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Aliases GPR132, G2A, G protein-coupled receptor 132
External IDs MGI: 1890220 HomoloGene: 8350 GeneCards: 29933
RNA expression pattern
PBB GE GPR132 221140 s at tn.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 14: 105.05 – 105.07 Mb Chr 12: 112.85 – 112.86 Mb
PubMed search [1] [2]
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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, OGR1 (GPR68), and TDAG8 (GPR65), G2A is a G protein coupled receptor that resides in the cell surface membrane, senses changes in extracellular pH, and can alter cellular function as a consequence of these changes.[3] 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 the polyunsaturated fatty acid, linoleic acid.

The G2A gene[edit]

G2A in humans is encoded by the GPR132 gene.[4][5] The G2A gene (Gene ID: 29933) 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 in Chinese hamster ovary cells, gave very similar results when analyzed for functionality.[6] G2A-a and G2A-b mRNA are expressed at similar levels in blood leukocytes ( macrophages, dendritic cells, neutrophils [PMN], mast cells, T lymphocytes and B lymphocytes at 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 (hydroxyurea and cytosine arabinoside) or a differentiation inducer (all-trans retinoic acid) in HL-60 human leukemic cells.[6][7]

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.[6]

G2A deficiency in mice[edit]

Targeted disruption of G2A in mice causes the development of a late onset (> 1 year) slowly progressive wasting and autoimmune disease characterized by lymphoid organ enlargement, lymphocytic infiltration into various tissues, glomerular immune complex deposition, and anti-nuclear autoantibodies.[8] Mice transplanted with bone marrow cells containing the BCR-ABL leukemia-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.[4] BCR-ABL is the oncogene of the Philadelphia chromosome that causes human Chronic myelogenous leukemia and is sometimes found associated with human acute lymphocytic leukemia and acute 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.[9] 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 (see Immunoglobulin heavy chain) by transfecting the cells with the human oncogene (i.e., cancer causing) BCR-ABL or by treating the cells with DNA damaging agents; its expression in these cells blocked their progression through the cell cycle specifically at the G2-M DNA damage checkpoint.[9] 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 knockout studies 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.[8] 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 extracellular pH.[10] Tissues suffering malignant cell growth, autoimmune reactions, poor blood flow ischemia, inflammation and allergy reactions, and tissue injury develop extracellular acidification due to the stimulation of anaerobic glycolysis; The proton-sensing function of G2A could be involved in combating or, in certain cases promoting these conditions.[7] An example implicating G2A's pH sensitivity in physiological responses involves pain perception. In rats, G2A, similar to other pH sensing GPCRs, is located in dorsal root ganglia neurons, small diameter neurons responsible for nociception, 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[11][7]

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 of thymocytes and splenocytes taken 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.[12] 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 human neutrophils proposed that G2A was a receptor for a phospholipid, lysophosphatidylcholine (LPC), and a Sphingomyelin, sphingosylphosphorylcholine.[13] However, these studies did not give evidence that these lyso-phospholipids actually bound to G2A; some 4 years later this report was withdrawn.[14] 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.[15] Lyso-phospholipids may act as a)) 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 or b) agents that intercalate or wedge into the cell's surface membrane to promote this vesicle movement or slow this visicle movement out of the membrane .[15][16] 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.[15]

LPCs that contain the unsaturated fatty acids hexadecanoic acid or octadecanoic acid bound to their sn-1 act to permeablize, while LPC with the monounsaturated fatty acid, oleic acid at sn-1 act to perturb target cell surface membranes.[16] 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 the chemotaxis of human monocytes, and protect mice from the lethal effects of experimentally induced bacterial sepsis endotoxin.[17][18] 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., lysophosphatidylserine and lysophosphatidylethanolamine; these two lyso-phospholipids stimulate calcium signaling pathways in human neutrophils by a G2A dependent mechanism.[16] 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 mouse macrophages in 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.[19][20] Lysophosphotidylserine-laden neutrophils stimulated the G2A-dependent production the anti-inflammatory mediator, prostaglandin E2, by macrophages in the in vitro studies and inhibited the production of pro-inflammatory mediators, interleukin-6 and keratinocyte chemoattractant, in in vivo studies. Taken together, these studies suggest that G2A, activated by certain phospholipids contributes not only to the development but also the resolution of certain inflammation and innate immune responses in mice and may also do so in humans.

Receptor for fatty acid metabolites[edit]

The linoleic acid metabolites, 9(S)-hydroxyoctadecadienoic acid (HODE), (9R)-HODE, and 13(R)-HODE (see 9-Hydroxyoctadecadienoic acid and 13-Hydroxyoctadecadienoic acid),[6][18] and the arachidonic acid metabolites 5(S)-hydroxyicosatetraenoic acid (see 5-HETE), 12(S)-HETE (see 12-HETE), 15(S)-HETE (see 15-hydroxyicosatetraenoic acid), and racemic 5-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.[6] 9-HODE induces cultured normal human epidermal keratinocytes to stop growing by inhibiting their cell cycle at the G1 stage; it also stimulates these cells to secrete three cytokines that stimulate keratinocyte growth vis., interleukin-6, interleukin-8, and GM-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 by UV light.[6]

See also[edit]


  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Damaghi M, Wojtkowiak JW, Gillies RJ (2013). "pH sensing and regulation in cancer". Front Physiol. 4: 370. doi:10.3389/fphys.2013.00370. PMC 3865727free to read. PMID 24381558. 
  4. ^ a b Le 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. PMID 12086852. 
  5. ^ "Entrez Gene: GPR132 G protein-coupled receptor 132". 
  6. ^ a b c d e f Obinata H, Izumi T (2009). "G2A as a receptor for oxidized free fatty acids". Prostaglandins Other Lipid Mediat. 89 (3-4): 66–72. doi:10.1016/j.prostaglandins.2008.11.002. PMID 19063986. 
  7. ^ a b c Okajima F (2013). "Regulation of inflammation by extracellular acidification and proton-sensing GPCRs". Cell. Signal. 25 (11): 2263–71. doi:10.1016/j.cellsig.2013.07.022. PMID 23917207. 
  8. ^ a b Le LQ, Kabarowski JH, Weng Z, Satterthwaite AB, Harvill ET, Jensen ER, Miller JF, Witte ON (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. PMID 11371358. 
  9. ^ a b Weng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, Hunter CA, Fernal AA, Le Beau MM, Witte ON (Oct 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. doi:10.1073/pnas.95.21.12334. PMC 22832free to read. PMID 9770487. 
  10. ^ Murakami N, Yokomizo T, Okuno T, Shimizu T (Oct 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. PMID 15280385. 
  11. ^ Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH (Oct 2007). "Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors". Molecular and Cellular Neurosciences. 36 (2): 195–210. doi:10.1016/j.mcn.2007.06.010. PMID 17720533. >
  12. ^ Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON (Feb 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. doi:10.1073/pnas.0409415102. PMC 545089free to read. PMID 15665078. 
  13. ^ Zhu K, Baudhuin LM, Hong G, Williams FS, Cristina KL, Kabarowski JH, Witte ON, Xu Y (Nov 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. PMID 11535583. 
  14. ^ "Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4". The Journal of Biological Chemistry. 280 (52): 43280. Dec 2005. PMID 16498716. 
  15. ^ a b c "Visualization of the pH-dependent dynamic distribution of G2A in living cells". FASEB J. 3965–74: 3965–74. Sep 2014. doi:10.1096/fj.14-252999. PMID 24891524. 
  16. ^ a b c Frasch 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. PMID 17475884. 
  17. ^ Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, Kim YH, Song DK (2004). "Therapeutic effects of lysophosphatidylcholine in experimental sepsis". Nat. Med. 10 (2): 161–7. doi:10.1038/nm989. PMID 14716308. 
  18. ^ a b Rolin J, Vego H, Maghazachi AA (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 (Basel). 6 (9): 2840–56. doi:10.3390/toxins6092840. PMC 4179163free to read. PMID 25251539. 
  19. ^ Frasch SC, Fernandez-Boyanapalli RF, Berry KZ, Leslie CC, Bonventre JV, Murphy RC, Henson PM, Bratton DL (Apr 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. PMID 21297111. 
  20. ^ Frasch SC, Fernandez-Boyanapalli RF, Berry KA, Murphy RC, Leslie CC, Nick JA, Henson PM, Bratton DL (Feb 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. PMID 23293064. 

Further reading[edit]

  • Bolick DT, Skaflen MD, Johnson LE, Kwon SC, Howatt D, Daugherty A, Ravichandran KS, Hedrick CC (Feb 2009). "G2A deficiency in mice promotes macrophage activation and atherosclerosis". Circulation Research. 104 (3): 318–27. doi:10.1161/CIRCRESAHA.108.181131. PMC 2716803free to read. PMID 19106413. 
  • Rikitake Y, Hirata K, Yamashita T, Iwai K, Kobayashi S, Itoh H, Ozaki M, Ejiri J, Shiomi M, Inoue N, Kawashima S, Yokoyama M (Dec 2002). "Expression of G2A, a receptor for lysophosphatidylcholine, by macrophages in murine, rabbit, and human atherosclerotic plaques". Arteriosclerosis, Thrombosis, and Vascular Biology. 22 (12): 2049–53. doi:10.1161/01.ATV.0000040598.18570.54. PMID 12482833. 
  • Lin P, Ye RD (Apr 2003). "The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis". The Journal of Biological Chemistry. 278 (16): 14379–86. doi:10.1074/jbc.M209101200. PMID 12586833. 
  • Lum H, Qiao J, Walter RJ, Huang F, Subbaiah PV, Kim KS, Holian O (Oct 2003). "Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells". American Journal of Physiology. Heart and Circulatory Physiology. 285 (4): H1786–9. doi:10.1152/ajpheart.00359.2003. PMID 12805023. 
  • Witte ON, Kabarowski JH, Xu Y, Le LQ, Zhu K (Jan 2005). "Retraction". Science. 307 (5707): 206. doi:10.1126/science.307.5707.206b. PMID 15653487. 
  • Obinata H, Hattori T, Nakane S, Tatei K, Izumi T (Dec 2005). "Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A". The Journal of Biological Chemistry. 280 (49): 40676–83. doi:10.1074/jbc.M507787200. PMID 16236715.