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GPR132

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GPR132
Identifiers
AliasesGPR132,G2A, G protein-coupled receptor 132
External IDsOMIM:606167;MGI:1890220;HomoloGene:8350;GeneCards:GPR132;OMA:GPR132 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

29933

56696

Ensembl

ENSG00000183484

ENSMUSG00000021298

UniProt

Q9UNW8

Q9Z282

RefSeq (mRNA)

NM_013345
NM_001278694
NM_001278695
NM_001278696

NM_019925

RefSeq (protein)

NP_001265623
NP_001265624
NP_001265625
NP_037477

NP_064309

Location (UCSC)Chr 14: 105.05 – 105.07 MbChr 12: 112.81 – 112.83 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

G protein coupled receptor 132,also termed G2A, is classified as a member of the proton sensing G protein coupled receptor (GPR) subfamily. Like other members of this subfamily, i.e.GPR4,GPR68(OGR1), andGPR65(TDAG8), G2A is aG protein coupled receptorthat resides in the cell surface membrane, senses changes in extracellularpH,and can alter cellular function as a consequence of these changes.[5]Subsequently, G2A was suggested to be a receptor for lysophosphatidylcholine (LPC). However, the roles of G2A as a pH-sensor or LPC receptor are disputed. Rather, current studies suggest that it is a receptor for certain metabolites of thepolyunsaturated fatty acid,linoleic acid.

The G2A gene[edit]

G2A in humans is encoded by theGPR132gene.[6][7]The G2A gene is located on chromosome 14q32.3 codes for two alternative splice variants, the original one, G2A-a, and G2A-b, that consist of 380 and 371 amino acids, respectively; the two receptor variants, when expressed inChinese hamster ovary cells,gave very similar results when analyzed for functionality.[8]G2A-a and G2A-b mRNA are expressed at similar levels in bloodleukocytes(macrophages,dendritic cells,neutrophils[PMN],mast cells,T lymphocytesandB lymphocytesat the highest levels followed by lower levels in spleen, lung and heart tissues; both variants are expressed at similar levels, and are almost equally induced by DNA synthesis inhibitors (hydroxyureaandcytosine arabinoside) or a differentiation inducer (all-trans retinoic acid) inHL-60human leukemic cells.[8][9]

The mouse G2A receptor, encoded by Gpr132, has 67% amino acid identity to human G2A but does not sense pH and does not respond to certain presumptive ligands (i.e. linoleic acid metabolites) that activate the human G2A.[8]

G2A deficiency in mice[edit]

Targeted disruption of G2A in mice causes the development of a late onset (> 1 year) slowly progressive wasting andautoimmune diseasecharacterized by lymphoid organ enlargement, lymphocytic infiltration into various tissues, glomerular immune complex deposition, andanti-nuclear autoantibodies.[10]Mice transplanted with bone marrow cells containing theBCR-ABLleukemia-inducing fusion gene but deficient in G2A exhibit expanded populations of leukemic cells compared to recipients of BCR-ABL-containing, G2A-sufficient bone marrow cells.[6]BCR-ABL is theoncogeneof thePhiladelphia chromosomethat causes humanChronic myelogenous leukemiaand is sometimes found associated with humanacute lymphocytic leukemiaandacute myelocytic leukemia;furthermore, the forced expression of BCR-ABL in cultured rodent cells induces the expression of G2A and the overexpression of G2A inhibits the malignant growth to these cells.[11]Thus, the G2A deficiency studies suggest that G2A functions in mice to suppress certain immune dysfunctions and BCR-ABL-related leukemic cell growth.

G2A function[edit]

pH sensor[edit]

G2A was initially defined as one of the gene products whose production was stimulated in mouse pre-B lymphocytes (seeImmunoglobulin heavy chain) by transfecting the cells with the humanoncogene(i.e., cancer causing) BCR-ABL or by treating the cells with DNA damaging agents; its expression in these cells blocked their progression through thecell cyclespecifically at theG2-M DNA damage checkpoint.[11]These studies allow that G2A limits the potentially malignant growth of certain cells in mice and possible could do so in humans. In addition,Gene knockoutstudies in mice find G2A to be necessary for suppressing an autoimmune syndrome (see G2A deficiency in mice). These results allow that G2A may function in blocking certain aspects of autoimmunity, particularly those involving the proliferation and tissue trafficking of lymphocytes.[10]Early studies first classified G2A as a proton-sensing receptor and suggested that G2A contributed to the regulation of proliferation in certain cells and the regulation of lymphocytes' contributions to certain immune functions by being activated by changes in extracellularpH.[12]Tissues suffering malignant cell growth, autoimmune reactions, poor blood flowischemia,inflammationandallergyreactions, and tissue injury develop extracellular acidification due to the stimulation ofanaerobic glycolysis;The proton-sensing function of G2A could be involved in combating or, in certain cases promoting these conditions.[9]An example implicating G2A's pH sensitivity in physiological responses involves pain perception. In rats, G2A, similar to other pH sensing GPCRs, is located indorsal root ganglianeurons,small diameter neurons responsible fornociception,and other nerve tissues responsible for sensing pain; it is suggested that G2A in these nerve tissues detects the acid changes that occur in the extracellular media of injured tissues and signal for the perception of pain[13][9]

However, the activity of the human G2A receptor and its mouse homolog are significantly less sensitive to pH fluctuations than other pH sensing GPCRs; indeed, in studies ofthymocytesandsplenocytestaken from mice deficient in either the G2A or another pH-sensing GPCR, TDAG8, TDAG8 was found critical while G2A was found dispensable for sensing pH changes.[14]Thus, the cited functions of G2A presumed due to its pH sensing ability could reflect other means for this receptor's activation.

Receptor for lyso-phospholipids[edit]

A report working with humanneutrophilsproposed that G2A was a receptor for aphospholipid,lysophosphatidylcholine(LPC), and aSphingomyelin,sphingosylphosphorylcholine.[15]However, these studies did not give evidence that these lyso-phospholipids actually bound to G2A; some 4 years later this report was withdrawn.[16]Nonetheless, many of LPC's activities do depend on G2A; more recent data suggest that rather than acting directly as a ligand that binds to G2A, LPC alters G2A's distribution within the cell by increasing its movement from the cell interior to the cell surface and/or by preventing its movement away from the cell surface to the cell interior. That is, in neutrophils and other cell types which have internal stores of G2A in membrane-bound secretory vesicles, G2A-containing vesicles continuously merge with and move back out of a cell's surface membrane.[17]Lyso-phospholipids may act asa))detergents to increase a cell's permeability thereby allowing entry of small extracellular molecules such as ionic calcium which trigger the movement of the intracellular vesicles to the surface membrane orb)agents that intercalate or wedge into the cell's surface membrane to promote this vesicle movement or slow this vesicle movement out of the membrane.[17][18]Such effects increase the expression of G2A at the cell surface membrane which, if G2A has a sub-stimulatory level of activity when normally express but stimulatory when it is overexpressed at the surface membrane, may lead to G2A-dependent cellular responses. With respect to this view, small decreases in extracellular pH reduce the internalization of G2A thereby increasing its surface membrane expression.[17]

LPCs that contain the unsaturated fatty acidshexadecanoic acidoroctadecanoic acidbound to theirsn-1act to permeablize, while LPC with the monounsaturated fatty acid,oleic acidatsn-1act to perturb target cell surface membranes.[18]While not involving G2A receptor binding, some actions of LPCs are G2A-dependent. For example, LPCs increase the bactericidal activity of rodent neutrophils, enhance hydrogen peroxide production in rodent neutrophils triggered by the ingestion of bacteria, stimulate thechemotaxisof humanmonocytes,and protect mice from the lethal effects of experimentally induced bacterial sepsisendotoxin.[19][20]G2A may similarly be responsible for the activities of other phospholipids which, like LPC have not been shown to bind to G2A but still require G2A for certain of their activities viz.,lysophosphatidylserineandlysophosphatidylethanolamine;these two lyso-phospholipids stimulate calcium signaling pathways in human neutrophils by a G2A dependent mechanism.[18]Furthermore, activated neutrophils greatly increase their surface membrane content of lysophosphatidylserine. In a mouse model, mouse neutrophils with increased levels of lysophosphatidylserine on their surface membrane due to cell activation or artificial addition showed an increase in there engulfment by mousemacrophagesin vitro that was dependent on the expression of G2A in the macrophages and an increased rate of clearance in mice by a mechanism that was dependent on the expression of G2A by the mice.[21][22]Lysophosphotidylserine-laden neutrophils stimulated the G2A-dependent production the proinflammatory mediator,prostaglandin E2,by macrophages in the in vitro studies and inhibited the production of pro-inflammatory mediators,interleukin-6and keratinocyte chemoattractant, for in vivo studies. G2A is also involved in blood-borne lysophosphatidylcholine (LPC) mediated amplification of microbial TLR ligands induced inflammatory responses from human cells.[23]Taken together, these studies suggest that G2A, activated by certain phospholipids contributes not only to the development but also the resolution of certaininflammationandinnate immune responsesin mice and may also do so in humans.

Receptor for fatty acid metabolites[edit]

Thelinoleic acidmetabolites, 9(S)-hydroxyoctadecadienoic acid (HODE),9(R)-HODE,and13(R)-HODE,[8][20]and thearachidonic acidmetabolites5(S)-hydroxyicosatetraenoic acid(HETE),12(S)-HETE,15(S)-HETE,andracemic5-HETE, 12-HETE, 15-HETE, 8-HETE, 9-HETE, and 11-HETE stimulate Chinese hamster ovary cells made to express G2A; these effects, unlike those of phospholipids, appear to involve and require the binding of the metabolites to G2A as evidenced by the ability of the most potent of these metabolites, 9-HODE to stimulate G2A-dependent functions in membranes isolated from these cells.[8]9-HODE induces cultured normal human epidermalkeratinocytesto stop growing by inhibiting their cell cycle at theG1stage;it also stimulates these cells to secrete threecytokinesthat stimulate keratinocyte growth vis.,interleukin-6,interleukin-8,andGM-CSF.These activities are G2A-dependent. It is suggested that 9-HODE acts in human skin to block the proliferation of damaged cells while concurrently, by triggering the secretion of the cited cytokines, stimulating the proliferation of undamaged skin cells; these actions may thereby serve to rejuvenate skin damaged for example byUV light.[8]

See also[edit]

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000183484–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000021298–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Damaghi M, Wojtkowiak JW, Gillies RJ (December 2013)."pH sensing and regulation in cancer".Frontiers in Physiology.4:370.doi:10.3389/fphys.2013.00370.PMC3865727.PMID24381558.
  6. ^abLe LQ, Kabarowski JH, Wong S, Nguyen K, Gambhir SS, Witte ON (May 2002)."Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene".Cancer Cell.1(4): 381–91.doi:10.1016/S1535-6108(02)00058-2.PMID12086852.
  7. ^"Entrez Gene: GPR132 G protein-coupled receptor 132".
  8. ^abcdefObinata H, Izumi T (September 2009). "G2A as a receptor for oxidized free fatty acids".Prostaglandins & Other Lipid Mediators.89(3–4): 66–72.doi:10.1016/j.prostaglandins.2008.11.002.PMID19063986.
  9. ^abcOkajima F (November 2013). "Regulation of inflammation by extracellular acidification and proton-sensing GPCRs".Cellular Signalling.25(11): 2263–71.doi:10.1016/j.cellsig.2013.07.022.PMID23917207.
  10. ^abLe LQ, Kabarowski JH, Weng Z, Satterthwaite AB, Harvill ET, Jensen ER, Miller JF, Witte ON (May 2001)."Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome".Immunity.14(5): 561–71.doi:10.1016/s1074-7613(01)00145-5.PMID11371358.
  11. ^abWeng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, Hunter CA, Fernal AA, Le Beau MM, Witte ON (October 1998)."A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M".Proceedings of the National Academy of Sciences of the United States of America.95(21): 12334–9.Bibcode:1998PNAS...9512334W.doi:10.1073/pnas.95.21.12334.PMC22832.PMID9770487.
  12. ^Murakami N, Yokomizo T, Okuno T, Shimizu T (October 2004)."G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine".The Journal of Biological Chemistry.279(41): 42484–91.doi:10.1074/jbc.M406561200.PMID15280385.
  13. ^Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH (October 2007)."Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors"(PDF).Molecular and Cellular Neurosciences.36(2): 195–210.doi:10.1016/j.mcn.2007.06.010.PMID17720533.S2CID38351962.>
  14. ^Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON (February 2005)."Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells".Proceedings of the National Academy of Sciences of the United States of America.102(5): 1632–7.Bibcode:2005PNAS..102.1632R.doi:10.1073/pnas.0409415102.PMC545089.PMID15665078.
  15. ^Zhu K, Baudhuin LM, Hong G, Williams FS, Cristina KL, Kabarowski JH, Witte ON, Xu Y (November 2001)."Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4".The Journal of Biological Chemistry.276(44): 41325–35.doi:10.1074/jbc.M008057200.PMID11535583.(Retracted, seedoi:10.1016/S0021-9258(19)47942-8,PMID16498716.If this is an intentional citation to a retracted paper, please replace{{retracted|...}}with{{retracted|...|intentional=yes}}.)
  16. ^"Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4".The Journal of Biological Chemistry.280(52): 43280. December 2005.doi:10.1016/S0021-9258(19)47942-8.PMID16498716.
  17. ^abcLan W, Yamaguchi S, Yamamoto T, Yamahira S, Tan M, Murakami N, Zhang J, Nakamura M, Nagamune T (September 2014)."Visualization of the pH-dependent dynamic distribution of G2A in living cells".FASEB Journal.28(9): 3965–74.doi:10.1096/fj.14-252999.PMC5395726.PMID24891524.
  18. ^abcFrasch SC, Zemski-Berry K, Murphy RC, Borregaard N, Henson PM, Bratton DL (May 2007)."Lysophospholipids of different classes mobilize neutrophil secretory vesicles and induce redundant signaling through G2A".Journal of Immunology.178(10): 6540–8.doi:10.4049/jimmunol.178.10.6540.PMID17475884.
  19. ^Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, Kim YH, Song DK (February 2004). "Therapeutic effects of lysophosphatidylcholine in experimental sepsis".Nature Medicine.10(2): 161–7.doi:10.1038/nm989.PMID14716308.S2CID32242606.
  20. ^abRolin J, Vego H, Maghazachi AA (September 2014)."Oxidized lipids and lysophosphatidylcholine induce the chemotaxis, up-regulate the expression of CCR9 and CXCR4 and abrogate the release of IL-6 in human monocytes".Toxins.6(9): 2840–56.doi:10.3390/toxins6092840.PMC4179163.PMID25251539.
  21. ^Frasch SC, Fernandez-Boyanapalli RF, Berry KZ, Leslie CC, Bonventre JV, Murphy RC, Henson PM, Bratton DL (April 2011)."Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity".The Journal of Biological Chemistry.286(14): 12108–22.doi:10.1074/jbc.M110.181800.PMC3069415.PMID21297111.
  22. ^Frasch SC, Fernandez-Boyanapalli RF, Berry KA, Murphy RC, Leslie CC, Nick JA, Henson PM, Bratton DL (February 2013)."Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine".The Journal of Biological Chemistry.288(7): 4583–93.doi:10.1074/jbc.M112.438507.PMC3576064.PMID23293064.
  23. ^Sharma, Naveen; Akhade, Ajay Suresh; Ismaeel, Sana; Qadri, Ayub (2020)."Serum-borne lipids amplify TLR-activated inflammatory responses".Journal of Leukocyte Biology.109(4): 821–831.doi:10.1002/JLB.3AB0720-241RR.PMID32717772.S2CID220842161.

Further reading[edit]

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