Cx43 phosphorylation on S279/282 and intercellular communication are regulated by IP3/IP3 receptor signaling

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• 作者：Man Kang (1)
  Na Lin (2)
  Chen Li (1) (4)
  Qingli Meng (1)
  Yuanyuan Zheng (1)
  Xinxin Yan (1)
  Jianxin Deng (2)
  Yang Ou (2)
  Chao Zhang (1)
  Junqi He (3)
  Dali Luo (1)
  
  1. Department of Pharmacology ; Capital Medical University ; Beijing ; 100069 ; China
  2. Institute of Molecular Medicine ; Peking University ; Beijing ; 100871 ; China
  4. Present address ; National Institute for Radiological Protection ; China CDC ; Beijing ; 100088 ; China
  3. Department of Biochemistry ; Capital Medical University ; Beijing ; 100069 ; China
  
• 关键词：Inositol 1 ; 4 ; 5 ; trisphosphate receptor ; Gap junction ; Connexin 43 ; Serine 279/282 phosphorylation ; Intercellular communication ; Ventricular myocyte
• 刊名：Cell Communication and Signaling
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：12
• 期：1
• 全文大小：1,956 KB
• 参考文献：1. Giepmans, BN (2004) Gap junctions and connexin-interacting proteins. Cardiovasc Res 62: pp. 233-245 CrossRef
  2. Goodenough, DA, Paul, DL (2003) Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4: pp. 285-294 CrossRef
  3. Roell, W, Lewalter, T, Sasse, P, Tallinin, YN, Choi, BR, Breitbach, M, Doran, R, Becher, UM, Hwang, SM, Bostani, T, Maltzahn, J, Hofmann, A, Reining, S, Eiberger, B, Gabris, B, Pfeifer, A, Welz, A, Willecke, K, Salama, G, Schrickel, JW, Kotlikoff, MI, Fleischmann, BK (2007) Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450: pp. 819-824 CrossRef
  4. Woodcock, EA, Reyes, N, Jacobsen, AN, Du, XJ (1999) Inhibition of inositol (1,4,5)trisphosphate generation by endothelin-1 during postischemic reperfusion: A novel antiarrhythmic mechanism. Circ 99: pp. 823-828 CrossRef
  5. Dhein, S (2006) Cardiac ischemia and uncoupling: gap junctions in ischemia and infarction. Adv Cardiol 42: pp. 198-212 CrossRef
  6. Laird, DW (2006) Life cycle of connexins in health and disease. Biochem J 394: pp. 527-543 CrossRef
  7. Wei, CJ, Xu, X, Lo, CW (2004) Connexins and cell signaling in development and disease. Annu Rev Cell Dev Biol 20: pp. 811-838 CrossRef
  8. Dobrowolski, R, Willecke, K (2009) Connexin-caused genetic diseases and corresponding mouse models. Antioxid Redox Signal 11: pp. 283-295 CrossRef
  9. Yeager, M (1998) Structure of cardiac gap junction intercellular channels. J Struct Biol 121: pp. 231-245 CrossRef
  10. Heyman, NS, Lampe, PD, Janis Burt, M (2006) Phosphorylation selectivity of connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res 98: pp. 1498-1505 CrossRef
  11. Warn-Cramer, BJ, Cottrell, GT, Burt, JM, Lau, AF (1998) Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase. J Biol Chem 273: pp. 9188-9196 CrossRef
  12. Solan, JL, Lampe, PD (2008) Connexin 43 in LA-25 cells with active v-src is phosphorylated on Y247, Y265, S262, S279/282, and S368 via multiple signaling pathways. Cell Commun Adhes 15: pp. 75-84 CrossRef
  13. Bruce, AF, Rothery, S, Dupont, E, Severs, NJ (2008) Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1. Cardiovasc Res 77: pp. 757-765 CrossRef
  14. Lin, R, Warn-Cramer, BJ, Kurata, WE, Lau, AF (2001) V-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication. J Cell Biol 154: pp. 815-827 CrossRef
  15. Grosely, R, Kopanic, JL, Nabors, S, Kieken, F, Spagnol, G, Al-Mugotir, M, Zach, S, Sorgen, PL (2013) Effects of phosphorylation on the structure and backbone dynamics of the intrinsically disordered Connexin43 carboxyl-terminal domain. J Biol Chem 288: pp. 24857-24870 CrossRef
  16. Signore, S, Sorrentino, A, Ferreira-Martins, J, Kannappan, R, Shafaie, M, Ben, FD, Isobe, K, Arranto, C, Wybieralska, E, Webster, A, Sanada, F, Og贸rek, B, Zheng, H, Liu, X, Monte, F, D鈥橝lessandro, DA, Wunimenghe, O, Michler, RE, Hosoda, T, Goichberg, P, Leri, A, Kajstura, J, Anversa, P, Rota, M (2013) Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circ 128: pp. 1286-1297 CrossRef
  17. Wu, X, Zhang, T, Bossuyt, J, Li, X, McKinsey, TA, Dedman, JR, Olson, EN, Chen, J, Brown, JH, Bers, DM (2006) Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling. J Clin Invest 116: pp. 675-682 CrossRef
  18. Luo, D, Yang, D, Lan, X, Li, K, Li, X, Chen, J, Zhang, Y, Xiao, RP, Han, Q, Cheng, H (2008) Nuclear Ca2+ sparks and waves mediated by inositol 1,4,5-trisphosphate receptors in neonatal rat cardiomyocytes. Cell Calcium 43: pp. 165-174 CrossRef
  19. Ju, YK, Liu, J, Lee, BH, Lai, D, Woodcock, EA, Lei, M, Cannell, MB, Allen, DG (2011) Distribution and functional role of inositol 1,4,5-trisphosphate receptors in mouse sinoatrial node. Circ Res 109: pp. 848-857 CrossRef
  20. Kijima, Y, Saito, A, Jetton, TL, Magnuson, MA, Fleischer, S (1993) Different intracellular localization of inositol 1,4,5-trisphosphate and ryanodine receptors in cardiomyocytes. J Biol Chem 268: pp. 3499-3506
  21. Isakson, BE (2008) Localized expression of an Ins (1,4,5)P3 receptor at the myoendothelial junction selectively regulates heterocellular Ca2+ communication. J Cell Sci 121: pp. 3664-3673 CrossRef
  22. Toews, JC, Schram, V, Weerth, SH, Mignery, GA, Russell, JT (2007) Signaling protein in the axoglial apparatus of sciatic nerve node of Ranvier. Glia 55: pp. 202-213 CrossRef
  23. Harrison, SN, Autelitano, DJ, Wang, BH, Milano, C, Du, XJ, Woodcock, EA (1998) Reduced reperfusion-induced Ins(1,4,5)P3 generation and arrhythmias in hearts expressing constitutively active alpha1B-adrenergic receptors. Circ Res 83: pp. 1232-1240 CrossRef
  24. Turner, MS, Haywood, GA, Andreka, P, You, L, Martin, PE, Evans, WH, Webster, KA, Bishopric, NH (2004) Reversible connexin 43 dephosphorylation during hypoxia and reoxygenation is linked to cellular ATP levels. Circ Res 95: pp. 726-733 CrossRef
  25. Clair, C, Chalumeau, C, Tordjmann, T, Poggioli, J, Erneux, C, Dupont, G, Combettes, L (2001) Investigation of the roles of Ca2+ and InsP3 diffusion in the coordination of Ca2+ signals between connected hepatocytes. J Cell Sci 114: pp. 1999-2007
  26. Pinheiro, AR, Paramos-de-Carvalho, D, Certal, M, Costa, C, Magalh茫es-Cardoso, MT, Ferreirinha, F, Costa, MA, Correia-de-S谩, P (2013) Bradykinin-induced Ca2+ signaling in human subcutaneous fibroblasts involves ATP release via hemichannels leading to P2Y12 receptors activation. Cell Commun Signal 11: pp. 70 CrossRef
  27. Kansui, Y, Garland, CJ, Dora, KA (2008) Enhanced spontaneous Ca2+ events in endothelial cells reflect signalling through myoendothelial gap junctions in pressurized mesenteric arteries. Cell Calcium 44: pp. 135-146 CrossRef
  28. Wang, X, Veruki, ML, Bukoreshtliev, NV, Hartveit, E, Gerdes, HH (2010) Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels. Proc Natl Acad Sci U S A 107: pp. 17194-17199 CrossRef
  29. Kizana, E, Chang, CY, Cingolani, E, Ramirez-Correa, GA, Sekar, RB, Abraham, MR, Ginn, SL, Tung, L, Alexander, IE, Marban, E (2007) Gene transfer of connexin43 mutants attenuates coupling in cardiomyocytes, novel basis for modulation of cardiac conduction by gene therapy. Circ Res 100: pp. 1597-1604 CrossRef
  30. Wade, MH, Trosko, JE, Schindler, M (1986) A fluorescence photobleaching assay of gap junction-mediated communication between human cells. Science 232: pp. 525-528 CrossRef
  31. Santiquet, NW, Develle, Y, Laroche, A, Robert, C, Richard, FJ (2012) Regulation of gap-junctional communication between cumulus cells during in vitro maturation in swine, a gap-FRAP study. Biol Reproduction 87: pp. 1-8 CrossRef
  32. Matsushita, S, Kurihara, H, Watanabe, M, Okada, T, Sakai, T, Amano, A (2006) Alterations of phosphorylation state of connexin 43 during hypoxia and reoxygenation are associated with cardiac function. J Histochem Cytochem 54: pp. 343-353 CrossRef
  33. Evans, WH, Leybaert, L (2007) Mimetic peptides as blockers of connexin channel-facilitated intercellular communication. Cell Commun Adhes 14: pp. 265-273 CrossRef
  34. Kwak, BR, Jongsma, HJ (1999) Selective inhibition of gap junction channel activity by synthetic peptides. J Physiol 516: pp. 679-685 CrossRef
  35. Doble, BW, Chen, Y, Bosc, DG, Litchfield, DW, Kardami, E (1996) Fibroblast growth factor-2 decreases metabolic coupling and stimulates phosphorylation as well as masking of connexin43 epitopes in cardiac myocytes. Circ Res 79: pp. 647-658 CrossRef
  36. Opsahl, H, Rivedal, E (2000) Quantitative determination of gap junction intercellular communication by scrape loading and image analysis. Cell Adhes Commun 7: pp. 367-375 CrossRef
  37. Dyce, PW, Norris, RP, Lampe, PD, Kidder, GM (2012) Phosphorylation of serine residues in the C-terminal cytoplasmic tail of connexin43 regulates proliferation of ovarian granulosa cells. J Membr Biol 245: pp. 291-301 CrossRef
  38. Li, C, Meng, Q, Yu, X, Jing, X, Xu, P, Luo, D (2012) Regulatory effect of connexin 43 on basal Ca2+ signaling in rat ventricular myocytes. PLoS One 7: pp. 361-365
  39. Harks, EG, Camina, JP, Peters, PH, Ypey, DL, Scheenen, WJ, Zoelen, EJ, Theuvenet, AP (2003) Besides affecting intracellular calcium signaling, 2-APB reversibly blocks gap junctional coupling in confluent monolayers, thereby allowing measurement of single-cell membrane currents in undissociated cells. FASEB J 17: pp. 941-943
  40. Chen, J, Pan, L, Wei, Z, Zhao, Y, Zhang, M (2008) Domain-swapped dimerization of ZO-1 PDZ2 generates specific and regulatory connexin43-binding sites. EMBO J 27: pp. 2113-2123 CrossRef
  41. Solan, JL, Marquez-Rosado, L, Sorgen, PL, Thornton, PJ, Gafken, PR, Lampe, PD (2007) Phosphorylation of Cx43 at S365 is a gatekeeper event that changes the structure of Cx43 and prevents downregulation by PKC. J Cell Biol 179: pp. 1301-1309 CrossRef
  42. Johnson, KE, Mitra, S, Katoch, P, Kelsey, LS, Johnson, KR, Mehta, PP (2013) Phosphorylation on Ser-279 and Ser-282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells. MBoC 24: pp. 715-733
  43. Kucera, JP, Rohr, S, Rudy, Y (2002) Localization of sodium channels in intercalated disks modulates cardiac conduction. Circ Res 91: pp. 1176-1182 CrossRef
  44. Jansen, JA, Noorman, M, Musa, H, Stein, M, Jong, S, Nagel, R, Hund, TJ, Mohler, PJ, Vos, MA, Veen, TA, Bakker, JM, Delmar, M, Rijen, HV (2012) Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. Heart Rhythm 9: pp. 600-607 CrossRef
  45. Rhett, JM, Ongstad, EL, Jourdan, J, Gourdie, RG (2012) Cx43 associates with Na(v)1.5 in the cardiomyocyte perinexus. J Membr Biol 245: pp. 411-422 CrossRef
  
• 刊物主题：Cell Biology; Protein-Ligand Interactions; Receptors; Cytokines and Growth Factors;
• 出版者：BioMed Central
• ISSN：1478-811X

文摘

Background Inositol 1,4,5-trisphosphate receptor (IP3R) plays a pivotal role in the Ca2+ release process in a variety of cell types. Additionally, IP3R is distributed in ventricular intercalated discs, but its function(s) in this particular site remains unknown. Connexin (Cx43), the predominant gap junction (GJ) protein in ventricular myocardium, is linked to several signaling pathways that regulate Cx43 properties by (de)phosphorylation on multiple residues. Here, we investigated the regulatory role of IP3R in cell-cell communication and the mechanism(s) underlying this effect. Results In neonatal rat and adult mouse ventricular myocytes IP3R co-localized and co-immunoprecipitated with Cx43 in GJ plaques detected by immunostaining and western blot assays. Blocking IP3R with antagonists or silencing pan-IP3R expression with shRNA hindered the 6-carboxyfluorescein (6-CFDA) diffusion through GJs and desynchronized Ca2+ transients among confluent neonatal myocytes in culture, whereas stimulation of IP3R with IP3 ester or ATP exerted the opposite effect. Likewise, 6-CFDA propagation through GJs was modulated by IP3R activation or inhibition in cell pairs of isolated adult cardiomyocytes. Furthermore, IP3R activation or IP3R suppression promoted or suppressed, respectively, Cx43 phosphorylation on S279/282. Site-directed mutagenesis indicated that expression of a mutant Cx43-S282A (alanine) inhibited S279/282 phosphorylation and GJ permeability, while the S279A mutant showed the opposite effect in ventricular myocytes. Expression of these mutants in HEK293 cells revealed that cells with a dual S279/282 mutation failed to express exogenous Cx43, whereas cells with a single S279 or S282 mutation displayed Cx43 overexpression with increased phosphorylation of S279/282 and promotion of intercellular communication. Conclusions These results demonstrated, for the first time, that IP3R physically interacts with Cx43 and participates in the regulation of Cx43 phosphorylation on S279/282, thereby affecting GJ intercellular communication in ventricular myocytes.