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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 380 | 14q32.33 | GPR132 | G protein-coupled receptor 132 | 27 |
| Mouse | 7 | 382 | 12 F1 | Gpr132 | G protein-coupled receptor 132 | |
| Rat | 7 | 376 | 6q32 | Gpr132 | G protein-coupled receptor 132 | |
| Previous and Unofficial Names |
| G protein-coupled receptor G2A | G2 accumulation protein |
| Database Links |
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| Specialist databases | |
| GPCRdb | gp132_human (Hs), gp132_mouse (Mm) |
| Other databases | |
| Alphafold | Q9UNW8 (Hs), Q9Z282 (Mm), D3ZIH1 (Rn) |
| ChEMBL Target | CHEMBL3085618 (Hs) |
| Ensembl Gene | ENSG00000183484 (Hs), ENSMUSG00000021298 (Mm), ENSRNOG00000013914 (Rn) |
| Entrez Gene | 29933 (Hs), 56696 (Mm), 314480 (Rn) |
| Human Protein Atlas | ENSG00000183484 (Hs) |
| KEGG Gene | hsa:29933 (Hs), mmu:56696 (Mm), rno:314480 (Rn) |
| OMIM | 606167 (Hs) |
| Pharos | Q9UNW8 (Hs) |
| RefSeq Nucleotide | NM_013345 (Hs), NM_019925 (Mm), NM_001170595 (Rn) |
| RefSeq Protein | NP_037477 (Hs), NP_064309 (Mm), NP_001164066 (Rn) |
| UniProtKB | Q9UNW8 (Hs), Q9Z282 (Mm), D3ZIH1 (Rn) |
| Wikipedia | GPR132 (Hs) |
| Natural/Endogenous Ligands |
| 9-hydroxyoctadecadienoic acid |
| (lyso)phospholipid mediators, protons |
| Endogenous ligand |
| Protons |
Download all structure-activity data for this target as a CSV file 
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GPR132 has been reported to be activated by lysophosphatidylserine [30], by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate [4] A report that the receptor was activated by lysophosphatidylcholine [8] was later retracted [28]. GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [3,13,25]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Lysophosphatidylcholine inhibited the pH-dependent activation of GPR132 in a dose dependent manner [13]. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Other - See Comments | |
| Comments: GPR132 has been proposed to signal through Gα13 and Gαs [5,11]. Both pertussis toxin-sensitive and -insensitive G-proteins have been implicated in phospholipase C activation through GPR132 [13]. | |
| References: 11,30 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| Colocalisation of GPR132 with macrophages identified in atherosclerotic plaques in humans and mice [24]. GPR132 is not expressed in human brain microvascular or dermal microvascular endothelial cells (RT-PCR) [12]. |
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| Expression Datasets |
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| Functional Assay Comments |
| The reported action of LPC in stimulating macrophage and T-cell chemotaxis (via GPR132) [23], was replicated in vivo in one study [29] but not in others [17-18]. |
| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Studies of GPR132 knockout mice have produced conflicting results regarding the role of the receptor in attenuation of experimental autoimmune encephalomyelitis. One study suggested that GPR132 negatively regulates T-cell recruitment [9], whilst a more recent study concluded that the proposed anti-proliferative and chemotactic functions of the receptor are not manifested in vivo and therefore therapeutic targeting of G2A is unlikely to be beneficial in the treatment of multiple sclerosis [17]. Studies of GPR132 knockout mice have also produced conflicting results regarding the role of the receptor in protection from [1-2] or promotion of [19] atherosclerosis. One study investigating GPR132 knockout in LDLR-/- and ApoE-/- mice, suggested an ApoE-dependent function for GPR132 in the control of hepatic HDL metabolism that might contribute to proatherogenic action [20]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Gene Expression and Pathophysiology Comments | |
| GPR132 is believed to be a tumour suppressor gene which is upregulated in response to DNA damage. Loss upregulates oncogene expression (c-myc and BCR-ABL) associated with chronic myelogeneous leukemia [27]. GPR132 is implicated in the pathogenesis of cholesterol gallstone formation [7]. |
| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||
| An alternative splice variant of GPR132 (G2A-b) has a different N terminus to the isoform originally reported (G2A-a). The two splice variants show similar tissue distributions, but G2A-b is expressed more abundantly and produces higher basal rates of IP accumulation [16]. |
| General Comments |
| Receptor is believed to be a proton sensor: transient expression of GPR132 causes significant activation of the zif 268 promoter and inositol phosphate (IP) accumulation at pH 7.6, and lowering extracellular pH augments the activation only in GPR132-expressing cells [13,15]. However, the histidine residues that were previously shown to be important for pH sensing by OGR1, GPR4, and TDAG8 were not conserved in GPR132 (G2A). In thymocytes and splenocytes explanted from receptor-deficient mice, TDAG8 was found to be critical for pH-dependent cAMP production, but GPR132 was found to be dispensable for this process [22]. |
1. Bolick DT, Skaflen MD, Johnson LE, Kwon SC, Howatt D, Daugherty A, Ravichandran KS, Hedrick CC. (2009) G2A deficiency in mice promotes macrophage activation and atherosclerosis. Circ Res, 104 (3): 318-27. [PMID:19106413]
2. Bolick DT, Whetzel AM, Skaflen M, Deem TL, Lee J, Hedrick CC. (2007) Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta. Circ Res, 100 (4): 572-80. [PMID:17255525]
3. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]
4. Frasch SC, Berry KZ, Fernandez-Boyanapalli R, Jin HS, Leslie C, Henson PM, Murphy RC, Bratton DL. (2008) NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A. J Biol Chem, 283 (48): 33736-49. [PMID:18824544]
5. Frasch SC, Zemski-Berry K, Murphy RC, Borregaard N, Henson PM, Bratton DL. (2007) Lysophospholipids of different classes mobilize neutrophil secretory vesicles and induce redundant signaling through G2A. J Immunol, 178 (10): 6540-8. [PMID:17475884]
6. Hattori T, Obinata H, Ogawa A, Kishi M, Tatei K, Ishikawa O, Izumi T. (2008) G2A plays proinflammatory roles in human keratinocytes under oxidative stress as a receptor for 9-hydroxyoctadecadienoic acid. J Invest Dermatol, 128 (5): 1123-33. [PMID:18034171]
7. Johnson LE, Elias MS, Bolick DT, Skaflen MD, Green RM, Hedrick CC. (2008) The G protein-coupled receptor G2A: involvement in hepatic lipid metabolism and gallstone formation in mice. Hepatology, 48 (4): 1138-48. [PMID:18821587]
8. Kabarowski JH, Zhu K, Le LQ, Witte ON, Xu Y. (2001) Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science, 293 (5530): 702-5. [PMID:11474113]
9. 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. [PMID:11371358]
10. Le LQ, Kabarowski JH, Wong S, Nguyen K, Gambhir SS, Witte ON. (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. [PMID:12086852]
11. Lin P, Ye RD. (2003) The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis. J Biol Chem, 278 (16): 14379-86. [PMID:12586833]
12. Lum H, Qiao J, Walter RJ, Huang F, Subbaiah PV, Kim KS, Holian O. (2003) Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells. Am J Physiol Heart Circ Physiol, 285 (4): H1786-9. [PMID:12805023]
13. Murakami N, Yokomizo T, Okuno T, Shimizu T. (2004) G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem, 279 (41): 42484-91. [PMID:15280385]
14. Nii T, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, Heese L, Nishida Y, Kojima K, Garnett MJ et al.. (2019) Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia, 33 (12): 2805-2816. [PMID:31127149]
15. Obinata H, Hattori T, Nakane S, Tatei K, Izumi T. (2005) Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. J Biol Chem, 280 (49): 40676-83. [PMID:16236715]
16. Ogawa A, Obinata H, Hattori T, Kishi M, Tatei K, Ishikawa O, Izumi T. (2010) Identification and analysis of two splice variants of human G2A generated by alternative splicing. J Pharmacol Exp Ther, 332 (2): 469-78. [PMID:19855098]
17. Osmers I, Smith SS, Parks BW, Yu S, Srivastava R, Wohler JE, Barnum SR, Kabarowski JH. (2009) Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis. J Neuroimmunol, 207 (1-2): 18-23. [PMID:19135725]
18. Parks BW, Gambill GP, Lusis AJ, Kabarowski JH. (2005) Loss of G2A promotes macrophage accumulation in atherosclerotic lesions of low density lipoprotein receptor-deficient mice. J Lipid Res, 46 (7): 1405-15. [PMID:15834123]
19. Parks BW, Lusis AJ, Kabarowski JH. (2006) Loss of the lysophosphatidylcholine effector, G2A, ameliorates aortic atherosclerosis in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol, 26 (12): 2703-9. [PMID:16990555]
20. Parks BW, Srivastava R, Yu S, Kabarowski JH. (2009) ApoE-dependent modulation of HDL and atherosclerosis by G2A in LDL receptor-deficient mice independent of bone marrow-derived cells. Arterioscler Thromb Vasc Biol, 29 (4): 539-47. [PMID:19164809]
21. Peter C, Waibel M, Radu CG, Yang LV, Witte ON, Schulze-Osthoff K, Wesselborg S, Lauber K. (2008) Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A. J Biol Chem, 283 (9): 5296-305. [PMID:18089568]
22. Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON. (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci USA, 102 (5): 1632-7. [PMID:15665078]
23. Radu CG, Yang LV, Riedinger M, Au M, Witte ON. (2004) T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proc Natl Acad Sci USA, 101 (1): 245-50. [PMID:14681556]
24. Rikitake Y, Hirata K, Yamashita T, Iwai K, Kobayashi S, Itoh H, Ozaki M, Ejiri J, Shiomi M, Inoue N et al.. (2002) Expression of G2A, a receptor for lysophosphatidylcholine, by macrophages in murine, rabbit, and human atherosclerotic plaques. Arterioscler Thromb Vasc Biol, 22 (12): 2049-53. [PMID:12482833]
25. Seuwen K, Ludwig MG, Wolf RM. (2006) Receptors for protons or lipid messengers or both?. J Recept Signal Transduct Res, 26 (5-6): 599-610. [PMID:17118800]
26. Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW et al.. (2023) Functional screening and rational design of compounds targeting GPR132 to treat diabetes. Nat Metab, 5 (10): 1726-1746. [PMID:37770763]
27. Weng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, Hunter CA, Fernal AA, Le Beau MM, Witte ON. (1998) A DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc Natl Acad Sci USA, 95 (21): 12334-9. [PMID:9770487]
28. Witte ON, Kabarowski JH, Xu Y, Le LQ, Zhu K. (2005) Retraction. Science, 307 (5707): 206. [PMID:15653487]
29. Yang LV, Radu CG, Wang L, Riedinger M, Witte ON. (2005) Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood, 105 (3): 1127-34. [PMID:15383458]
30. Zohn IE, Klinger M, Karp X, Kirk H, Symons M, Chrzanowska-Wodnicka M, Der CJ, Kay RJ. (2000) G2A is an oncogenic G protein-coupled receptor. Oncogene, 19 (34): 3866-77. [PMID:10951580]
