View source for Biology:Hydroxycarboxylic acid receptor 2

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox gene}}
'''Hydroxycarboxylic acid receptor 2''' ('''HCA<sub>2</sub>'''), also known as '''niacin receptor 1''' ('''NIACR1''') and '''GPR109A''',<ref>{{cite journal | vauthors = Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP | title = International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B) | journal = Pharmacological Reviews | volume = 63 | issue = 2 | pages = 269–90 | date = June 2011 | pmid = 21454438 | doi = 10.1124/pr.110.003301 | doi-access = free }}</ref> is a [[Biology:Protein|protein]] which in humans is encoded by the ''HCAR2'' [[Biology:Gene|gene]].<ref name="pmid12044878">{{cite journal | vauthors = Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S | title = Identification of G protein-coupled receptor genes from the human genome sequence | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 97–101 | date = June 2002 | pmid = 12044878 | doi = 10.1016/S0014-5793(02)02775-8 | s2cid = 7116392 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GPR109A G protein-coupled receptor 109A| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=338442}}</ref><ref name="pmid12522134">{{cite journal | vauthors = 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 | title = Molecular identification of high and low affinity receptors for nicotinic acid | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9869–74 | date = March 2003 | pmid = 12522134 | doi = 10.1074/jbc.M210695200 | doi-access = free }}</ref><ref name="pmid12646212">{{cite journal | vauthors = Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K | title = Molecular identification of nicotinic acid receptor | journal = Biochemical and Biophysical Research Communications | volume = 303 | issue = 1 | pages = 364–9 | date = March 2003 | pmid = 12646212 | doi = 10.1016/S0006-291X(03)00342-5 }}</ref> HCA<sub>2</sub>, like the other hydroxycarboxylic acid receptors HCA<sub>1</sub> and HCA<sub>3</sub>, is a [[Biology:Gi alpha subunit|G<sub>i/o</sub>-coupled]] [[Biology:G protein-coupled receptor|G protein-coupled receptor]] (GPCR).<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" /> The primary endogenous [[Biology:Agonist|agonist]]s of HCA<sub>2</sub> are [[Chemistry:Beta-Hydroxybutyric acid|{{smallcaps all|D}}-β-hydroxybutyric acid]] and [[Chemistry:Butyric acid|butyric acid]] (and their conjugate bases, β-hydroxybutyrate and [[Chemistry:Butyrate|butyrate]]).<ref name="IUPHAR's comprehensive 2011 review on HCARs">{{cite journal | vauthors = Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP | title = International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B) | journal = Pharmacological Reviews | volume = 63 | issue = 2 | pages = 269–90 | date = June 2011 | pmid = 21454438 | doi = 10.1124/pr.110.003301 | doi-access = free }}</ref><ref name="IUPHAR-DB HCAR family page">{{cite web |author1=S Offermanns, SL Colletti, AP IJzerman, TW Lovenberg, G Semple, A Wise, MG Waters |title=Hydroxycarboxylic acid receptors |url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=48 |website=IUPHAR/BPS Guide to Pharmacology |publisher=International Union of Basic and Clinical Pharmacology |access-date=13 July 2018}}</ref> HCA<sub>2</sub> is also a high-affinity biomolecular target for [[Chemistry:Niacin (substance)|niacin]] (aka nicotinic acid).<ref name="pmid12522134"/><ref name="pmid12646212"/>

HCA<sub>2</sub> activation inhibits lipolytic and atherogenic activity (i.e., it inhibits the breakdown of fats and the development of [[Medicine:Atherosclerosis|atherosclerosis]]), induces [[Medicine:Vasodilation|vasodilation]] (i.e., the dilation of blood vessels), and is responsible for mediating [[Chemistry:Niacin (substance)|niacin]]-induced flushing.<ref>{{cite web | title = HCA2 receptor | publisher = International Union of Basic and Clinical Pharmacology | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=312  | access-date = 24 March 2016 }}</ref>

== Function ==
HCA<sub>2</sub> is a high-affinity G<sub>i</sub>/G<sub>o</sub>-coupled [[Biology:G protein-coupled receptor|G protein-coupled receptor]] (GPCR) for nicotinic acid (niacin),<ref name="pmid12522134"/><ref name="pmid12646212"/> and is a member of the nicotinic acid receptor family of GPCRs. HCA<sub>2</sub> activation inhibits lipolytic and atherogenic activity (i.e., it inhibits the breakdown of fats and the development of [[Medicine:Atherosclerosis|atherosclerosis]]), induces [[Medicine:Vasodilation|vasodilation]] (i.e., the dilation of blood vessels), and is responsible for niacin-induced flushing.<ref>{{cite web | title = HCA2 receptor | publisher = International Union of Basic and Clinical Pharmacology | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=312  | access-date = 24 March 2016 }}</ref>

=== 5-oxo-ETE ===
The mouse ortholog of HCA<sub>2</sub>, Niacr1, has been proposed to mediate the ability of 5-oxo-ETE, a member of the 5-HETE family of eicosanoids, to stimulate the production of [[Biology:Steroidogenic acute regulatory protein|steroidogenic acute regulatory protein]] mRNA, Steroidogenic acute regulatory protein, and thereby progesterone in mouse cultured [[Biology:MA-10 cell|MA-10]] Leydig cells.<ref name="pmid23159987">{{cite journal | vauthors = Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F | title = Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells | journal = Molecular and Cellular Endocrinology | volume = 371 | issue = 1–2 | pages = 71–8 | date = May 2013 | pmid = 23159987 | doi = 10.1016/j.mce.2012.11.003 | s2cid = 8520991 }}</ref>  Human tissues respond to 5-oxo-ETE and other 5-HETE family members though the OXER1 G protein-coupled receptor. The roles, if any, of Niacr1 in the response of leydig cells to other 5-HETE family members, of Niacr1 in the response of other mouse cells to 5-HETE family members, and the role of HCA<sub>2</sub> in the response of human tissues to 5-HETE family members has not been determined.

== Clinical significance ==
HCA<sub>2</sub> is an important [[Biology:Biological target|biomolecular target]] of niacin which is a widely prescribed drug for the treatment of dyslipidemia and to increase [[Medicine:High-density lipoprotein|HDL cholesterol]] but whose therapeutic use is limited by flushing.<ref name="pmid16322787">{{cite journal | vauthors = Pike NB | title = Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3400–3 | date = December 2005 | pmid = 16322787 | pmc = 1297267 | doi = 10.1172/JCI27160 }}</ref> In HCA<sub>2</sub> [[Biology:Knockout mouse|knockout mice]], the effects of niacin on both lipids<ref name="pmid12563315">{{cite journal | vauthors = Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S | title = PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect | journal = Nature Medicine | volume = 9 | issue = 3 | pages = 352–5 | date = March 2003 | pmid = 12563315 | doi = 10.1038/nm824 | s2cid = 20451806 }}</ref> and flushing<ref name="pmid16322797">{{cite journal | vauthors = Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S | title = GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3634–40 | date = December 2005 | pmid = 16322797 | pmc = 1297235 | doi = 10.1172/JCI23626 }}</ref> is eliminated.  Furthermore, in arrestin beta 1 knockout mice, niacin's effect on flushing is greatly reduced while the lipid modifying effects are maintained.<ref name="pmid19349687">{{cite journal | vauthors = Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ | title = beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice | journal = The Journal of Clinical Investigation | volume = 119 | issue = 5 | pages = 1312–21 | date = May 2009 | pmid = 19349687 | pmc = 2673863 | doi = 10.1172/JCI36806 }}</ref> At high doses, niacin produces marked anti-inflammatory effects in a variety of tissues&nbsp;– including the brain, gastrointestinal tract, skin, and [[Medicine:Inflammation#Vascular component|vascular tissue]]&nbsp;– through activation of HCA<sub>2</sub>.<ref name="Niacin neuroinflammation">{{cite journal | vauthors = Offermanns S, Schwaninger M | title = Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation | journal = Trends in Molecular Medicine | volume = 21 | issue = 4 | pages = 245–55 | date = April 2015 | pmid = 25766751 | doi = 10.1016/j.molmed.2015.02.002 | quote = Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation. }}</ref><ref name="Niacin vascular inflammation">{{cite journal | vauthors = Chai JT, Digby JE, Choudhury RP | title = GPR109A and vascular inflammation | journal = Current Atherosclerosis Reports | volume = 15 | issue = 5 | pages = 325 | date = May 2013 | pmid = 23526298 | pmc = 3631117 | doi = 10.1007/s11883-013-0325-9 | quote = This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein β-arrestins. }}</ref><ref name="NIACR1 anti-inflammatory effects">{{cite journal | vauthors = Graff EC, Fang H, Wanders D, Judd RL | title = Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2 | journal = Metabolism | volume = 65 | issue = 2 | pages = 102–13 | date = February 2016 | pmid = 26773933 | doi = 10.1016/j.metabol.2015.10.001 | quote = HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types.&nbsp;... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes. }}</ref><ref name="Niacin-NIACR1 in PD">{{cite journal | vauthors = Wakade C, Chong R | title = A novel treatment target for Parkinson's disease | journal = Journal of the Neurological Sciences | volume = 347 | issue = 1–2 | pages = 34–8 | date = December 2014 | pmid = 25455298 | doi = 10.1016/j.jns.2014.10.024 | s2cid = 29760853 | quote = GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina. }}</ref> Niacin has also been shown to attenuate [[Biology:Neuroinflammation|neuroinflammation]] in part through NIACR1 binding;<ref name="Niacin neuroinflammation" /> consequently, HCA<sub>2</sub> has been identified as a potential therapeutic target for treating [[Biology:Neuroimmune system|neuroimmune disorders]] such as multiple sclerosis and [[Medicine:Parkinson's disease|Parkinson's disease]].<ref name="Niacin neuroinflammation" /><ref name="Niacin-NIACR1 in PD" />

The precise mechanism of action of niacin therapeutic effects has not been fully elucidated, but appears to work in part through activation of HCA<sub>2</sub> which reduces the levels of intracellular [[Chemistry:Cyclic adenosine monophosphate|cAMP]] thereby inhibiting [[Biology:Lipolysis|lipolysis]] in [[Biology:Adipocyte|adipocyte]]s.<ref name="pmid16018973">{{cite journal | vauthors = Zhang Y, Schmidt RJ, Foxworthy P, Emkey R, Oler JK, Large TH, Wang H, Su EW, Mosior MK, Eacho PI, Cao G | title = Niacin mediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A | journal = Biochemical and Biophysical Research Communications | volume = 334 | issue = 2 | pages = 729–32 | date = August 2005 | pmid = 16018973 | doi = 10.1016/j.bbrc.2005.06.141 }}</ref>  In contrast, the flushing effect is due to HCA<sub>2</sub> activation of [[Biology:Extracellular signal-regulated kinases|ERK 1/2]] [[Biology:Mitogen-activated protein kinase|MAP kinase]]<ref name="pmid17452318">{{cite journal | vauthors = 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 | title = Nicotinic acid receptor agonists differentially activate downstream effectors | journal = The Journal of Biological Chemistry | volume = 282 | issue = 25 | pages = 18028–36 | date = June 2007 | pmid = 17452318 | doi = 10.1074/jbc.M701866200 | doi-access = free }}</ref> mediated by arrestin beta 1.<ref name="pmid19349687"/> Activation of MAP kinase in turn causes release of prostaglandin D2 from [[Biology:Langerhans cell|Langerhans cell]]s in the skin.<ref name="pmid16674924">{{cite journal | vauthors = Tang Y, Zhou L, Gunnet JW, Wines PG, Cryan EV, Demarest KT | title = Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A | journal = Biochemical and Biophysical Research Communications | volume = 345 | issue = 1 | pages = 29–37 | date = June 2006 | pmid = 16674924 | doi = 10.1016/j.bbrc.2006.04.051 }}</ref>

NIACR1 is essential for the anti-inflammatory effect of beta-hydroxybutyrate in many cell types,<ref name="pmid28178565">{{cite journal | vauthors=Puchalska P, Crawford PA | title=Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics | journal=[[Biology:Cell Metabolism|Cell Metabolism]] | volume=25 | issue=2 | pages=262–284 | year=2017 |  doi = 10.1016/j.cmet.2016.12.022 | pmc=5313038 | pmid=28178565 }}</ref><ref name="pmid33014275">{{cite journal | vauthors = Bradshaw PC, Seeds WA, Curtis WM | title = COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm | journal = Oxidative Medicine and Cellular Longevity | volume = 2020 | pages = 6401341 | date = 2020 | doi = 10.1155/2020/6401341  | pmc = 7519203 | pmid = 33014275| doi-access = free }}</ref> but the inhibition of the NLRP3 inflammasome by beta-hydroxybutyrate in [[Biology:Macrophage|macrophage]]s is independent of NIACR1.<ref name="pmid31244753">{{cite journal | vauthors = Yang H, Shan W, Wang Q | title = Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms| journal = Frontiers in Neurology | volume = 10 | pages = 585 | date = 2019 | doi = 10.3389/fneur.2019.00585  | pmc = 6581710 | pmid = 31244753| doi-access = free}}</ref>

==Ligands==
Full agonists of HCA<sub>2</sub> include:
* [[Chemistry:Beta-Hydroxybutyric acid|{{smallcaps all|D}}-β-Hydroxybutyric acid]] and β-hydroxybutyrate<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" />
* [[Chemistry:Butyric acid|Butyric acid]] and [[Chemistry:Butyrate|butyrate]]<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" /><ref name="Review - General summary as of April 2015, excluding neuroepigenetic research">{{cite journal | vauthors = Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I | title = Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation | journal = Nutrients | volume = 7 | issue = 4 | pages = 2839–49 | date = April 2015 | pmid = 25875123 | pmc = 4425176 | doi = 10.3390/nu7042839 | quote = Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. | doi-access = free }}</ref><ref name="Review butyrate human T-cell HDACs">{{cite journal | vauthors = Hoeppli RE, Wu D, Cook L, Levings MK | title = The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome | journal = Frontiers in Immunology | volume = 6 | pages = 61 | date = February 2015 | pmid = 25741338 | pmc = 4332351 | doi = 10.3389/fimmu.2015.00061 | quote = Specific species that have been recognized by their high levels of butyrate production include ''Faecalibacterium prausnitzii'' and the cluster IV and XIVa of genus ''Clostridium''&nbsp;... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of ''Clostridium'' colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192). | doi-access = free }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332351/figure/F1/ Figure 1: Microbial-derived molecules promote colonic Treg differentiation.]</ref>
* Niacin (also known as nicotinic acid, a form of vitamin B<sub>3</sub>)<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" />

== References ==
{{reflist|33em}}

{{G protein-coupled receptors}}

[[Category:G protein-coupled receptors]]

{{Sourceattribution|Hydroxycarboxylic acid receptor 2|1}}