P2X7 Reseptörü Aracılı Hücre Membran Geçirgenlik Artıșı

Pürinerjik reseptörler P2X ve P2Y olmak üzere iki ana aileden olușmaktadır. P2Y reseptörleri G-proteini kenetli reseptörler (GPKR), P2X reseptörleri seçici olmayan katyon kanallarıdır. P2X reseptörlerinin 7 üyesinden biri olan P2X7 reseptörü immün hücreler bașta olmak üzere birçok tip hücrede bulunmak-tadır. IL-1β salınımı, kaspaz aktivasyonu gibi hücre içinde birçok sinyal yolağını aktive etmekle beraber, diğer üyelerden farklı olarak membranda büyük bir geçirgenlik aktive etmektedir. Membran geçirgen-liğini incelemek için spektroskopik ve elektrofizyolojik yöntemler kullanılmaktadır. Büyük geçirgenli-ğin mekanizmasını açıklamak için çeșitli hipotezler öne sürülmektedir. Bunlardan biri P2X7 kanalının genișleyerek büyük moleküllere geçirgen hale geldiği, diğeri ise geçirgenliğin bașka bir protein aracı-lığıyla olduğudur. P2X7 reseptörü inflamasyon, ağrı, kanser ve Alzhzeimer gibi birçok hastalıkta rolü olduğu gösterilen bir reseptör olduğu için antagonistleri ve modülatörleri iyi birer ilaç hedefi olarak görülmektedir. Aktivasyon mekanizmasının aydınlatılması da birçok hastalığın tedavisi için önem tașı-maktadır.

P2X7 Receptor Mediated Increase In Cell Membrane Permeability

Purinergic receptors consist of two main families; P2X and P2Y. P2Y receptors are G protein coupled receptors (GPCR), whereas P2X receptors are non-selective cation channels. P2X7 receptors which is a member of P2X receptors, have been found myriad types of cells including immune cells. The activa-tion of this receptor leads to IL-1β release and caspase activation as well as an increase in membrane permeability to big molecules. Spectroscopic and electrophysiologic methods have been used to in-vestigate membrane permeability. Different hypotheses have been proposed as an explanation for big permeability. One of them proposes that P2X7 channel itself dilates and becomes permeable to big molecules, whereas the other proposes participation of another channels to big permeability. Since it has been demonstrated that P2X7 receptor has a role in many disease processes including inflamation, pain, cancer and Alzheimer’s disease, its antagonists and modulators have been regarded as a good drug target. The uncovering of its activation mechanism is important for treatment of many diseases.

PDF

___

30. Pelegrin P, Surprenant A. Pannexin-1 me-diates large pore formation and interleu-kin-1b release by the ATP-gated P2X7 re-ceptor. EMBO J. 2006; 25:5071–5082.
29. Dahl G, Keane RW. Pannexin: From dis-covery to bedside in 11±4 years? BrainRe-search. 2012; 1487:150-9
28. Faria RX, Defarias FP, Alves LA. Are se-cond messengers crucial for opening the pore associated with P2X7 receptor? Am J Physiol Cell Physiol. 2005; 288: C260-71.
27. Alves LA, Coutinho-Silva R, Persechini PM, et al. Are there functional gap juncti-ons or junctional hemichannels in mac-rophages? Blood. 1996; 88: 328-334.
26. Beyer EC, Steinberg TH. Evidence that the gap junction protein connexin-43 is the ATP-induced pore of mouse macrop-hages. J Biol Chem. 1991; 266:7971-7974.
25. Nielsen MS, Axelsen LN, Sorgen PL, et al. Holstein-Rathlou NH Gap junctions. Compr Physiol. 2012; Jul2(3):1981-2035.
24. Ferreira LGB, Reis RAM, Alves LA, et al. Intracellular Signaling Pathways Integrating the Pore Associated with P2X7R Receptor with Other Large Pores. Patch Clamp Technique. Intech; Chapter 2:37-54
23. Cankurtaran-Sayar S, Sayar K, Ugur M. P2X7 receptor activates multiple selective dye permeation pathways in RAW 264.7 and human embryonic kidney 293 cells. Mol Pharmacol. 2009; 76:1323-1332.
22. Schachter J, Motta AP, de Souza Za-morano A, et al. ATP-induced P2X7-asso-ciated uptake of large molecules involves distinct mechanisms for cations and anions in macrophages. J Cell Sci. 2008; 121: 3261-3270.
21. Thomas H. Steinberg, Alan S. Newman, Joel A. Swanson, Samuel C. Silverstein. ATP4- Permeabilizes the plasma memb-rane of mouse macrophages to fluorescent dyes. The Journal of Biological Chemistry. 1987; 262(18):8884-8888.
20. Virginio C, Mackenzie A, North RA, Surp-renant A. Kinetics of cell lysis, dye uptake and permeability changes in cells expres-sing the rat P2X7 receptor. J Physiol 1999; 519: 335–346.
19. Virginio C, Church D, North RA, Surpre-nant A. Effects of divalent cations, protons and calmidazolium at the rat P2X7 receptor. Neuropharmacology. 1997; 36(9):1285-94.
18. Yan Z, Lı S, Lıang Z, et al.The P2X7 re-ceptor channel pore dilates under physio-logical ion conditions. J Gen Physiol. 2008; 132(5):563-73.
17. Jıang, LH. Inhibition of P2X(7) receptors by divalent cations: old action and new in-sight. Eur Biophys J. 2009; 38(3):339-46
16. Saul A, Hausmann R, Kless A, et al. Hete-romeric assembly of P2X subunits. Front Cell Neurosci. 2013; 18:7:250
15. Donnelly-Roberts D L, Namovic MT, Surber B, et al. [3H]A-804598 ([3H]2-cyano-1-[(1S)-1 phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selec-tive antagonist radioligand for P2X7 re-ceptors. Neuropharmacology. 2009; 56(1):223-9.
14. Jarvis MF, Khakh BS. ATP-gated P2X ca-tion-channels. Neuropharmacology. 2009; 56(1):208-15
13. Coddou C, Yan Z, Obsil T, et al. Activa-tion and regulation of purinergic P2X re-ceptor channels. Pharmacol Rev. 2011; 63(3):641-83.
12. North RA, Surprenant A. pharmacology of cloned P2X receptors. Annu Rev Phar-macol Toxicol. 2000; 40:563-80. Review.
11. North RA. Molecular physiology of P2X re-ceptors. Physiol Rev. 2002; 82: 1013–1067.
10. Jacobson KA, Müller CE. Medicinal che-mistry of adenosine, P2Y and P2X receptors. Neuropharmacology. 2016; May 104:31-49.
9. Bartlett R, Stokes L, Sluyter R. The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol Rev. 2014; 66(3):638-75.
8. Surprenant A, Rassendren F, Kawashima E et al. The cytolytic P2Z receptor for extra-cellular ATP identified as a P2X receptor (P2X7). Science. 1996; 272: 735–738.
7. Burnstock G. Purinergic signalling: from discovery to current developments. Exp Physiol. 2014; 99(1):16-34
6. Surprenant A ve North RA. Signaling at purinergic P2X receptors. Annu Rev Phy-siol. 2009; 71:333-59
5. North RA ve Barnard EA. Nucleotide re-ceptors. Curr Opin Neurobiol. 1997; Jun 110(3):415-32
4. Ivar von Kügelgen. Pharmacological pro-files of cloned mammalian P2Y-receptor subtypes. Biotrend Reviews. 2008; 9:1-12
3. Burnstock G. Introduction and perspec-tive, historical note. Front Cell Neurosci. 2013;7:1-13
2. Schwiebert EM, Zsembery A, Geibely JP. Cellular Mechanisms and Physiology of Nucleotide and Nucleoside Release from Cells: Current Knowledge, Novel Assays to Detect Purinergic Agonists, and Future Directions. Current Topics in Membranes. 2003; Volume 54:31-58
1. Burnstock G, Campbell G, Satchell D, et al. Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhi-bitory nerves in the gut. Br J Pharmacol. 1970; 40:668–688.