Purinergic signaling in gut inflammation: The role of connexins and pannexins

Frontiers in Neuroscience

Volumn 10, Issue JUN, 2016, Pages

  Diezmos, Erica F ^a   Bertrand, Paul P ^a,b   Liu, Lu ^a  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

^b RMIT UNIVERSITY   (Australia)

Author keywords

Connexins; Gastrointestinal inflammation; Inflammatory bowel disease; Pannexins; Purinergic receptors

Indexed keywords

ADENOSINE TRIPHOSPHATE; CONNEXIN 32; CONNEXIN 36; CONNEXIN 37; CONNEXIN 43; CONNEXIN 45; ECTONUCLEOTIDASE; GAP JUNCTION PROTEIN; MEMBRANE PROTEIN; NUCLEOTIDASE; PANNEXIN; PURINERGIC P2X RECEPTOR; PURINERGIC P2X7 RECEPTOR; PURINERGIC RECEPTOR; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; DISEASE COURSE; HUMAN; INFLAMMATORY BOWEL DISEASE; INNATE IMMUNITY; INTESTINE INNERVATION; KNOCKOUT MOUSE; NONHUMAN; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN LOCALIZATION; REVIEW;

EID: 84980340058     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2016.00311     Document Type: Review

References (145)

1. Adinolfi, E., Raffaghello, L., Giuliani, A. L., Cavazzini, L., Capece, M., Chiozzi, P., et al. (2012). Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res. 72, 2957-2969. doi: 10.1158/0008-5472.CAN-11-1947
2. Alberto, A. V., Faria, R. X., Couto, C. G., Ferreira, L. G., Souza, C. A., Teixeira, P. C., et al. (2013). Is pannexin the pore associated with the P2X7 receptor? Naunyn Schmiedebergs Arch. Pharmacol. 386, 775-787. doi: 10.1007/s00210-013-0868-x
3. Antonioli, L., Giron, M. C., Colucci, R., Pellegrini, C., Sacco, D., Caputi, V., et al. (2014). Involvement of the P2X7 purinergic receptor in colonic motor dysfunction associated with bowel inflammation in rats. PLoS ONE 9:e116253. doi: 10.1371/journal.pone.0116253
4. Antonioli, L., Pacher, P., Vizi, E. S., and Hasko, G. (2013). CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19, 355-367. doi: 10.1016/j.molmed.2013.03.005
5. Avendaño, B. C., Montero, T. D., Chávez, C. E., von Bernhardi, R., and Orellana, J. A. (2015). Prenatal exposure to inflammatory conditions increases Cx43 and Panx1 unopposed channel opening and activation of astrocytes in the offspring effect on neuronal survival. Glia 63, 2058-2072. doi: 10.1002/glia.22877
6. Bao, L., Locovei, S., and Dahl, G. (2004). Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett. 572, 65-68. doi: 10.1016/j.febslet.2004.07.009
7. Bao, Y., Chen, Y., Ledderose, C., Li, L., and Junger, W. G. (2013). Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils. J. Biol. Chem. 288, 22650-22657. doi: 10.1074/jbc.M113.476283
8. Baranova, A., Ivanov, D., Petrash, N., Pestova, A., Skoblov, M., Kelmanson, I., et al. (2004). The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics 83, 706-716. doi: 10.1016/j.ygeno.2003.09.025
9. Bargiotas, P., Krenz, A., Hormuzdi, S. G., Ridder, D. A., Herb, A., Barakat, W., et al. (2011). Pannexins in ischemia-induced neurodegeneration. Proc. Natl. Acad. Sci. U.S.A. 108, 20772-20777. doi: 10.1073/pnas.1018262108
10. Bargiotas, P., Krenz, A., Monyer, H., and Schwaninger, M. (2012). Functional outcome of pannexin-deficient mice after cerebral ischemia. Channels 6, 453-456. doi: 10.4161/chan.22315
11. Bartlett, R., Stokes, L., and Sluyter, R. (2014). The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol. Rev. 66, 638-675. doi: 10.1124/pr.113.008003
12. Baxter, M., Eltom, S., Dekkak, B., Yew-Booth, L., Dubuis, E. D., Maher, S. A., et al. (2014). Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 69, 1080-1089. doi: 10.1136/thoraxjnl-2014-205467
13. Beckel, J. M., Argall, A. J., Lim, J. C., Xia, J., Lu, W., Coffey, E. E., et al. (2014). Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain. Glia 62, 1486-1501. doi: 10.1002/glia.22695
14. Bianco, F., Pravettoni, E., Colombo, A., Schenk, U., Moller, T., Matteoli, M., et al. (2005). Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J. Immunol. 174, 7268-7277. doi: 10.4049/jimmunol.174.11.7268
15. Boisse, L., Chisholm, S. P., Lukewich, M. K., and Lomax, A. E. (2009). Clinical and experimental evidence of sympathetic neural dysfunction during inflammatory bowel disease. Clin. Exp. Pharmacol. Physiol. 36, 1026-1033. doi: 10.1111/j.1440-1681.2009.05242.x
16. Bou Saab, J., Losa, D., Chanson, M., and Ruez, R. (2014). Connexins in respiratory and gastrointestinal mucosal immunity. FEBS Lett. 588, 1288-1296. doi: 10.1016/j.febslet.2014.02.059
17. Brown, I. A., McClain, J. L., Watson, R. E., Patel, B. A., and Gulbransen, B. D. (2016). Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. Cell Mol. Gastroenterol. Hepatol. 2, 77-91. doi: 10.1016/j.jcmgh.2015.08.007
18. Bruzzone, R., Hormuzdi, S. G., Barbe, M. T., Herb, A., and Monyer, H. (2003). Pannexins, a family of gap junction proteins expressed in brain. Proc. Natl. Acad. Sci. U.S.A. 100, 13644-13649. doi: 10.1073/pnas.2233464100
19. Burnstock, G. (2014). Purinergic signalling in the gastrointestinal tract and related organs in health and disease. Purinergic Signal. 10, 3-50. doi: 10.1007/s11302-013-9397-9
20. Burnstock, G., and Williams, M. (2000). P2 purinergic receptors: modulation of cell function and therapeutic potential. J. Pharmacol. Exp. Ther. 295, 862-869.
21. Burra, S., and Jiang, J. X. (2009). Connexin 43 hemichannel opening associated with Prostaglandin E(2) release is adaptively regulated by mechanical stimulation. Commun. Integr. Biol. 2, 239-240. doi: 10.4161/cib.2.3.8154
22. Bynoe, M. S., Waickman, A. T., Mahamed, D. A., Mueller, C., Mills, J. H., and Czopik, A. (2012). CD73 is critical for the resolution of murine colonic inflammation. J. Biomed. Biotechnol. 2012:260983. doi: 10.1155/2012/260983
23. Castelucci, P., Robbins, H. L., Poole, D. P., and Furness, J. B. (2002). The distribution of purine P2X(2) receptors in the guinea-pig enteric nervous system. Histochem. Cell Biol. 117, 415-422. doi: 10.1007/s00418-002-0404-4
24. Cesaro, A., Brest, P., Hofman, V., Hebuterne, X., Wildman, S., Ferrua, B., et al. (2010). Amplification loop of the inflammatory process is induced by P2X7R activation in intestinal epithelial cells in response to neutrophil transepithelial migration. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G32-G42. doi: 10.1152/ajpgi.00282.2009
25. Chekeni, F. B., Elliott, M. R., Sandilos, J. K., Walk, S. F., Kinchen, J. M., Lazarowski, E. R., et al. (2010). Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature 467, 863-867. doi: 10.1038/nature09413
26. Cherian, P. P., Siller-Jackson, A. J., Gu, S., Wang, X., Bonewald, L. F., Sprague, E., et al. (2005). Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Mol. Biol. Cell 16, 3100-3106. doi: 10.1091/mbc.E04-10-0912
27. Clair, C., Combettes, L., Pierre, F., Sansonetti, P., and Tran Van Nhieu, G. (2008). Extracellular-loop peptide antibodies reveal a predominant hemichannel organization of connexins in polarized intestinal cells. Exp. Cell Res. 314, 1250-1265. doi: 10.1016/j.yexcr.2007.12.021
28. Corriden, R., and Insel, P. A. (2010). Basal release of ATP: an autocrine-paracrine mechanism for cell regulation. Sci Signal. 3:re1. doi: 10.1126/scisignal.3104re1
29. Csoka, B., Nemeth, Z. H., Toro, G., Idzko, M., Zech, A., Koscso, B., et al. (2015). Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing. FASEB J. 29, 3626-3637. doi: 10.1096/fj.15-272450
30. da Silva, M. V., Marosti, A. R., Mendes, C. E., Palombit, K., and Castelucci, P. (2015). Differential effects of experimental ulcerative colitis on P2X7 receptor expression in enteric neurons. Histochem. Cell Biol. 143, 171-184. doi: 10.1007/s00418-014-1270-6
31. de Campos, N. E., Marques-da-Silva, C., Correa, G., Castelo-Branco, M. T., de Souza, H. S., and Coutinho-Silva, R. (2012). Characterizing the presence and sensitivity of the P2X7 receptor in different compartments of the gut. J. Innate Immun. 4, 529-541. doi: 10.1159/000336628
32. Decrock, E., De Vuyst, E., Vinken, M., Van Moorhem, M., Vranckx, K., Wang, N., et al. (2009). Connexin 43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cell model. Cell Death Differ. 16, 151-163. doi: 10.1038/cdd.2008.138
33. De Vuyst, E., Decrock, E., Cabooter, L., Dubyak, G. R., Naus, C. C., Evans, W. H., et al. (2006). Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J. 25, 34-44. doi: 10.1038/sj.emboj.7600908
34. De Vuyst, E., Wang, N., Decrock, E., De Bock, M., Vinken, M., Van Moorhem, M., et al. (2009). Ca(2+) regulation of connexin 43 hemichannels in C6 glioma and glial cells. Cell Calcium 46, 176-187. doi: 10.1016/j.ceca.2009.07.002
35. D'Hondt, C., Ponsaerts, R., De Smedt, H., Bultynck, G., and Himpens, B. (2009). Pannexins, distant relatives of the connexin family with specific cellular functions? Bioessays 31, 953-974. doi: 10.1002/bies.200800236
36. Diezmos, E. F., Sandow, S. L., Markus, I., Shevy Perera, D., Lubowski, D. Z., King, D. W., et al. (2013). Expression and localization of pannexin-1 hemichannels in human colon in health and disease. Neurogastroenterol. Motil. 25, e395-e405. doi: 10.1111/nmo.12130
37. Diezmos, E. F., Sandow, S. L., Perera, D. S., King, D. W., Bertrand, P. P., and Liu, L. (2015). Pannexin-2 is expressed in the human colon with extensive localization in the enteric nervous system. Neurogastroenterol. Motil. 27, 672-683. doi: 10.1111/nmo.12541
38. Doctor, R. B., Matzakos, T., McWilliams, R., Johnson, S., Feranchak, A. P., and Fitz, J. G. (2005). Purinergic regulation of cholangiocyte secretion: identification of a novel role for P2X receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G779-G786. doi: 10.1152/ajpgi.00325.2004
39. Donnelly-Roberts, D. L., and Jarvis, M. F. (2007). Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br. J. Pharmacol. 151, 571-579. doi: 10.1038/sj.bjp.0707265
40. Doring, B., Pfitzer, G., Adam, B., Liebregts, T., Eckardt, D., Holtmann, G., et al. (2007). Ablation of connexin43 in smooth muscle cells of the mouse intestine: functional insights into physiology and morphology. Cell Tissue Res. 327, 333-342. doi: 10.1007/s00441-006-0281-6
41. Eltzschig, H. K., Eckle, T., Mager, A., Kuper, N., Karcher, C., Weissmuller, T., et al. (2006). ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ. Res. 99, 1100-1108. doi: 10.1161/01.RES.0000250174.31269.70
42. Ezumi, K., Yamamoto, H., Murata, K., Higashiyama, M., Damdinsuren, B., Nakamura, Y., et al. (2008). Aberrant expression of connexin 26 is associated with lung metastasis of colorectal cancer. Clin. Cancer Res. 14, 677-684. doi: 10.1158/1078-0432.CCR-07-1184
43. Fiocchi, C. (1998). Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115, 182-205. doi: 10.1016/S0016-5085(98)70381-6
44. Fortes, F. S., Pecora, I. L., Persechini, P. M., Hurtado, S., Costa, V., Coutinho-Silva, R., et al. (2004). Modulation of intercellular communication in macrophages: possible interactions between GAP junctions and P2 receptors. J. Cell Sci. 117(Pt 20), 4717-4726. doi: 10.1242/jcs.01345
45. Friedman, D. J., Kunzli, B. M., A-Rahim, Y. I., Sevigny, J., Berberat, P. O., Enjyoji, K., et al. (2009). From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc. Natl. Acad. Sci. U.S.A. 106, 16788-16793. doi: 10.1073/pnas.0902869106
46. Frinchi, M., Di Liberto, V., Turimella, S., D'Antoni, F., Theis, M., Belluardo, N., et al. (2013). Connexin36 (Cx36) expression and protein detection in the mouse carotid body and myenteric plexus. Acta Histochem. 115, 252-256. doi: 10.1016/j.acthis.2012.07.005
47. Fuss, I. J., Neurath, M., Boirivant, M., Klein, J. S., de la Motte, C., Strong, S. A., et al. (1996). Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261-1270.
48. Gallego, D., Hernandez, P., Clave, P., and Jimenez, M. (2006). P2Y1 receptors mediate inhibitory purinergic neuromuscular transmission in the human colon. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G584-G594. doi: 10.1152/ajpgi.00474.2005
49. Gallego, D., Vanden Berghe, P., Farre, R., Tack, J., and Jimenez, M. (2008). P2Y1 receptors mediate inhibitory neuromuscular transmission and enteric neuronal activation in small intestine. Neurogastroenterol. Motil. 20, 159-168. doi: 10.1111/j.1365-2982.2007.01004.x
50. Gibson, D. J., Elliott, L., McDermott, E., Tosetto, M., Keegan, D., Byrne, K., et al. (2015). Heightened expression of cd39 by regulatory t lymphocytes is associated with therapeutic remission in inflammatory bowel disease. Inflamm. Bowel Dis. 21, 2806-2814. doi: 10.1097/MIB.0000000000000566
51. Good, M. E., Begandt, D., DeLalio, L. J., Keller, A. S., Billaud, M., and Isakson, B. E. (2015). Emerging concepts regarding pannexin 1 in the vasculature. Biochem. Soc. Trans. 43, 495-501. doi: 10.1042/BST20150045
52. Guerrero, P. A., Schuessler, R. B., Davis, L. M., Beyer, E. C., Johnson, C. M., Yamada, K. A., et al. (1997). Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J. Clin. Invest. 99, 1991-1998. doi: 10.1172/JCI119367
53. Gulbransen, B. D., Bashashati, M., Hirota, S. A., Gui, X., Roberts, J. A., MacDonald, J. A., et al. (2012). Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat. Med. 18, 600-604. doi: 10.1038/nm.2679
54. Guttman, J. A., Lin, A. E., Li, Y., Bechberger, J., Naus, C. C., Vogl, A. W., et al. (2010). Gap junction hemichannels contribute to the generation of diarrhoea during infectious enteric disease. Gut 59, 218-226. doi: 10.1136/gut.2008.170464
55. Guzman, J., Yu, J. G., Suntres, Z., Bozarov, A., Cooke, H., Javed, N., et al. (2006). ADOA3R as a therapeutic target in experimental colitis: proof by validated high-density oligonucleotide microarray analysis. Inflamm. Bowel Dis. 12, 766-789. doi: 10.1097/00054725-200608000-00014
56. Hansen, D. B., Ye, Z. C., Calloe, K., Braunstein, T. H., Hofgaard, J. P., Ransom, B. R., et al. (2014). Activation, permeability, and inhibition of astrocytic and neuronal large pore (hemi)channels. J. Biol. Chem. 289, 26058-26073. doi: 10.1074/jbc.M114.582155
57. Hofman, P., Cherfils-Vicini, J., Bazin, M., Ilie, M., Juhel, T., Hebuterne, X., et al. (2015). Genetic and pharmacological inactivation of the purinergic P2RX7 receptor dampens inflammation but increases tumor incidence in a mouse model of colitis-associated cancer. Cancer Res. 75, 835-845. doi: 10.1158/0008-5472.CAN-14-1778
58. Idzko, M., Ferrari, D., and Eltzschig, H. K. (2014). Nucleotide signalling during inflammation. Nature 509, 310-317. doi: 10.1038/nature13085
59. Iglesias, R., Dahl, G., Qiu, F., Spray, D. C., and Scemes, E. (2009). Pannexin 1: the molecular substrate of astrocyte "hemichannels". J. Neurosci. 29, 7092-7097. doi: 10.1523/JNEUROSCI.6062-08.2009
60. Ishikawa, M., Iwamoto, T., Nakamura, T., Doyle, A., Fukumoto, S., and Yamada, Y. (2011). Pannexin 3 functions as an ER Ca(2+) channel, hemichannel, and gap junction to promote osteoblast differentiation. J. Cell Biol. 193, 1257-1274. doi: 10.1083/jcb.201101050
61. Junger, W. G. (2011). Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201-212. doi: 10.1038/nri2938
62. Kanczuga-Koda, L., Sulkowski, S., Koda, M., Sobaniec-Lotowska, M., and Sulkowska, M. (2004). Expression of connexins 26, 32 and 43 in the human colon-an immunohistochemical study. Folia Histochem. Cytobiol. 42, 203-207.
63. Kang, J., Kang, N., Lovatt, D., Torres, A., Zhao, Z., Lin, J., et al. (2008). Connexin 43 hemichannels are permeable to ATP. J. Neurosci. 28, 4702-4711. doi: 10.1523/JNEUROSCI.5048-07.2008
64. Kanjanamekanant, K., Luckprom, P., and Pavasant, P. (2014). P2X7 receptor-Pannexin1 interaction mediates stress-induced interleukin-1 beta expression in human periodontal ligament cells. J. Periodont. Res. 49, 595-602. doi: 10.1111/jre.12139
65. Khor, B., Gardet, A., and Xavier, R. J. (2011). Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317. doi: 10.1038/nature10209
66. Koutsoumpas, A., Polymeros, D., Tsiamoulos, Z., Smyk, D., Karamanolis, G., Triantafyllou, K., et al. (2011). Peculiar antibody reactivity to human connexin 37 and its microbial mimics in patients with Crohn's disease. J. Crohns. Colitis 5, 101-109. doi: 10.1016/j.crohns.2010.10.009
67. Kuhny, M., Hochdorfer, T., Ayata, C. K., Idzko, M., and Huber, M. (2014). CD39 is a negative regulator of P2X7-mediated inflammatory cell death in mast cells. Cell Commun. Signal. 12:40. doi: 10.1186/s12964-014-0040-3
68. Kurashima, Y., Amiya, T., Nochi, T., Fujisawa, K., Haraguchi, T., Iba, H., et al. (2012). Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors. Nat. Commun. 3, 1034. doi: 10.1038/ncomms2023
69. Lai, C., Bechberger, J., and Naus, C. (2009). Pannexin2 as a novel growth regulator in C6 glioma cells. Oncogene 28, 4402-4408. doi: 10.1038/onc.2009.283
70. Lemaire, I., Falzoni, S., Zhang, B., Pellegatti, P., and Di Virgilio, F. (2011). The P2X7 receptor and Pannexin-1 are both required for the promotion of multinucleated macrophages by the inflammatory cytokine GM-CSF. J. Immunol. 187, 3878-3887. doi: 10.4049/jimmunol.1002780
71. Li, S., Bjelobaba, I., Yan, Z., Kucka, M., Tomic, M., and Stojilkovic, S. S. (2011). Expression and roles of pannexins in ATP release in the pituitary gland. Endocrinology 152, 2342-2352. doi: 10.1210/en.2010-1216
72. Linan-Rico, A., Wunderlich, J. E., Grants, I. S., Frankel, W. L., Xue, J., Williams, K. C., et al. (2013). Purinergic autocrine regulation of mechanosensitivity and serotonin release in a human EC model: ATP-gated P2X3 channels in EC are downregulated in ulcerative colitis. Inflamm. Bowel Dis. 19, 2366-2379. doi: 10.1097/MIB.0b013e31829ecf4d
73. Lo, C. W. (2000). Role of gap junctions in cardiac conduction and development: insights from the connexin knockout mice. Circ. Res. 87, 346-348. doi: 10.1161/01.RES.87.5.346
74. Locovei, S., Bao, L., and Dahl, G. (2006a). Pannexin 1 in erythrocytes: function without a gap. Proc. Natl. Acad. Sci. U.S.A. 103, 7655-7659. doi: 10.1073/pnas.0601037103
75. Locovei, S., Scemes, E., Qiu, F., Spray, D. C., and Dahl, G. (2007). Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex. FEBS Lett. 581, 483-488. doi: 10.1016/j.febslet.2006.12.056
76. Locovei, S., Wang, J., and Dahl, G. (2006b). Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett. 580, 239-244. doi: 10.1016/j.febslet.2005.12.004
77. Lohman, A. W., and Isakson, B. E. (2014). Differentiating connexin hemichannels and pannexin channels in cellular ATP release. FEBS Lett. 588, 1379-1388. doi: 10.1016/j.febslet.2014.02.004
78. Lohman, A. W., Leskov, I. L., Butcher, J. T., Johnstone, S. R., Stokes, T. A., Begandt, D., et al. (2015). Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation. Nat. Commun. 6, 7965. doi: 10.1038/ncomms8965
79. Lomax, A. E., O'Reilly, M., Neshat, S., and Vanner, S. J. (2007). Sympathetic vasoconstrictor regulation of mouse colonic submucosal arterioles is altered in experimental colitis. J. Physiol. 583(Pt 2), 719-730. doi: 10.1113/jphysiol.2007.136838
80. Longhi, M. S., Moss, A., Bai, A., Wu, Y., Huang, H., Cheifetz, A., et al. (2014). Characterization of human CD39+ Th17 cells with suppressor activity and modulation in inflammatory bowel disease. PLoS ONE 9:e87956. doi: 10.1371/journal.pone.0087956
81. Lurtz, M. M., and Louis, C. F. (2007). Intracellular calcium regulation of connexin43. Am. J. Physiol. Cell Physiol. 293, C1806-C1813. doi: 10.1152/ajpcell.00630.2006
82. Lutz, S. E., Gonzalez-Fernandez, E., Ventura, J. C., Perez-Samartin, A., Tarassishin, L., Negoro, H., et al. (2013). Contribution of pannexin1 to experimental autoimmune encephalomyelitis. PLoS ONE. 8:e66657. doi: 10.1371/journal.pone.0066657
83. Ma, Y., Cao, W., Wang, L., Jiang, J., Nie, H., Wang, B., et al. (2014). Basal CD38/cyclic ADP-ribose-dependent signaling mediates ATP release and survival of microglia by modulating connexin 43 hemichannels. Glia 62, 943-955. doi: 10.1002/glia.22651
84. Mahi, N., Kumar, A., Jaggi, A. S., Singh, N., and Dhawan, R. (2015). Possible role of pannexin 1/P2x7 purinoceptor in neuroprotective mechanism of ischemic postconditioning in mice. J. Surg. Res. 196, 190-199. doi: 10.1016/j.jss.2015.02.050
85. Marques, C. C., Castelo-Branco, M. T., Pacheco, R. G., Buongusto, F., do Rosario, A. Jr., Schanaider, A., et al. (2014). Prophylactic systemic P2X7 receptor blockade prevents experimental colitis. Biochim. Biophys. Acta. 1842, 65-78. doi: 10.1016/j.bbadis.2013.10.012
86. Martin, C. A., el-Sabban, M. E., Zhao, L., Burakoff, R., and Homaidan, F. R. (1998). Adhesion and cytosolic dye transfer between macrophages and intestinal epithelial cells. Cell Adhes. Commun. 5, 83-95. doi: 10.3109/15419069809040283
87. McClain, J. L., Grubisic, V., Fried, D., Gomez-Suarez, R. A., Leinninger, G. M., Sevigny, J., et al. (2014). Ca2+ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice. Gastroenterology 146, 497-507. e1. doi: 10.1053/j.gastro.2013.10.061
88. Monro, R. L., Bertrand, P. P., and Bornstein, J. C. (2004). ATP participates in three excitatory postsynaptic potentials in the submucous plexus of the guinea pig ileum. J. Physiol. 556(Pt 2), 571-584. doi: 10.1113/jphysiol.2004.060848
89. Monteleone, G., Biancone, L., Marasco, R., Morrone, G., Marasco, O., Luzza, F., et al. (1997). Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 112, 1169-1178. doi: 10.1016/S0016-5085(97)70128-8
90. Moon, P. M., Penuela, S., Barr, K., Khan, S., Pin, C. L., Welch, I., et al. (2015). Deletion of Panx3 prevents the development of surgically induced osteoarthritis. J Mol. Med. (Berl). 93, 845-856. doi: 10.1007/s00109-015-1311-1
91. Morita, H., Katsuno, T., Hoshimoto, A., Hirano, N., Saito, Y., and Suzuki, Y. (2004). Connexin 26-mediated gap junctional intercellular communication suppresses paracellular permeability of human intestinal epithelial cell monolayers. Exp. Cell Res. 298, 1-8. doi: 10.1016/j.yexcr.2004.03.046
92. Nemeth, L., Maddur, S., and Puri, P. (2000). Immunolocalization of the gap junction protein Connexin43 in the interstitial cells of Cajal in the normal and Hirschsprung's disease bowel. J. Pediatr. Surg. 35, 823-828. doi: 10.1053/jpsu.2000.6851
93. Neves, A. R., Castelo-Branco, M. T., Figliuolo, V. R., Bernardazzi, C., Buongusto, F., Yoshimoto, A., et al. (2014). Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn's disease. Inflamm. Bowel Dis. 20, 444-457. doi: 10.1097/01.MIB.0000441201.10454.06
94. Nicotra, L. L., Vu, M., Harvey, B. S., and Smid, S. D. (2013). Prostaglandin ethanolamides attenuate damage in a human explant colitis model. Prostaglandins Other Lipid Mediat. 100-101, 22-29. doi: 10.1016/j.prostaglandins.2013.01.003
95. North, R. A. (2002). Molecular physiology of P2X receptors. Physiol. Rev. 82, 1013-1067. doi: 10.1152/physrev.00015.2002
96. O'Carroll, S. J., Alkadhi, M., Nicholson, L. F., and Green, C. R. (2008). Connexin 43 mimetic peptides reduce swelling, astrogliosis, and neuronal cell death after spinal cord injury. Cell Commun. Adhes. 15, 27-42. doi: 10.1080/15419060802014164
97. Ochoa-Cortes, F., Linan-Rico, A., Jacobson, K. A., and Christofi, F. L. (2014). Potential for developing purinergic drugs for gastrointestinal diseases. Inflamm. Bowel Dis. 20, 1259-1287. doi: 10.1097/MIB.0000000000000047
98. Ohbuchi, T., Takenaga, F., Hohchi, N., Wakasugi, T., Ueta, Y., and Suzuki, H. (2014). Possible contribution of pannexin-1 to ATP release in human upper airway epithelia. Physiol. Rep. 2:e00227. doi: 10.1002/phy2.227
99. Orellana, J. A., Montero, T. D., and von Bernhardi, R. (2013). Astrocytes inhibit nitric oxide-dependent Ca(2+) dynamics in activated microglia: involvement of ATP released via pannexin 1 channels. Glia 61, 2023-2037. doi: 10.1002/glia.22573
100. Papadakis, K. A., and Targan, S. R. (2000). Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu. Rev. Med. 51, 289-298. doi: 10.1146/annurev.med.51.1.289
101. Patel, B. A. (2014). Mucosal adenosine triphosphate mediates serotonin release from ileal but not colonic guinea pig enterochromaffin cells. Neurogastroenterol. Motil. 26, 237-246. doi: 10.1111/nmo.12254
102. Pelegrin, P., Barroso-Gutierrez, C., and Surprenant, A. (2008). P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage. J. Immunol. 180, 7147-7157. doi: 10.4049/jimmunol.180.11.7147
103. Pelegrin, P., and Surprenant, A. (2006). Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071-5082. doi: 10.1038/sj.emboj.7601378
104. Pelegrin, P., and Surprenant, A. (2009). The P2X(7) receptor-pannexin connection to dye uptake and IL-1beta release. Purinergic Signal. 5, 129-137. doi: 10.1007/s11302-009-9141-7
105. Penuela, S., Bhalla, R., Nag, K., and Laird, D. W. (2009). Glycosylation regulates pannexin intermixing and cellular localization. Mol. Biol. Cell 20, 4313-4323. doi: 10.1091/mbc.E09-01-0067
106. Penuela, S., Gehi, R., and Laird, D. W. (2013). The biochemistry and function of pannexin channels. Biochim. Biophys. Acta 1828, 15-22. doi: 10.1016/j.bbamem.2012.01.017
107. Plevy, S. E., Landers, C. J., Prehn, J., Carramanzana, N. M., Deem, R. L., Shealy, D., et al. (1997). A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J. Immunol. 159, 6276-6282.
108. Poole, D. P., Castelucci, P., Robbins, H. L., Chiocchetti, R., and Furness, J. B. (2002). The distribution of P2X3 purine receptor subunits in the guinea pig enteric nervous system. Auton. Neurosci. 101, 39-47. doi: 10.1016/S1566-0702(02)00179-0
109. Poon, I. K., Chiu, Y. H., Armstrong, A. J., Kinchen, J. M., Juncadella, I. J., Bayliss, D. A., et al. (2014). Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature 507, 329-334. doi: 10.1038/nature13147
110. Qiu, F., and Dahl, G. (2009). A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP. Am. J. Physiol. Cell Physiol. 296, C250-C255. doi: 10.1152/ajpcell.00433.2008
111. Ralevic, V., and Burnstock, G. (1998). Receptors for purines and pyrimidines. Pharmacol. Rev. 50, 413-492.
112. Ransford, G. A., Fregien, N., Qiu, F., Dahl, G., Conner, G. E., and Salathe, M. (2009). Pannexin 1 contributes to ATP release in airway epithelia. Am. J. Respir. Cell Mol. Biol. 41, 525-534. doi: 10.1165/rcmb.2008-0367OC
113. Ren, J., and Bertrand, P. P. (2008). Purinergic receptors and synaptic transmission in enteric neurons. Purinergic Signal. 4, 255-266. doi: 10.1007/s11302-007-9088-5
114. Retamal, M. A., Froger, N., Palacios-Prado, N., Ezan, P., Saez, P. J., Saez, J. C., et al. (2007). Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J. Neurosci. 27, 13781-13792. doi: 10.1523/JNEUROSCI.2042-07.2007
115. Rigato, C., Swinnen, N., Buckinx, R., Couillin, I., Mangin, J. M., Rigo, J. M., et al. (2012). Microglia proliferation is controlled by P2X7 receptors in a Pannexin-1-independent manner during early embryonic spinal cord invasion. J. Neurosci. 32, 11559-11573. doi: 10.1523/JNEUROSCI.1042-12.2012
116. Riteau, N., Gasse, P., Fauconnier, L., Gombault, A., Couegnat, M., Fick, L., et al. (2010). Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 182, 774-783. doi: 10.1164/rccm.201003-0359OC
117. Roberts, J. A., Lukewich, M. K., Sharkey, K. A., Furness, J. B., Mawe, G. M., and Lomax, A. E. (2012). The roles of purinergic signaling during gastrointestinal inflammation. Curr. Opin. Pharmacol. 12, 659-666. doi: 10.1016/j.coph.2012.09.011
118. Rouach, N., Segal, M., Koulakoff, A., Giaume, C., and Avignone, E. (2003). Carbenoxolone blockade of neuronal network activity in culture is not mediated by an action on gap junctions. J. Physiol. 553(Pt 3), 729-745. doi: 10.1113/jphysiol.2003.053439
119. Ruan, H. Z., and Burnstock, G. (2005). The distribution of P2X5 purinergic receptors in the enteric nervous system of mouse. Cell Tissue Res. 319, 191-200. doi: 10.1007/s00441-004-1002-7
120. Rybaczyk, L., Rozmiarek, A., Circle, K., Grants, I., Needleman, B., Wunderlich, J. E., et al. (2009). New bioinformatics approach to analyze gene expressions and signaling pathways reveals unique purine gene dysregulation profiles that distinguish between CD and UC. Inflamm. Bowel Dis. 15, 971-984. doi: 10.1002/ibd.20893
121. Sanchez-Munoz, F., Dominguez-Lopez, A., and Yamamoto-Furusho, J. K. (2008). Role of cytokines in inflammatory bowel disease. World J. Gastroenterol. 14, 4280-4288. doi: 10.3748/wjg.14.4280
122. Schenk, U., Westendorf, A. M., Radaelli, E., Casati, A., Ferro, M., Fumagalli, M., et al. (2008). Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels. Sci. Signal. 1:ra6. doi: 10.1126/scisignal.1160583
123. Schock, S. C., Leblanc, D., Hakim, A. M., and Thompson, C. S. (2008). ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro. Biochem. Biophys. Res. Commun. 368, 138-144. doi: 10.1016/j.bbrc.2008.01.054
124. Shoji, K. F., Saez, P. J., Harcha, P. A., Aguila, H. L., and Saez, J. C. (2014). Pannexin1 channels act downstream of P2X 7 receptors in ATP-induced murine T-cell death. Channels 8, 142-156. doi: 10.4161/chan.28122
125. Sohl, G., and Willecke, K. (2004). Gap junctions and the connexin protein family. Cardiovasc. Res. 62, 228-232. doi: 10.1016/j.cardiores.2003.11.013
126. Solle, M., Labasi, J., Perregaux, D. G., Stam, E., Petrushova, N., Koller, B. H., et al. (2001). Altered cytokine production in mice lacking P2X(7) receptors. J. Biol. Chem. 276, 125-132. doi: 10.1074/jbc.M006781200
127. Strober, W., and Fuss, I. J. (2011). Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1756-1767. doi: 10.1053/j.gastro.2011.02.016
128. Surprenant, A., and North, R. A. (2009). Signaling at purinergic P2X receptors. Annu. Rev. Physiol. 71, 333-359. doi: 10.1146/annurev.physiol.70.113006.100630
129. Swayne, L. A., Sorbara, C. D., and Bennett, S. A. (2010). Pannexin 2 is expressed by postnatal hippocampal neural progenitors and modulates neuronal commitment. J. Biol. Chem. 285, 24977-24986. doi: 10.1074/jbc.M110.130054
130. Tanaka, J., Murate, M., Wang, C. Z., Seino, S., and Iwanaga, T. (1996). Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats. Arch. Histol. Cytol. 59, 485-490. doi: 10.1679/aohc.59.485
131. Tenneti, L., Gibbons, S. J., and Talamo, B. R. (1998). Expression and trans-synaptic regulation of P2x4 and P2z receptors for extracellular ATP in parotid acinar cells. Effects of parasympathetic denervation. J. Biol. Chem. 273, 26799-26808. doi: 10.1074/jbc.273.41.26799
132. Thi, M. M., Islam, S., Suadicani, S. O., and Spray, D. C. (2012). Connexin43 and pannexin1 channels in osteoblasts: who is the "hemichannel"? J. Membr. Biol. 245, 401-409. doi: 10.1007/s00232-012-9462-2
133. Vanderwinden, J. M., Timmermans, J. P., and Schiffmann, S. N. (2003). Glial cells, but not interstitial cells, express P2X7, an ionotropic purinergic receptor, in rat gastrointestinal musculature. Cell Tissue Res. 312, 149-154. doi: 10.1007/s00441-003-0716-2
134. Velasquez Almonacid, L. A., Tafuri, S., Dipineto, L., Matteoli, G., Fiorillo, E., Della Morte, R., et al. (2009). Role of connexin-43 hemichannels in the pathogenesis of Yersinia enterocolitica. Vet. J. 182, 452-457. doi: 10.1016/j.tvjl.2008.08.011
135. Verselis, V. K., and Srinivas, M. (2013). Connexin channel modulators and their mechanisms of action. Neuropharmacology 75, 517-524. doi: 10.1016/j.neuropharm.2013.03.020
136. Vinken, M., Vanhaecke, T., and Rogiers, V. (2010). Emerging roles of connexin hemichannels in gastrointestinal and liver pathophysiology. World J. Gastrointest. Pathophysiol. 1, 115-117. doi: 10.4291/wjgp.v1.i4.115
137. von Kugelgen, I., and Harden, T. K. (2011). Molecular pharmacology, physiology, and structure of the P2Y receptors. Adv. Pharmacol. 61, 373-415. doi: 10.1016/B978-0-12-385526-8.00012-6
138. Wang, N., De Bock, M., Decrock, E., Bol, M., Gadicherla, A., Vinken, M., et al. (2013a). Paracrine signaling through plasma membrane hemichannels. Biochim. Biophys. Acta 1828, 35-50. doi: 10.1016/j.bbamem.2012.07.002
139. Wang, N., De Vuyst, E., Ponsaerts, R., Boengler, K., Palacios-Prado, N., Wauman, J., et al. (2013b). Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res. Cardiol. 108:309. doi: 10.1007/s00395-012-0309-x
140. Wang, Y. F., and Daniel, E. E. (2001). Gap junctions in gastrointestinal muscle contain multiple connexins. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G533-G543.
141. Wei, L., Sheng, H., Chen, L., Hao, B., Shi, X., and Chen, Y. (2016). Effect of pannexin-1 on the release of glutamate and cytokines in astrocytes. J. Clin. Neurosci. 23, 135-141. doi: 10.1016/j.jocn.2015.05.043
142. Woehrle, T., Yip, L., Elkhal, A., Sumi, Y., Chen, Y., Yao, Y., et al. (2010a). Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse. Blood 116, 3475-3484. doi: 10.1182/blood-2010-04-277707
143. Woehrle, T., Yip, L., Manohar, M., Sumi, Y., Yao, Y., Chen, Y., et al. (2010b). Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors. J. Leukoc. Biol. 88, 1181-1189. doi: 10.1189/jlb.0410211
144. Xia, J., Lim, J. C., Lu, W., Beckel, J. M., Macarak, E. J., Laties, A. M., et al. (2012). Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors. J. Physiol. 590(Pt 10), 2285-2304. doi: 10.1113/jphysiol.2012.227983
145. Yiangou, Y., Facer, P., Baecker, P. A., Ford, A. P., Knowles, C. H., Chan, C. L., et al. (2001). ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease. Neurogastroenterol. Motil. 13, 365-369. doi: 10.1046/j.1365-2982.2001.00276.x