Disease relevance of GPR132

• This finding implicates a role for LPC-G2A interaction in the etiology of inflammatory autoimmune disease and atherosclerosis [1].
• Human immunodeficiency virus type 1 cell cycle control: Vpr is cytostatic and mediates G2 accumulation by a mechanism which differs from DNA damage checkpoint control [2].
• On the whole, our results indicate that hyperthermia can stabilize the G2 accumulation induced by melphalan in human melanoma cells [3].
• All strains from congenital megacolon infants existed in G2A only, and all from asymptomatic infants existed in G2B peculiarly [4].
• Mn-superoxide dismutase overexpression enhances G2 accumulation and radioresistance in human oral squamous carcinoma cells [5].

High impact information on GPR132

• Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils [6].
• Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A [1].
• We show that LPC is a high-affinity ligand for G2A, a lymphocyte-expressed G protein-coupled receptor whose genetic ablation results in the development of autoimmunity [1].
• Activation of G2A by LPC increased intracellular calcium concentration, induced receptor internalization, activated ERK mitogen-activated protein kinase, and modified migratory responses of Jurkat T lymphocytes [1].
• However, in contrast to adriamycin, a marked phase-dependent sensitivity for the induction of G2-accumulation was observed; cells treated in early and mid-S-phase were most sensitive [7].

Chemical compound and disease context of GPR132

• Our recent identification of the first lysophosphatidylcholine receptor as an immunoregulatory G protein-coupled receptor named G2A whose genetic ablation results in the development of inflammatory autoimmune disease has, therefore, provided a new perspective on the role of this lysophospholipid as a modulator of immune responses [8].

Biological context of GPR132

• G2A can be induced in lymphocytes and to a lesser extent in nonlymphocyte cell lines or tissues by multiple stimuli including different classes of DNA-damaging agents and serves as a response to damage and cellular stimulation which functions to slow cell cycle progression [9].
• Furthermore, G2A-induced apoptosis can be rescued by the caspase inhibitors, z-vad-fmk and CrmA [10].
• These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate [11].
• G2A has previously been shown to be a potent transforming oncogene for murine 3T3 cells [12].
• Using HSV-TK reporter gene directed positron emission tomography (PET), we demonstrate that prior to any indication of the onset of illness, mice transplanted with BCR-ABL transduced G2A-deficient bone marrow harbor expanded populations of leukemic cells compared to recipients of wild-type bone marrow [13].

Anatomical context of GPR132

• Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells [14].
• G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis [11].
• Although apoptosis occurs without LPC stimulation, LPC further enhances G2A-mediated apoptosis and correlates with its ability to induce cAMP elevation in both HeLa cells and primary lymphocytes [10].
• G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages [11].
• Similarly, G2 accumulation and PAF receptor are variably expressed in these subsets of NK cells [15].

Associations of GPR132 with chemical compounds

• However, we found the activity of the human G2A receptor and its mouse homolog to be significantly less sensitive to pH fluctuations as measured by inositol phosphate and cAMP accumulation [14].
• G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine [16].
• Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A(2) also evoked intracellular calcium mobilization in G2A-expressing cells [11].
• Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE [11].
• Rescue from G2A-induced apoptosis was achieved by co-expression of a G alpha(12/13)-specific inhibitor, p115RGS (regulator of G protein signaling), in combination with 2',5'-dideoxyadenosine treatment [10].

Other interactions of GPR132

• As OGR1 and GPR4 were reported as proton-sensing GPCRs (Ludwig, M. G., Vanek, M., Guerini, D., Gasser, J. A., Jones, C. E., Junker, U., Hofstetter, H., Wolf, R. M., and Seuwen, K. (2003) Nature 425, 93-98), we evaluated the proton-sensing function of G2A [16].
• The original publications describing GPR4, OGR1, and G2A as receptors for LPC or SPC have now been retracted, and the first studies exploring receptors of this family as pH sensors in physiology have appeared [17].
• Degradation of exogenous p21 led to a shift to G2 accumulation in the cells exposed to BL [18].
• In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment [19].
• After UVC irradiation, synchronized gelsolin-overexpressing UMUC2 cells had a prolonged S phase followed by delayed G2 accumulation compared to neotransfected UMUC2 cells as determined by cell cycle analysis [20].

Analytical, diagnostic and therapeutic context of GPR132

• The expression of G2A protein was detected in human and murine monocytes/macrophages by immunoblotting [21].
• RT-PCR analysis indicated that neither the G2A receptor nor the GPR4 receptor is expressed in the U937 monocytes [22].
• Quantitative analysis of orphan G protein-coupled receptor mRNAs by TaqMan Real-Time PCR: G2A and GPR4 lysophospholipid receptor expression in leukocytes and in a rat myocardial infarction-heart failure model [23].
• METHODS AND RESULTS: Immunohistochemistry with an anti-G2A antibody revealed that G2A was expressed predominantly by macrophages within atherosclerotic lesions at the aortic root of apolipoprotein E-deficient mice and the thoracic aortas of Watanabe heritable hyperlipidemic rabbits [21].
• The level of cyclin B was measured using an anti-cyclin B antibody and flow cytometry in order to investigate the cause of the G2 accumulation induced by hyperthermia [24].

References