HCA<sub>2</sub> receptor | Hydroxycarboxylic acid receptors | IUPHAR/BPS Guide to PHARMACOLOGY

HCA2 receptor

Target id: 312

Nomenclature: HCA2 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.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for HCA2 receptor in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 363 12q24.31 HCAR2 hydroxycarboxylic acid receptor 2
Mouse 7 360 5 F Hcar2 hydroxycarboxylic acid receptor 2
Rat 7 360 12q15 Hcar2 hydroxycarboxylic acid receptor 2
Previous and Unofficial Names
PUMAG | G-protein coupled receptor HM74A | Nicotinic acid receptor | Nic1 | G protein-coupled receptor 109A | Niacr1 | niacin receptor 1
Database Links
Specialist databases
GPCRDB hcar2_human (Hs), hcar2_mouse (Mm), hcar2_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
β-D-hydroxybutyric acid
Potency order of endogenous ligands (Human)
β-D-hydroxybutyric acid > butyric acid

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]nicotinic acid Hs Full agonist 7.0 – 7.3 pKd 24,30,33
pKd 7.0 – 7.3 (Kd 1x10-7 – 5.01x10-8 M) [24,30,33]
MK 6892 Hs Full agonist 8.4 pKi 21
pKi 8.4 (Ki 4x10-9 M) [21]
5-butyl-1H-pyrazole-3-carboxylic acid Rn Partial agonist 7.1 pKi 31
pKi 7.1 [31]
monomethyl fumarate Hs Full agonist 6.7 pKi 32
pKi 6.7 (Ki 1.8x10-7 M) [32]
SCH 900271 Hs Agonist 8.7 pEC50 15
pEC50 8.7 [15]
MK 6892 Hs Full agonist 7.8 pEC50 21
pEC50 7.8 (EC50 1.6x10-8 M) [21]
MK 1903 Hs Full agonist 7.6 pEC50 4
pEC50 7.6 (EC50 2.75x10-8 M) [4]
GSK256073 Hs Agonist 7.5 pEC50 25
pEC50 7.5 [25]
compound (+)17a [PMID: 20363624] Hs Full agonist 7.3 pEC50 5
pEC50 7.3 (EC50 4.5x10-8 M) [5]
(+)-5-(5-bromothiophen-3-yl)-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid Hs Full agonist 7.3 pEC50 10,26
pEC50 7.3 [10,26]
nicotinic acid Hs Full agonist 6.0 – 7.2 pEC50 24,30,33
pEC50 6.0 – 7.2 (EC50 1x10-6 – 6.31x10-8 M) [24,30,33]
acifran Hs Full agonist 5.7 – 5.9 pEC50 10,13,26,33
pEC50 5.7 – 5.9 [10,13,26,33]
MK 0354 Hs Partial agonist 5.8 pEC50 19
pEC50 5.8 (EC50 1.65x10-6 M) [19]
acipimox Hs Full agonist 5.2 – 5.6 pEC50 24,33
pEC50 5.2 – 5.6 (EC50 6.31x10-6 – 2.51x10-6 M) [24,33]
3-pyridine-acetic acid Hs Full agonist 5.3 pEC50 33
pEC50 5.3 [33]
5-methyl nicotinic acid Hs Full agonist 5.1 pEC50 33
pEC50 5.1 [33]
monomethyl fumarate Hs Full agonist 5.0 pEC50 27
pEC50 5.0 (EC50 9.4x10-6 M) [27]
cinnamic acid Hs Full agonist 3.6 pEC50 16
pEC50 3.6 (EC50 2.4x10-4 M) [16]
para-coumaric acid Hs Full agonist 3.5 pEC50 16
pEC50 3.5 (EC50 3.1x10-4 M) [16]
β-D-hydroxybutyric acid Mm Full agonist 3.5 pEC50 26
pEC50 3.5 [26]
β-D-hydroxybutyric acid Hs Full agonist 3.1 pEC50 26
pEC50 3.1 [26]
butyric acid Hs Agonist 2.8 pEC50
pEC50 2.8
compound 21 [PMID: 21185185] Hs Full agonist 7.9 pIC50 9
pIC50 7.9 (IC50 1.2x10-8 M) [9]
compound 2g [PMID: 19309152] Hs Full agonist 7.9 pIC50 20
pIC50 7.9 (IC50 1.3x10-8 M) [20]
compound 1q [PMID: 18029181] Hs Partial agonist 6.8 pIC50 22
pIC50 6.8 (IC50 1.4x10-7 M) [22]
compound 8f [PMID: 20615702] Hs Full agonist 6.4 pIC50 8
pIC50 6.4 (IC50 3.9x10-7 M) [8]
View species-specific agonist tables
Agonist Comments
Nicotinic acid has equal affinity for rat and mouse homologs of the receptor, both in the 'cold' and tritiated form.
Antagonist Comments
Currently no antagonists are known for the HCA2 receptor.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
compound 9n [PMID: 18752940] Hs Positive 6.8 pEC50 23
pEC50 6.8 (EC50 1.7x10-7 M) [23]
compound 42 [PMID: 22420767] Hs Positive 5.6 pEC50 3
pEC50 5.6 (EC50 2.6x10-6 M) [3]
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Phospholipase A2 stimulation
Comments:  HCA2 is also shown to activate the MAPK cascade (ERK1/ERK2).
References:  17,28,30,33
Tissue Distribution
Adipose tissue.
Species:  Human
Technique:  Northern blotting.
References:  24,30,33
Intestinal epithelial cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  29
Keratinocytes.
Species:  Human
Technique:  RT-PCR.
References:  27
Adipose tissue.
Species:  Human
Technique:  RT-PCR.
References:  24,30,33
Neutrophils, Langerhans cells.
Species:  Human
Technique:  RT-PCR.
References:  12
Spleen, macrophages.
Species:  Mouse
Technique:  Northern blotting.
References:  18
Keratinocytes.
Species:  Mouse
Technique:  RT-PCR, genetic reporter mouse.
References:  7
Adipose tissue.
Species:  Mouse
Technique:  RT-PCR.
References:  24,30,33
Adipose tissue.
Species:  Mouse
Technique:  Northern blotting.
References:  24,30,33
Intestinal epithelial cells.
Species:  Mouse
Technique:  Immunohistochemistry.
References:  29
Retinal pigment epithelial cells.
Species:  Mouse
Technique:  Immunocytochemistry, RT-PCR.
References:  14
Expression Datasets

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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
Measurement of arachidonic acid release in human epidermoid A431 cells endogenously expressing the HCA2 receptor.
Species:  Human
Tissue:  A431 cells.
Response measured:  Enhancement of arachidonic acid release.
References:  28
Measurement of ERK1/2 phosphorylation in CHO cells transfected with the mouse HCA2 receptor.
Species:  Mouse
Tissue:  CHO cells.
Response measured:  Stimulation of ERK1/2 phosphorylation.
References:  13,30
Measurement of prostaglandin D2 release in Langerhans cells endogenously expressing the HCA2 receptor.
Species:  Human
Tissue:  Epidermal Langerhans cells.
Response measured:  Increase in prostaglandin D2 release.
References:  12
Measurement of intracellular [Ca2+] in epidermal Langerhans cells endogenously expressing the HCA2 receptor.
Species:  Mouse
Tissue:  Epidermal Langerhans cells.
Response measured:  Transient increase in intracellular [Ca2+].
References:  2
Measurement of cAMP accumulation in CHO cells transfected with the mouse HCA2 receptor
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  30
Measurement of cAMP accumulation in HEK293 cells transfected with the mouse HCA2 receptor.
Species:  Mouse
Tissue:  HEK 293 cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  24
Measurement of intracellular [Ca2+] in human epidermoid A431 cells endogenously expressing the HCA2 receptor.
Species:  Human
Tissue:  A431 cells.
Response measured:  Transient increase in intracellular [Ca2+].
References:  28
Measurement of cAMP accumulation in CHO cells transfected with the human HCA2 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  30
Measurement of [35S]GTPγS incorporation in membranes from HEK 293 cells transfected with the human HCA2 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Stimulation of [35S]GTPγS binding.
References:  33
Measurement of cAMP accumulation in HEK 293 cells transfected with the human HCA2 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Inhibition of forskolin-stimulated cAMP accumulation.
References:  24
Measurement of [35S]GTPγS incorporation in membranes from HEK 293 cells transfected with the mouse HCA2 receptor.
Species:  Mouse
Tissue:  HEK 293 cells.
Response measured:  Stimulation of [35S]GTPγS binding.
References:  33
Physiological Functions
Increase in dermal blood flow.
Species:  Mouse
Tissue:  Skin.
References:  2
Increase in ear blood flow.
Species:  Rat
Tissue:  Skin.
References:  6
Inhibition of lipolytic activity.
Species:  Mouse
Tissue:  Adipocytes.
References:  30,34
HCA2 mediates nicotinic acid-induced flushing.
Species:  Mouse
Tissue: 
References:  1-2,6-7
HCA2 mediates the antilipolytic and anti-atherogenic effects of nicotinic acid.
Species:  Mouse
Tissue: 
References:  11,30
HCA2 mediates nicotinic acid-induced flushing.
Species:  Rat
Tissue: 
References:  1-2,6-7
Physiological Consequences of Altering Gene Expression
HCA2 receptor knockout mice do not flush in response to nicotinic acid.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  2
HCA2 receptor knockout mice do not respond with a decrease in plasma free fatty acid and triglyceride levels to nicotinic acid.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  30
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Niacr1tm1Soff Niacr1tm1Soff/Niacr1tm1Soff
involves: 129P2/OlaHsd * C57BL/6
MGI:1933383  MP:0002118 abnormal lipid homeostasis PMID: 12563315 

References

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1. Benyó Z, Gille A, Bennett CL, Clausen BE, Offermanns S. (2006) Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells. Mol. Pharmacol., 70 (6): 1844-9. [PMID:17008386]

2. Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S. (2005) GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest, 115: 3634-3640. [PMID:16322797]

3. Blad CC, van Veldhoven JP, Klopman C, Wolfram DR, Brussee J, Lane JR, Ijzerman AP. (2012) Novel 3,6,7-substituted pyrazolopyrimidines as positive allosteric modulators for the hydroxycarboxylic acid receptor 2 (GPR109A). J. Med. Chem., 55 (7): 3563-7. [PMID:22420767]

4. Boatman PD, Lauring B, Schrader TO, Kasem M, Johnson BR, Skinner P, Jung JK, Xu J, Cherrier MC, Webb PJ et al.. (2012) (1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans. J. Med. Chem., 55 (8): 3644-66. [PMID:22435740]

5. Boatman PD, Schrader TO, Kasem M, Johnson BR, Skinner PJ, Jung JK, Xu J, Cherrier MC, Webb PJ, Semple G et al.. (2010) Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a). Bioorg. Med. Chem. Lett., 20 (9): 2797-800. [PMID:20363624]

6. Carballo-Jane E, Gerckens LS, Luell S, Parlapiano AS, Wolff M, Colletti SL, Tata JR, Taggart AK, Waters MG, Richman JG, McCann ME, Forrest MJ. (2007) Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists. J Pharmacol Toxicol Methods, 56: 308-316. [PMID:17643322]

7. Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen BE, Ahmed K, Tunaru S, Wirth A, Offermanns S. (2010) Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J. Clin. Invest., 120 (8): 2910-9. [PMID:20664170]

8. Imbriglio JE, Chang S, Liang R, Raghavan S, Schmidt D, Smenton A, Tria S, Schrader TO, Jung JK, Esser C et al.. (2010) GPR109a agonists. Part 2: pyrazole-acids as agonists of the human orphan G-protein coupled receptor GPR109a. Bioorg. Med. Chem. Lett., 20 (15): 4472-4. [PMID:20615702]

9. Imbriglio JE, DiRocco D, Bodner R, Raghavan S, Chen W, Marley D, Esser C, Holt TG, Wolff MS, Taggart AK et al.. (2011) The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties. Bioorg. Med. Chem. Lett., 21 (9): 2721-4. [PMID:21185185]

10. 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 Chem, 50: 1445-1448. [PMID:17358052]

11. Lukasova M, Malaval C, Gille A, Kero J, Offermanns S. (2011) Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J. Clin. Invest., 121 (3): 1163-73. [PMID:21317532]

12. Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT. (2006) Langerhans cells release prostaglandin D2 in response to nicotinic acid. J Invest Dermatol, 126: 2637-2646. [PMID:17008871]

13. 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: 482-490. [PMID:16389067]

14. Martin PM, Ananth S, Cresci G, Roon P, Smith S, Ganapathy V. (2009) Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium. Mol. Vis., 15: 362-72. [PMID:19223991]

15. Palani A, Rao AU, Chen X, Huang X, Su J, Tang H, Huang Y, Qin J, Xiao D, Degrado S et al.. (2012) Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia. ACS Med Chem Lett, 3 (1): 63-8. [PMID:24900372]

16. Ren N, Kaplan R, Hernandez M, Cheng K, Jin L, Taggart AK, Zhu AY, Gan X, Wright SD, Cai TQ. (2009) Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J. Lipid Res., 50 (5): 908-14. [PMID:19136666]

17. Richman JG, Kanemitsu-Parks M, Gaidarov I, Cameron JS, Griffin P, Zheng H, Guerra NC, Cham L, Maciejewski-Lenoir D, Behan DP, Boatman D, Chen R, Skinner P, Ornelas P, Waters MG, Wright SD, Semple G, Connolly DT. (2007) Nicotinic acid receptor agonists differentially activate downstream effectors. J Biol Chem, 282: 18028-18036. [PMID:17452318]

18. Schaub A, Fütterer A, Pfeffer K. (2001) PUMA-G, an IFN-gamma-inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily. Eur J Immunol, 31: 3714-3725. [PMID:11745392]

19. Semple G, Skinner PJ, Gharbaoui T, Shin YJ, Jung JK, Cherrier MC, Webb PJ, Tamura SY, Boatman PD, Sage CR et al.. (2008) 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. J. Med. Chem., 51 (16): 5101-8. [PMID:18665582]

20. Shen HC, Ding FX, Deng Q, Wilsie LC, Krsmanovic ML, Taggart AK, Carballo-Jane E, Ren N, Cai TQ, Wu TJ et al.. (2009) Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats. J. Med. Chem., 52 (8): 2587-602. [PMID:19309152]

21. Shen HC, Ding FX, Raghavan S, Deng Q, Luell S, Forrest MJ, Carballo-Jane E, Wilsie LC, Krsmanovic ML, Taggart AK et al.. (2010) Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. J. Med. Chem., 53 (6): 2666-70. [PMID:20184326]

22. Shen HC, Szymonifka MJ, Kharbanda D, Deng Q, Carballo-Jane E, Wu KK, Wu TJ, Cheng K, Ren N, Cai TQ et al.. (2007) Discovery of orally bioavailable and novel urea agonists of the high affinity niacin receptor GPR109A. Bioorg. Med. Chem. Lett., 17 (24): 6723-8. [PMID:18029181]

23. Shen HC, Taggart AK, Wilsie LC, Waters MG, Hammond ML, Tata JR, Colletti SL. (2008) Discovery of pyrazolopyrimidines as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. Bioorg. Med. Chem. Lett., 18 (18): 4948-51. [PMID:18752940]

24. 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: 364-369. [PMID:12646212]

25. Sprecher D, Maxwell M, Goodman J, White B, Tang CM, Boullay V, de Gouville AC. (2015) Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist. Eur. J. Pharmacol., 756: 1-7. [PMID:25773497]

26. 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 Chem, 280: 26649-26652. [PMID:15929991]

27. Tang H, Lu JY, Zheng X, Yang Y, Reagan JD. (2008) The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem. Biophys. Res. Commun., 375 (4): 562-5. [PMID:18722346]

28. Tang Y, Zhou L, Gunnet JW, Wines PG, Cryan EV, Demarest KT. (2006) Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A. Biochem Biophys Res Commun, 345: 29-37. [PMID:16674924]

29. 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]

30. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. (2003) PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med, 9: 352-355. [PMID:12563315]

31. van Herk T, Brussee J, van den Nieuwendijk AM, van der Klein PA, Ijzerman AP, Stannek C, Burmeister A, Lorenzen A. (2003) Pyrazole derivatives as partial agonists for the nicotinic acid receptor. J Med Chem, 46: 3945-3951. [PMID:12930155]

32. van Veldhoven JP, Blad CC, Artsen CM, Klopman C, Wolfram DR, Abdelkadir MJ, Lane JR, Brussee J, Ijzerman AP. (2011) Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A). Bioorg. Med. Chem. Lett., 21 (9): 2736-9. [PMID:21167710]

33. 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 Chem, 278: 9869-9874. [PMID:12522134]

34. Zhang Y, Schmidt RJ, Foxworthy P, Emkey R, Oler JK, Large TH, Wang H, Su EW, Mosior MK, Eacho PI, Cao G. (2005) Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A. Biochem Biophys Res Commun, 334: 729-732. [PMID:16018973]

Contributors

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How to cite this page

Stefan Offermanns, Steven L. Colletti, Adriaan P. IJzerman, Timothy W. Lovenberg, Graeme Semple, Alan Wise.
Hydroxycarboxylic acid receptors: HCA2 receptor. Last modified on 20/02/2018. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=312.