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P2Y12 receptor expression is a critical determinant of functional responsiveness to ATX’s MORFO domain

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Abstract

In the central nervous system, the formation of the myelin sheath and the differentiation of the myelinating cells, namely oligodendrocytes, are regulated by complex signaling networks that involve purinergic receptors and the extracellular matrix. However, the exact nature of the molecular interactions underlying these networks still needs to be defined. In this respect, the data presented here reveal a signaling mechanism that is characterized by an interaction between the purinergic P2Y12 receptor and the matricellular extracellular matrix protein autotaxin (ATX), also known as ENPP2, phosphodiesterase-Iα/ATX, or lysoPLD. ATX has been previously described by us to mediate intermediate states of oligodendrocyte adhesion and to enable changes in oligodendrocyte morphology that are thought to be crucial for the formation of a fully functional myelin sheath. This functional property of ATX is mediated by ATX’s modulator of oligodendrocyte remodeling and focal adhesion organization (MORFO) domain. Here, we show that the expression of the P2Y12 receptor is necessary for ATX’s MORFO domain to exert its effects on differentiating oligodendrocytes. In addition, our data demonstrate that exogenous expression of the P2Y12 receptor can render cells responsive to the known effects of ATX’s MORFO domain, and they identify Rac1 as an intracellular factor mediating the effect of ATX-MORFO-P2Y12 signaling on the assembly of focal adhesions. Our data further support the idea that a physical interaction between ATX and the P2Y12 receptor provides the basis for an ATX-MORFO-P2Y12 signaling axis that is crucial for mediating cellular states of intermediate adhesion and morphological/structural plasticity.

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References

  1. Burnstock G, Krugel U, Abbracchio MP, Illes P (2011) Purinergic signalling: from normal behaviour to pathological brain function. Prog 95(2):229–274

    CAS  Google Scholar 

  2. Frenguelli BG (2011) Purinergic signalling between neurones and glia: for those about to rock. Semin 22(2):193

    Google Scholar 

  3. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009) Purinergic signalling in the nervous system: an overview. Trends Neurosci 32(1):19–29

    Article  PubMed  CAS  Google Scholar 

  4. Fields RD (2006) Nerve impulses regulate myelination through purinergic signalling. Novartis Found Symp 276:148–158

    Article  PubMed  CAS  Google Scholar 

  5. Fields RD, Burnstock G (2006) Purinergic signalling in neuron–glia interactions. Nat Rev Neurosci 7(6):423–436

    Article  PubMed  CAS  Google Scholar 

  6. Pfeiffer SE, Warrington AE, Bansal R (1993) The oligodendrocyte and its many cellular processes. Trends Cell Biol 3:191–197

    Article  PubMed  CAS  Google Scholar 

  7. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81(2):871–927

    PubMed  CAS  Google Scholar 

  8. Fulton D, Paez PM, Campagnoni AT (2010) The multiple roles of myelin protein genes during the development of the oligodendrocyte. ASN Neuro 2(1):e00027

    Article  PubMed  Google Scholar 

  9. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28(1):264–278

    Article  PubMed  CAS  Google Scholar 

  10. Dugas JC, Tai YC, Speed TP, Ngai J, Barres BA (2006) Functional genomic analysis of oligodendrocyte differentiation. J Neurosci 26(43):10967–10983

    Article  PubMed  CAS  Google Scholar 

  11. Verkhratsky A, Krishtal OA, Burnstock G (2009) Purinoceptors on neuroglia. Mol Neurobiol 39(3):190–208

    Article  PubMed  CAS  Google Scholar 

  12. Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304

    Article  PubMed  CAS  Google Scholar 

  13. He M, McCarthy KD (1994) Oligodendroglial signal transduction systems are developmentally regulated. J Neurochem 63(2):501–508

    Article  PubMed  CAS  Google Scholar 

  14. Butt AM (2011) ATP: a ubiquitous gliotransmitter integrating neuron-glial networks. Semin 22(2):205–213

    CAS  Google Scholar 

  15. Othman T, Yan H, Rivkees SA (2003) Oligodendrocytes express functional A1 adenosine receptors that stimulate cellular migration. Glia 44(2):166–172

    Article  PubMed  Google Scholar 

  16. Stevens B, Porta S, Haak LL, Gallo V, Fields RD (2002) Adenosine: a neuron–glial transmitter promoting myelination in the CNS in response to action potentials. Neuron 36(5):855–868

    Article  PubMed  CAS  Google Scholar 

  17. Matute C, Cavaliere F (2011) Neuroglial interactions mediated by purinergic signalling in the pathophysiology of CNS disorders. Semin 22(2):252–259

    CAS  Google Scholar 

  18. Matute C (2008) P2X7 receptors in oligodendrocytes: a novel target for neuroprotection. Mol Neurobiol 38(2):123–128

    Article  PubMed  CAS  Google Scholar 

  19. Amadio S, Tramini G, Martorana A, Viscomi MT, Sancesario G, Bernardi G, Volonté C (2006) Oligodendrocytes express P2Y12 metabotropic receptor in adult rat brain. Neuroscience 141(3):1171–1180

    Article  PubMed  CAS  Google Scholar 

  20. James G, Butt AM (2001) P2X and P2Y purinoreceptors mediate ATP-evoked calcium signalling in optic nerve glia in situ. Cell Calcium 30(4):251–259

    Article  PubMed  CAS  Google Scholar 

  21. Moran-Jimenez MJ, Matute C (2000) Immunohistochemical localization of the P2Y(1) purinergic receptor in neurons and glial cells of the central nervous system. Brain Res Mol Brain Res 78(1–2):50–58

    Article  PubMed  CAS  Google Scholar 

  22. Agresti C, Meomartini ME, Amadio S, Ambrosini E, Serafini B, Franchini L, Volonté C, Aloisi F, Visentin S (2005) Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development. Glia 50(2):132–144

    Article  PubMed  CAS  Google Scholar 

  23. Agresti C, Meomartini ME, Amadio S, Ambrosini E, Volonté C, Aloisi F, Visentin S (2005) ATP regulates oligodendrocyte progenitor migration, proliferation, and differentiation: involvement of metabotropic P2 receptors. Brain Res Rev 48(2):157–165

    Article  PubMed  CAS  Google Scholar 

  24. Lafrenaye AD, Fuss B (2010) Focal adhesion kinase can play unique and opposing roles in regulating the morphology of differentiating oligodendrocytes. J Neurochem 115(1):269–282

    Article  PubMed  CAS  Google Scholar 

  25. Gil JE, Woo DH, Shim JH, Kim SE, You HJ, Park SH, Paek SH, Kim SK, Kim JH (2009) Vitronectin promotes oligodendrocyte differentiation during neurogenesis of human embryonic stem cells. FEBS Lett 583(3):561–567

    Article  PubMed  CAS  Google Scholar 

  26. Siskova Z, Yong VW, Nomden A, van Strien M, Hoekstra D, Baron W (2009) Fibronectin attenuates process outgrowth in oligodendrocytes by mislocalizing MMP-9 activity. Mol Cell Neurosci 42(3):234–242

    Article  PubMed  CAS  Google Scholar 

  27. Siskova Z, Baron W, de Vries H, Hoekstra D (2006) Fibronectin impedes “myelin” sheet-directed flow in oligodendrocytes: a role for a beta 1 integrin-mediated PKC signaling pathway in vesicular trafficking. Mol Cell Neurosci 33(2):150–159

    Article  PubMed  CAS  Google Scholar 

  28. Colognato H, ffrench-Constant C, Feltri ML (2005) Human diseases reveal novel roles for neural laminins. Trends Neurosci 28(9):480–486

    Article  PubMed  CAS  Google Scholar 

  29. Buttery PC, ffrench-Constant C (1999) Laminin-2/integrin interactions enhance myelin membrane formation by oligodendrocytes. Mol Cell Neurosci 14(3):199–212

    Article  PubMed  CAS  Google Scholar 

  30. Bornstein P (2009) Matricellular proteins: an overview. J Cell Commun Signal 3(3–4):163–165

    Article  PubMed  Google Scholar 

  31. Murphy-Ullrich JE (2001) The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? J Clin Invest 107(7):785–790

    Article  PubMed  CAS  Google Scholar 

  32. Orend G, Chiquet-Ehrismann R (2000) Adhesion modulation by antiadhesive molecules of the extracellular matrix. Exp Cell Res 261(1):104–110

    Article  PubMed  CAS  Google Scholar 

  33. Sage EH, Bornstein P (1991) Extracellular proteins that modulate cell-matrix interactions. SPARC, tenascin, and thrombospondin. J Biol Chem 266(23):14831–14834

    PubMed  CAS  Google Scholar 

  34. Dennis J, White MA, Forrest AD, Yuelling LM, Nogaroli L, Afshari FS, Fox MA, Fuss B (2008) Phosphodiesterase-I alpha/autotaxin’s MORFO domain regulates oligodendroglial process network formation and focal adhesion organization. Mol Cell Neurosci 37(2):412–424

    Article  PubMed  CAS  Google Scholar 

  35. Fox MA, Alexander JK, Afshari FS, Colello RJ, Fuss B (2004) Phosphodiesterase-I alpha/autotaxin controls cytoskeletal organization and FAK phosphorylation during myelination. Mol Cell Neurosci 27(2):140–150

    Article  PubMed  CAS  Google Scholar 

  36. Fox MA, Colello RJ, Macklin WB, Fuss B (2003) Phosphodiesterase-I alpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci 23(3):507–519

    Article  PubMed  CAS  Google Scholar 

  37. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409(6817):202–207

    Article  PubMed  CAS  Google Scholar 

  38. Simon J, Filippov AK, Goransson S, Wong YH, Frelin C, Michel AD, Brown DA, Barnard EA (2002) Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells. J Biol Chem 277(35):31390–31400

    Article  PubMed  CAS  Google Scholar 

  39. Soulet C, Sauzeau V, Plantavid M, Herbert JM, Pacaud P, Payrastre B, Savi P (2004) Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor. J Thromb Haemost 2(1):135–146

    Article  PubMed  CAS  Google Scholar 

  40. Ohsawa K, Kohsaka S (2011) Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain. Glia Sep 7 (in press)

  41. Ohsawa K, Irino Y, Nakamura Y, Akazawa C, Inoue K, Kohsaka S (2007) Involvement of P2X4 and P2Y12 receptors in ATP-induced microglial chemotaxis. Glia 55(6):604–616

    Article  PubMed  Google Scholar 

  42. Laitinen JT, Uri A, Raidaru G, Miettinen R (2001) [(35)S]GTP gamma S autoradiography reveals a wide distribution of G(i/o)-linked ADP receptors in the nervous system: close similarities with the platelet P2Y(ADP) receptor. J Neurochem 77(2):505–518

    Article  PubMed  CAS  Google Scholar 

  43. von Kugelgen I (2006) Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 110(3):415–432

    Article  Google Scholar 

  44. Takasaki J, Kamohara M, Saito T, Matsumoto M, Matsumoto S, Ohishi T, Soga T, Matsushime H, Furuichi K (2001) Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor. Mol Pharmacol 60(3):432–439

    PubMed  CAS  Google Scholar 

  45. Zhang FL, Luo L, Gustafson E, Lachowicz J, Smith M, Qiao X, Liu YH, Chen G, Pramanik B, Laz TM, Palmer K, Bayne M, Monsma FJ Jr (2001) ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem 276(11):8608–8615

    Article  PubMed  CAS  Google Scholar 

  46. Lahiri P, Chaudhuri U, Chattopadhyay A, Chakraborty P, Mandal D, Dasgupta AK (2005) Structural insights in platelet receptor synergism-antiplatelet therapy in post-ischemic cerebrovascular events. Blood Cells Mol Dis 34(3):248–256

    Article  PubMed  CAS  Google Scholar 

  47. Nonaka Y, Hiramoto T, Fujita N (2005) Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods. Biochem Biophys Res Commun 337(1):281–288

    Article  PubMed  CAS  Google Scholar 

  48. Barres BA, Hart IK, Coles HSR, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70(1):31–46

    Article  PubMed  CAS  Google Scholar 

  49. Sommer I, Schachner M (1981) Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol 83(2):311–327

    Article  PubMed  CAS  Google Scholar 

  50. Schnitzer J, Schachner M (1982) Cell type specificity of a neural cell surface antigen recognized by the monoclonal antibody A2B5. Cell Tissue Res 224(3):625–636

    Article  PubMed  CAS  Google Scholar 

  51. Abney ER, Williams BP, Raff MC (1983) Tracing the development of oligodendrocytes from precursor cells using monoclonal antibodies, fluorescence-activated cell sorting, and cell culture. Dev Biol 100(1):166–171

    Article  PubMed  CAS  Google Scholar 

  52. Pausch MH, Lai M, Tseng E, Paulsen J, Bates B, Kwak S (2004) Functional expression of human and mouse P2Y12 receptors in Saccharomyces cerevisiae. Biochem Biophys Res Commun 324(1):171–177

    Article  PubMed  CAS  Google Scholar 

  53. Abramoff MD, Magelhaes PJ, Ram SJ (2004) Image processing with ImageJ. Biophotonics Int 11(7):36–42

    Google Scholar 

  54. Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y (2003) Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol Cell Biol 23(5):1534–1545

    Article  PubMed  CAS  Google Scholar 

  55. Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158(2):227–233

    Article  PubMed  CAS  Google Scholar 

  56. Marcet B, Vr C, Delmas P, Verrier B (2004) Pharmacological and signaling properties of endogenous P2Y1 receptors in cystic fibrosis transmembrane conductance regulator-expressing Chinese hamster ovary cells. J Pharmacol Exp Ther 309(2):533–539

    Article  PubMed  CAS  Google Scholar 

  57. Laukaitis CM, Webb DJ, Donais K, Horwitz AF (2001) Differential dynamics of alpha 5 integrin, paxillin, and alpha-actinin during formation and disassembly of adhesions in migrating cells. J Cell Biol 153(7):1427–1440

    Article  PubMed  CAS  Google Scholar 

  58. Unterberger U, Moskvina E, Scholze T, Freissmuth M, Boehm S (2002) Inhibition of adenylyl cyclase by neuronal P2Y receptors. Br J Pharmacol 135(3):673–684

    Article  PubMed  CAS  Google Scholar 

  59. Berrier AL, Yamada KM (2007) Cell-matrix adhesion. J Cell Physiol 213(3):565–573

    Article  PubMed  CAS  Google Scholar 

  60. Geiger B, Spatz JP, Bershadsky AD (2009) Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10(1):21–33

    Article  PubMed  CAS  Google Scholar 

  61. Erb L, Liao Z, Seye CI, Weisman GA (2006) P2 receptors: intracellular signaling. Pflugers Arch 452(5):552–562

    Article  PubMed  CAS  Google Scholar 

  62. Fulkerson Z, Wu T, Sunakura M, Vander Kooi C, Morris AJ, Smyth SS (2011) Binding of autotaxin to integrins localizes lysophosphatidic acid production to platelets and mammalian cells. J Biol Chem Aug 10 (in press)

  63. Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A (2011) Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol 18(2):198–204

    Article  PubMed  CAS  Google Scholar 

  64. Franke H, Krugel U, Illes P (1999) P2 receptor-mediated proliferative effects on astrocytes in vivo. Glia 28(3):190–200

    Article  PubMed  CAS  Google Scholar 

  65. Baer AS, Syed YA, Kang SU, Mitteregger D, Vig R, Ffrench-Constant C, Franklin RJ, Altmann F, Lubec G, Kotter MR (2009) Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain 132(Pt 2):465–481

    PubMed  Google Scholar 

  66. Paintlia AS, Paintlia MK, Singh AK, Singh I (2008) Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis. Mol Pharmacol 73(5):1381–1393

    Article  PubMed  CAS  Google Scholar 

  67. Amadio S, Montilli C, Magliozzi R, Bernardi G, Reynolds R, Volonte C (2010) P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. Cereb Cortex 20(6):1263–1273

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant from the NIH-NINDS (BF) and a postdoctoral fellowship award from the National Multiple Sclerosis Society (JD). We thank Steve Pfeiffer for providing the O4 hybridoma cells and Christopher Waggener for graphical assistance. Microscopy was performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, supported, in part, with funding from the NIH-NINDS Center Core Grant 5 P30 NS047463. Flow cytometry was performed at the VCU Flow Cytometry and Imaging Shared Resource Facility, supported, in part, with funding from the NIH-NCI Cancer Center Support Grant 5 P30 CA016059.

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Authors and Affiliations

  1. Departments of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA, 23298, USA

    Jameel Dennis, Magdalena K. Morgan & Babette Fuss

  2. Neurosurgery, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA, 23298, USA

    Martin R. Graf

  3. Gencia Corporation, 706 Forest Street Suite B, Charlottesville, VA, 22903, USA

    Jameel Dennis

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  1. Jameel Dennis
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  2. Magdalena K. Morgan
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Correspondence to Jameel Dennis or Babette Fuss.

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Supplementary Fig. S1

P2Y12 receptor protein levels are significantly reduced in differentiating oligodendrocytes upon siRNA-mediated gene silencing. Bar graph representing P2Y12 receptor protein levels in cells treated with an siRNA specific for P2Y12 (siP2Y12) or control siRNA (siControl). For Western blot analysis, 50 μg of protein for each sample were separated by SDS-PAGE on 10% polyacrylamide gels. Proteins were transferred to PVDF membranes and probed first with anti-P2Y12 receptor antibodies (Alomone Labs, Jerusalem, Israel) at a dilution of 1:2,000 in PBS containing 0.05% Tween 20 and 0.1% casein overnight at 4°C and then with anti-GAPDH antibodies (Millipore, Billerica, MA) at a dilution of 1:5,000 in PBS containing 0.05% Tween 20 and 5% nonfat dry milk for 1 h at room temperature. P2Y12 receptor and GAPDH protein levels were quantified using enhanced chemiluminescence (ECL) detection in combination with VersaDoc imaging and the QuantityOne software package (BioRad Laboratories, Hercules, CA). A representative Western blot is shown in the inset, and consistent with previous data [19], the P2Y12 receptor was recognized as a protein band of approximately 42–44 kDa. Numbers to the left indicate molecular weight markers in kilodalton. GAPDH protein levels were used for normalization. For the bar graph, three independent experiments were analyzed. P2Y12 receptor protein levels in cells treated with control siRNA (siControl) were set to 100%. Experimental values were calculated accordingly. Statistical significance was determined using the one-sample t test [69, 70]. The star indicates an overall significance level of p < 0.05 (GIF 17 kb)

High resolution (TIFF 2954 kb)

Supplementary Fig. S2

CHO-P2Y12 cells are characterized by functional P2Y12 receptor expression. A cell line stably expressing the P2Y12 receptor (CHO-P2Y12 cells) was assessed for P2Y12 receptor functionality. As control, a cell line expressing β-galactosidase was used (CHO-LacZ). a Representative images of phalloidin-labeled untreated and 2-MeS-ADP-treated CHO-P2Y12 and CHO-LacZ cells. To assess actin stress fiber formation, cells were plated onto glass coverslips pre-coated with fibronectin (10 μg/ml) and cultured in serum-free medium for 24 h. Cells were then treated for 1 h with 10 nM 2-Me-S-ADP or vehicle, fixed, permeabilized, and stained with Alexa 594-conjugated phalloidin. Cells were analyzed using a Leica TCS-SP2 AOBS laser scanning microscope (Leica Microsystems Inc., Bannockburn, IL). Images represent 2D maximum projections of stacks of 0.5 μm optical sections. Scale bars, 20 μm. b Bar graph depicting cAMP levels in untreated CHO-P2Y12 and CHO-LacZ cells and in cells treated with forskolin alone or in combination with 2-MeS-ADP. cAMP levels were measured using the cAMP assay kit from Cisbio Bioassays (Bedford, MA). Homogenous time resolved fluorescence (HTRF) was recorded using a PHERAstar microplate reader (BMG LABTECH GmbH, Offenburg, Germany). The mean value for the cAMP levels measured in CHO-LacZ cells upon forskolin treatment was set to 100% and experimental values were calculated accordingly. Three independent experiments were performed in duplicates. Mean values and SEMs are shown. Stars indicate an overall two-tailed significance level of p < 0.05 as determined by Student’s t test analysis (GIF 33 kb)

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Dennis, J., Morgan, M.K., Graf, M.R. et al. P2Y12 receptor expression is a critical determinant of functional responsiveness to ATX’s MORFO domain. Purinergic Signalling 8, 181–190 (2012). https://doi.org/10.1007/s11302-011-9283-2

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