed, awaiting update  » Email us

Contents:

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 7 387 12q24.31 HCAR3 hydroxycarboxylic acid receptor 3
Previous and Unofficial Names Click here for help
NIACR2 | Low affinity nicotinic acid receptor | Nic2 | G protein-coupled receptor 109B
Database Links Click here for help
Specialist databases
GPCRdb hcar3_human (Hs)
Other databases
Alphafold P49019 (Hs)
ChEMBL Target CHEMBL4421 (Hs)
DrugBank Target P49019 (Hs)
Ensembl Gene ENSG00000255398 (Hs)
Entrez Gene 8843 (Hs)
Human Protein Atlas ENSG00000255398 (Hs)
KEGG Gene hsa:8843 (Hs)
OMIM 606039 (Hs)
Pharos P49019 (Hs)
RefSeq Nucleotide NM_006018 (Hs)
RefSeq Protein NP_006009 (Hs)
UniProtKB P49019 (Hs)
Wikipedia HCAR3 (Hs)
Natural/Endogenous Ligands Click here for help
3-hydroxyoctanoic acid

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 6o [PMID: 19524438] Small molecule or natural product Hs Full agonist 8.5 pEC50 9
⤷ pEC50 8.5 (EC50 3x10-9 M) [9]
4-(n-propyl)amino-3-nitrobenzoic acid Small molecule or natural product Ligand has a PDB structure Hs Full agonist 7.5 pEC50 8
⤷ pEC50 7.5 (EC50 3x10-8 M) [8]
D-phenyllactic acid Small molecule or natural product Ligand has a PDB structure Hs Agonist 6.8 pEC50 6
⤷ pEC50 6.8 (EC50 1.5x10-7 M) [6]
5-methyl-5-(5-methylthiophen-3-yl)-4-oxo-4,5-dihydrofuran-2-carboxylic acid Small molecule or natural product Hs Full agonist 6.7 pEC50 3
⤷ pEC50 6.7 [3]
IBC 293 Small molecule or natural product Hs Full agonist 6.4 pEC50 7
⤷ pEC50 6.4 (EC50 3.98x10-7 M) [7]
D-kynurenine Small molecule or natural product Hs Full agonist 5.6 pEC50 2
⤷ pEC50 5.6 (EC50 2.61x10-6 M) [2]
2-hydroxyoctanoic acid Small molecule or natural product Hs Full agonist 5.4 pEC50 1
⤷ pEC50 5.4 (EC50 4x10-6 M) [1]
compound 5b [PMID: 17358052] Small molecule or natural product Hs Full agonist 5.3 pEC50 3
⤷ pEC50 5.3 [3]
nicotinic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.0 – 6.5 pEC50 13
⤷ pEC50 4.0 – 6.5 [13]
3-hydroxyoctanoic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.1 pEC50 1
⤷ pEC50 5.1 (EC50 8x10-6 M) [1]
D-phenylalanine Small molecule or natural product Ligand has a PDB structure Hs Full agonist 5.0 pEC50 2
⤷ pEC50 5.0 (EC50 9.02x10-6 M) [2]
D-tryptophan Small molecule or natural product Ligand has a PDB structure Hs Full agonist 5.0 pEC50 2
⤷ pEC50 5.0 (EC50 9.72x10-6 M) [2]
acifran Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.7 – 5.2 pEC50 3,5,11,13
⤷ pEC50 4.7 – 5.2 [3,5,11,13]
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 [13].
Antagonist Comments
Currently no antagonists are known for HCA3.
Allosteric Modulator Comments
Currently no allosteric regulators are known for HCA3.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
Other - See Comments
Comments:  HCA3 is also shown to activate the MAPK cascade (ERK1/ERK2) in a PTX-sensitive manner.
References:  3,5,11,13
Tissue Distribution Click here for help
Adipose tissue, spleen, lung.
Species:  Human
Technique:  RT-PCR.
References:  10,13
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:  12
Functional Assays Click here for help
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:  3,7
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:  13
Physiological Functions Click here for help
Inhibition of lipolytic activity.
Species:  Human
Tissue:  Adipocytes.
References:  7
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.

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 USA, 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 et al.. (2007) Analogues of acifran: agonists of the high and low affinity niacin receptors, GPR109a and GPR109b. J Med Chem, 50 (7): 1445-8. [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 Pharmacol, 71 (5): 646-56. [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 Commun, 340 (2): 482-90. [PMID:16389067]

6. Peters A, Krumbholz P, Jäger E, Heintz-Buschart A, Çakir MV, Rothemund S, Gaudl A, Ceglarek U, Schöneberg T, Stäubert C. (2019) Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor 3. PLoS Genet, 15 (5): e1008145. [PMID:31120900]

7. 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 Chem, 49 (4): 1227-30. [PMID:16480258]

8. 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]

9. 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]

10. 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 Commun, 303 (1): 364-9. [PMID:12646212]

11. Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ et al.. (2005) (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem, 280 (29): 26649-52. [PMID:15929991]

12. 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]

13. 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]

Contributors

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