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Pannexins or Connexins?

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Book cover Connexins

Abstract

Pannexins are a family of three vertebrate proteins that have moderate sequence homology with the innexin proteins, which compose gap junction channels in protostomes, including most invertebrates. However, it appears that in contrast to innexins, pannexins do not have the ability to form gap junction channels. They do, however, form nonjunctional plasma membrane channels (pannexons) that mediate regulated flux of molecules in the size range of second messengers between cytoplasm and the extracellular space. The dye permeability and pharmacological sensitivities of pannexin channels overlap those of connexin hemichannels, so it is possible that many of the phenomena that have been attributed to connexin hemichannels are in fact mediated by pannexons. For this reason, identifying which protein is involved in a particular cellular physiology requires careful evaluation of the specific conditions and requirements in each case. Several lines of experimentation have led to the suggestion that the adenosine triphosphate (ATP) release channel, a crucial element in the initiation and propagation of intercellular Ca2+ waves, is a connexin hemichannel. However, based on recently revealed properties of pannexin channels, which include mechanosensitivity and activation by cytoplasmic Ca2+, the pannexon must be considered a prime candidate for the ATP release channel. Pannexons also appear to form the large ATP-permeable pore that is activated by the purinergic P2X7 receptor complex, which is involved in inflammation.

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References

  1. Söhl G, Willecke K. Gap junctions and the connexin protein family. Cardiovasc Res. 2004;62:228–32.

    Article  PubMed  Google Scholar 

  2. Phelan P, Bacon JP, Davies JA, Phelan P, Bacon JP, Davies JA, Davies JA, Stebbings LA, Todman MG, Avery L, Baines RA, Barnes TM, Ford C, Hekimi S, Lee R, Shaw JE, Starich TA, Curtin KD, Sun YA and Wyman RJ. Innexins: a family of invertebrate gap-junction proteins. Trends Genet. 1998;14:348–9.

    Article  CAS  PubMed  Google Scholar 

  3. Panchin Y, Kelmanson I, Matz M, Lukyanov K, Usman N, Lukyanov S. A ubiquitous family of putative gap junction molecules. Curr Biol. 2000;10:R473–4.

    Article  CAS  PubMed  Google Scholar 

  4. Panchin YV. Evolution of gap junction proteins-the pannexin alternative. J Exp Biol. 2005;208:1415–9.

    Article  CAS  PubMed  Google Scholar 

  5. Locovei S, Bao L, Dahl G. Pannexin 1 in erythrocytes: function without a gap. Proc Natl Acad Sci USA. 2006;103:7655–9.

    Google Scholar 

  6. Boassa D, Ambrosi C, Qiu F, Dahl G, Gaietta G, Sosinsky G. Pannexin1 channels contain a glycosylation site that targets the hexamer to the plasma membrane. J Biol Chem. 2007;282:31733–43.

    Google Scholar 

  7. Bruzzone R, Hormuzdi SG, Barbe MT, Herb A, Monyer H. Pannexins, a family of gap junction proteins expressed in brain. Proc Natl Acad Sci USA. 2003;100:13644–9.

    Google Scholar 

  8. Bao L, Locovei S, Dahl G. Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett. 2004;572:65–8.

    Article  CAS  PubMed  Google Scholar 

  9. Vanden Abeele F, Bidaux G, Gordienko D, Beck, B, Panchin, YV, Baranova, AV, Ivanov, DV, Skryma, R, Prevarskaya, N. Functional implications of calcium permeability of the channel formed by pannexin 1. J Cell Biol. 2006;174:535–46.

    Article  CAS  PubMed  Google Scholar 

  10. Lai CP, Bechberger JF, Thompson RJ, MacVicar BA, Bruzzone R, Naus CC. Tumor-suppressive effects of pannexin 1 in C6 glioma cells. Cancer Res. 2007;67:1545–54.

    Article  CAS  PubMed  Google Scholar 

  11. Huang Y, Grinspan JB, Abrams CK, Scherer SS. Pannexin1 is expressed by neurons and glia but does not form functional gap junctions. Glia. 2007;55:46–56.

    Article  PubMed  Google Scholar 

  12. Paul DL. Molecular cloning of cDNA for rat liver gap junction protein. J Cell Biol. 1986;103:123–34.

    Article  CAS  PubMed  Google Scholar 

  13. Bauer R, Lehmann C, Martini J, Eckardt F, Hoch M. Gap junction channel protein innexin 2 is essential for epithelial morphogenesis in the Drosophila embryo. Mol Biol Cell. 2004;15:2992–3004.

    Article  CAS  PubMed  Google Scholar 

  14. Dahl G, Locovei S. Pannexin: to gap or not to gap, is that a question? IUBMB Life. 2006;58:409–19.

    Article  CAS  PubMed  Google Scholar 

  15. Ransford GA, Dahl G, Fregien N, Conner GE, Salathe M. Pannexin 1 expression in airway epithelia. Am J Respir Crit Care Med. 2007;175:A887.

    Google Scholar 

  16. Zoidl G, Petrasch-Parwez E, Ray A, Meier C, Bunse S, Habbes H-W, Dahl G and Dermietzel R. Localization of the pannexin1 protein at postsynaptic sites in the cerebral cortex and hippocampus. Neuroscience. 2007;146:9–16.

    Article  CAS  PubMed  Google Scholar 

  17. Penuela S, Bhalla R, Gong XQ, Cowan KN, Celetti SJ, Cowan BJ, Bai D, Shao Q, Laird DW. Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins. J Cell Sci. 2007;120:3772–83.

    Article  CAS  PubMed  Google Scholar 

  18. Dahl G, Nonner W, Werner R. Attempts to define functional domains of gap junction proteins with synthetic peptides. Biophys J. 1994;67:1816–22.

    Article  CAS  PubMed  Google Scholar 

  19. Thornhill WB, Levinson SR. Biosynthesis of electroplax sodium channels in Electrophorus electrocytes and Xenopus oocytes. Biochemistry. 1987;26:4381–8.

    Article  CAS  PubMed  Google Scholar 

  20. Goldberger G, Arnaout MA, Aden D, Kay R, Rits M, Colten HR. Biosynthesis and postsynthetic processing of human C3b/C4b inactivator (factor I) in three hepatoma cell lines. J Biol Chem. 1984;259:6492–7.

    CAS  PubMed  Google Scholar 

  21. Mous JM, Peeters BL, Heyns WJ, Rombauts WA. Assembly, glycosylation, and secretion of the oligomeric rat prostatic binding protein in Xenopus oocytes. J Biol Chem. 1982;257:11822–8.

    Google Scholar 

  22. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I. Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born T L, Usman N, Staroverov D, Lukyanov S and Panchin Y. The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics. 2004;83:706–16.

    Article  CAS  PubMed  Google Scholar 

  23. Wang J, Ma M, Locovei S, Keane R, Dahl GP. Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters. Am J Physiol Cell Physiol. 2007;293:C1112–9.

    Article  CAS  PubMed  Google Scholar 

  24. Locovei S, Wang J, Dahl G. Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett. 2006;580:239–44.

    Article  CAS  PubMed  Google Scholar 

  25. Sanderson MJ, Charles AC, Dirksen ER. Mechanical stimulation and intercellular communication increases intracellular Ca2+ in epithelial cells. Cell Regul. 1990;1:585–96.

    CAS  PubMed  Google Scholar 

  26. Sigurdson WJ, Sachs F, Diamond SL. Mechanical perturbation of cultured human endothelial cells causes rapid increases of intracellular calcium. Am J Physiol. 1993;264:H1745–52.

    CAS  PubMed  Google Scholar 

  27. Newman EA. Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J Neurosci. 2001;21:2215–23.

    CAS  PubMed  Google Scholar 

  28. Jorgensen NR, Geist ST, Civitelli R, Steinberg TH. ATP- and gap junction-dependent intercellular calcium signaling in osteoblastic cells. J Cell Biol. 1997;139:497–506.

    Article  CAS  PubMed  Google Scholar 

  29. Osipchuk Y, Cahalan M. Cell-to-cell spread of calcium signals mediated by ATP receptors in mast cells. Nature. 1992;359:241–44.

    Article  CAS  PubMed  Google Scholar 

  30. Hassinger TD, Guthrie PB, Atkinson PB, Bennett MVL, Kater SB. An extracellular signaling component in propagation of astrocytic calcium waves. Proc Natl Acad Sci USA. 1996;93:13268–73.

    Google Scholar 

  31. Bergfeld GR, Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res. 1992;26:40–7.

    Article  CAS  PubMed  Google Scholar 

  32. Stout CE, Costantin JL, Naus CC, Charles AC. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem. 2002;277:10482–8.

    Google Scholar 

  33. Zhao HB, Yu N, Fleming CR. Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear. Proc Natl Acad Sci USA. 2005;102:18724–9.

    Google Scholar 

  34. Hofer A, Dermietzel R. Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes. Glia. 1998;24:141–154.

    Article  CAS  PubMed  Google Scholar 

  35. Leybaert L, Braet K, Vandamme W, Cabooter L, Martin PE, Evans WH. Connexin channels, connexin mimetic peptides and ATP release. Cell Commun Adhes. 2003;10:251–7.

    CAS  PubMed  Google Scholar 

  36. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S. Li J, Azmi-Ghadimi H, Kang J, Naus CC and Nedergaard M. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA. 1998;95:15735–40.

    Google Scholar 

  37. Locovei S, Scemes E, Qiu F, Spray DC, Dahl G. Pannexin1 is part of the pore forming unit of the P2X7 receptor death complex. FEBS Lett. 2007;581:483–8.

    Article  CAS  PubMed  Google Scholar 

  38. Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 2006;25:5071–82.

    Article  CAS  PubMed  Google Scholar 

  39. Musil LS, Goodenough DA. Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J Cell Biol. 1991;115:1357–74.

    Article  CAS  PubMed  Google Scholar 

  40. Musil LS, Goodenough DA. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell. 1993;74:1065–77.

    Article  CAS  PubMed  Google Scholar 

  41. Ebihara L, Liu X, Pal JD. Effect of external magnesium and calcium on human connexin46 hemichannels. Biophys J. 2003;84:277–86.

    Article  CAS  PubMed  Google Scholar 

  42. Ebihara L. Physiology and biophysics of hemi-gap-junctional channels expressed in Xenopus oocytes. Acta Physiol Scand. 2003;179:5–8.

    Article  CAS  PubMed  Google Scholar 

  43. Peracchia C, Wang X, Li L, Peracchia LL. Inhibition of calmodulin expression prevents low-pH-induced gap junction uncoupling in Xenopus oocytes. Pflügers Arch Eur J Physiol. 1996;431:379–87.

    Article  CAS  Google Scholar 

  44. Spray DC, Harris AL, Bennett MVL. Comparison of pH and calcium dependence of gap junctional conductance. Kroc Found Ser. 1981;15:445–61.

    CAS  PubMed  Google Scholar 

  45. Trexler EB, Bennett MVL, Bargiello TA, Verselis VK. Voltage-gating and permeation in a gap junction hemichannel. Proc Natl Acad Sci USA. 1996;93:5836–41.

    Google Scholar 

  46. Trexler EB, Verselis VK. The study of connexin hemichannels (connexons) in Xenopus oocytes. Methods Mol Biol. 2001;154:341–55.

    CAS  PubMed  Google Scholar 

  47. Pfahnl A, Zhou XW, Werner R, Dahl G. A chimeric connexin forming gap junction hemichannels. Pflügers Arch. 1997;433:773–9.

    Article  CAS  PubMed  Google Scholar 

  48. Pfahnl A, Dahl G. Gating of Cx46 gap junction hemichannels by calcium and voltage. Pflügers Arch. 1999;437:345–53.

    Article  CAS  PubMed  Google Scholar 

  49. Li H, Liu TF, Lazrak A, Peracchia C, Goldberg GS, Lampe PD and Johnson RG. Properties and regulation of gap junctional hemichannels in the plasma membranes of cultured cells. J Cell Biol. 1996;134:1019–30.

    Article  CAS  PubMed  Google Scholar 

  50. Stout C, Charles A. Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium. Glia. 2003;43:265–73.

    Article  PubMed  Google Scholar 

  51. Ebihara L, Steiner E. Properties of a nonjunctional current expressed from a rat connexin46 cDNA in Xenopus oocytes. J Gen Physiol. 1993;102:59–74.

    Article  CAS  PubMed  Google Scholar 

  52. Zanotti S, Charles A. Extracellular calcium sensing by glial cells: low extracellular calcium induces intracellular calcium release and intercellular signaling. J Neurochem. 1997;69:594–602.

    Article  CAS  PubMed  Google Scholar 

  53. Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, Lonigro AJ. Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol. 1998;275:H1726–32.

    CAS  PubMed  Google Scholar 

  54. Huang YJ, Maruyama Y, Dvoryanchikov G, Pereira E, Chaudhari N, Roper SD. The role of pannexin 1 hemichannels in ATP release and cell-cell communication in mouse taste buds. Proc Natl Acad Sci USA. 2007;104:6436–41.

    Google Scholar 

  55. Romanov RA, Rogachevskaja OA, Bystrova MF, Jiang P, Margolskee RF, Kolesnikov SS. Afferent neurotransmission mediated by hemichannels in mammalian taste cells. EMBO J. 2007;26:657–67.

    Article  CAS  PubMed  Google Scholar 

  56. Scemes E, Dermietzel R, Spray DC. Calcium waves between astrocytes from Cx43 knockout mice. Glia. 1998;24:65–73.

    Article  CAS  PubMed  Google Scholar 

  57. Iacobas DA, Scemes E, Spray DC. Gene expression alterations in connexin null mice extend beyond the gap junction. Neurochem Int. 2004;45:243–50.

    Article  CAS  PubMed  Google Scholar 

  58. Iacobas DA, Iacobas S, Urban-Maldonado M, Spray DC. Sensitivity of the brain transcriptome to connexin ablation. Biochim Biophys Acta. 2005;1711:183–96.

    Article  CAS  PubMed  Google Scholar 

  59. Iacobas DA, Iacobas S, Spray DC. Connexin43 and the brain transcriptome of newborn mice. Genomics. 2007;89:113–23.

    Article  CAS  PubMed  Google Scholar 

  60. Bahima L, Aleu J, Elias M, Martin-Satue M, Muhaisen A, Blasi J, Marsal J and Solsona C. Endogenous hemichannels play a role in the release of ATP from Xenopus oocytes. J Cell Physiol. 2006;206:95–102.

    Article  CAS  PubMed  Google Scholar 

  61. Maroto R, Hamill OP. Brefeldin A block of integrin-dependent mechanosensitive ATP release from Xenopus oocytes reveals a novel mechanism of mechanotransduction. J Biol Chem. 2001;276:23867–72.

    Google Scholar 

  62. Brule G, Haudecoeur G, Jdaiaa H, Guilbault P. Inhibition, by an amphiphilic substance, niflumic acid, of the inward rectification of the crustacean muscle fiber. Arch Int Physiol Biochim. 1983;91:269–77.

    Article  CAS  PubMed  Google Scholar 

  63. Benoit E, Corbier A, Dubois JM. Evidence for two transient sodium currents in the frog node of Ranvier. J Physiol. 1985;361:339–60.

    CAS  PubMed  Google Scholar 

  64. Vessey JP, Lalonde MR, Mizan HA, Welch NC, Kelly ME, Barnes S. Carbenoxolone inhibition of voltage-dependent Ca channels and synaptic transmission in the retina. J Neurophysiol. 2004;92:1252–56.

    Article  CAS  PubMed  Google Scholar 

  65. Guan X, Cravatt BF, Ehring GR,, Hall JE, Boger DL, Lerner RA, Gilula NB. The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells. J Cell Biol. 1997;139:1785–92.

    Article  CAS  PubMed  Google Scholar 

  66. Braet K, Vandamme W, Martin PE, Evans WH, Leybaert L. Photoliberating inositol-1,4,5-trisphosphate triggers ATP release that is blocked by the connexin mimetic peptide gap 26. Cell Calcium. 2003;33:37–48.

    Article  CAS  PubMed  Google Scholar 

  67. Purnick PE, Oh S, Abrams CK, Verselis VK, Bargiello TA. Reversal of the gating polarity of gap junctions by negative charge substitutions in the N-terminus of connexin 32. Biophys J. 2000;79:2403–15.

    Article  CAS  PubMed  Google Scholar 

  68. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science. 1996;272:735–8.

    Article  CAS  PubMed  Google Scholar 

  69. Suadicani SO, Brosnan CF, Scemes E. P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J Neurosci. 2006;26:1378–85.

    Article  CAS  PubMed  Google Scholar 

  70. Bruzzone R, Barbe MT, Jakob NJ, Monyer H. Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes. J Neurochem. 2005;92:1033–43.

    Article  CAS  PubMed  Google Scholar 

  71. Coutinho-Silva R, Persechini PM. P2Z purinoceptor-associated pores induced by extracellular ATP in macrophages and J774 cells. Am J Physiol. 1997;273:C1793–C1800.

    CAS  PubMed  Google Scholar 

  72. Bao L, Sachs F, Dahl G. Connexins are mechanosensitive. Am J Physiol Cell Physiol. 2004;287:89–95.

    Article  CAS  PubMed  Google Scholar 

  73. De Vuyst E, Decrock E, Cabooter L, Dubyak GR, Naus CC, Evans WH and Leybaert L. Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J. 2006;25:34–44.

    Article  PubMed  Google Scholar 

  74. Paul DL, Ebihara L, Takemoto LJ, Swenson KI, Goodenough DA. Connexin46, a novel lens gap junction protein, induces voltage-dependent currents in nonjunctional plasma membrane of Xenopus oocytes. J Cell Biol. 1991;115:1077–89.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Drs. Nirupa Chaudhari, Silviu Locovei, Ken Muller, and William Silverman for helpful discussions and reading the manuscript. Work in the lab of G.D. on pannexin channels is supported by National Institutes of Health (NIH) grant GM48610.

Note added in proof: A reagent known to attenuate nucleotide release has been recently reported to inhibit pannexin but not connexin channels; Silverman W, Locovei S, Dahl GP. Proenecid, a gout remedy, inhibits pannexin 1 channels. Am J Physiol. 2008;295:C761-7.

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  1. Department of Physiology and Biophysics, University of Miami School of Medicine, PO Box 016430, Miami, FL 33101, US

    Gerhard Dahl

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Dahl, G., Harris, A.L. (2009). Pannexins or Connexins?. In: Harris, A.L., Locke, D. (eds) Connexins. Humana Press. https://doi.org/10.1007/978-1-59745-489-6_12

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