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Increasing Gap Junctional Coupling: A Tool for Dissecting the Role of Gap Junctions

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Abstract

Much of our current knowledge about the physiological and pathophysiological role of gap junctions is based on experiments where coupling has been reduced by either chemical agents or genetic modification. This has brought evidence that gap junctions are important in many physiological processes. In a number of cases, gap junctions have been implicated in the initiation and progress of disease, and experimental uncoupling has been used to investigate the exact role of coupling. The inverse approach, i.e., to increase coupling, has become possible in recent years and represents a new way of testing the role of gap junctions. The aim of this review is to summarize the current knowledge obtained with agents that selectively increase gap junctional intercellular coupling. Two approaches will be reviewed: increasing coupling by the use of antiarrhythmic peptide and its synthetic analogs and by interfering with the gating of gap junctional channels.

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References

  • Ai Z, Fischer A, Spray DC, Brown AM, Fishman GI (2000) Wnt-1 regulation of connexin43 in cardiac myocytes. J Clin Invest 105:161–171

    PubMed  CAS  Google Scholar 

  • Anyukhovsky EP, Sosunov EA, Plotnikov A, Gainullin RZ, Jhang JS, Marboe CC, Rosen MR (2002) Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res 54:462–469

    Article  PubMed  CAS  Google Scholar 

  • Aonuma S, Kohama Y, Akai K, Komiyama Y, Nakajima S, Wakabayashi M, Makino T (1980) Studies on heart. XIX. Isolation of an atrial peptide that improves the rhythmicity of cultured myocardial cell clusters. Chem Pharm Bull (Tokyo) 28:3332–3339

    CAS  Google Scholar 

  • Aonuma S, Kohama Y, Makino T, Fujisawa Y (1982) Studies of heart. XXI. Amino acid sequence of antiarrhythmic peptide (AAP) isolated from atria. J Pharmacobiodyn 5:40–48

    PubMed  CAS  Google Scholar 

  • Argentieri T, Cantor E, Wiggins JR (1989) Antiarrhythmic peptide has no direct cardiac actions. Experientia 45:737–738

    Article  PubMed  CAS  Google Scholar 

  • Axelsen LN, Stahlhut M, Mohammed S, Larsen BD, Nielsen MS, Holstein-Rathlou NH, Andersen S, Jensen ON, Hennan JK, Kjolbye AL (2006) Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol 40:790–798

    Article  PubMed  CAS  Google Scholar 

  • Azarnia R, Loewenstein WR (1984) Intercellular communication and the control of growth: XI. Alteration of junctional permeability by the src gene in a revertant cell with normal cytoskeleton. J Membr Biol 82:207–212

    Article  PubMed  CAS  Google Scholar 

  • Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, Saffitz JE (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    PubMed  CAS  Google Scholar 

  • Bernus O, Zemlin CW, Zaritsky RM, Mironov SF, Pertsov AM (2005) Alternating conduction in the ischaemic border zone as precursor of reentrant arrhythmias: a simulation study. Europace 7(Suppl 2):93–104

    Article  PubMed  Google Scholar 

  • Blanc EM, Bruce-Keller AJ, Mattson MP (1998) Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death. J Neurochem 70:958–970

    Article  PubMed  CAS  Google Scholar 

  • Bukauskas FF, Peracchia C (1997) Two distinct gating mechanisms in gap junction channels: CO2-sensitive and voltage-sensitive. Biophys J 72:2137–2142

    PubMed  CAS  Google Scholar 

  • Cabo C, Boyden PA (2006) Heterogeneous gap junction remodeling stabilizes reentrant circuits in the epicardial border zone of the healing canine infarct: a computational study. Am J Physiol 291:H2606-H2616

    CAS  Google Scholar 

  • Calero G, Kanemitsu M, Taffet SM, Lau AF, Delmar M (1998) A 17mer peptide interferes with acidification-induced uncoupling of connexin43. Circ Res 82:929–935

    PubMed  CAS  Google Scholar 

  • Cherian PP, Cheng B, Gu S, Sprague E, Bonewald LF, Jiang JX (2003) Effects of mechanical strain on the function of gap junctions in osteocytes are mediated through the prostaglandin EP2 receptor. J Biol Chem 278:43146–43156

    Article  PubMed  CAS  Google Scholar 

  • Chung DJ, Castro CH, Watkins M, Stains JP, Chung MY, Szejnfeld VL, Willecke K, Theis M, Civitelli R (2006) Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43. J Cell Sci 119:4187–4198

    Article  PubMed  CAS  Google Scholar 

  • Civitelli R, Beyer EC, Warlow PM, Robertson AJ, Geist ST, Steinberg TH (1993) Connexin43 mediates direct intercellular communication in human osteoblastic cell networks. J Clin Invest 91:1888–1896

    PubMed  CAS  Google Scholar 

  • Civitelli R, Ziambaras K, Warlow PM, Lecanda F, Nelson T, Harley J, Atal N, Beyer EC, Steinberg TH (1998) Regulation of connexin43 expression and function by prostaglandin E2 (PGE2) and parathyroid hormone (PTH) in osteoblastic cells. J Cell Biochem 68:8–21

    Article  PubMed  CAS  Google Scholar 

  • Clarke TC, Thomas D, Petersen JS, Evans WH, Martin PE (2006) The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43. Br J Pharmacol 147:486–495

    Article  PubMed  CAS  Google Scholar 

  • Dhein S, Hammerath SB (2001) Aspects of the intercellular communication in aged hearts: effects of the gap junction uncoupler palmitoleic acid. Naunyn Schmiedebergs Arch Pharmacol 364:397–408

    Article  PubMed  CAS  Google Scholar 

  • Dhein S, Larsen BD, Petersen JS, Mohr FW (2003) Effects of the new antiarrhythmic peptide ZP123 on epicardial activation and repolarization pattern. Cell Commun Adhes 10:371–378

    Article  PubMed  CAS  Google Scholar 

  • Dhein S, Manicone N, Müller A, Gerwin R, Ziskoven U, Irankhani A, Minke C, Klaus W (1994) A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study. Naunyn Schmiedebergs Arch Pharmacol 350:174–184

    Article  PubMed  CAS  Google Scholar 

  • Dikshit M, Srivastava R, Kundu B, Mathur KB, Kar K (1988) Antiarrhythmic and antithrombotic effect of antiarrhythmic peptide and its synthetic analogues. Indian J Exp Biol 26:874–876

    PubMed  CAS  Google Scholar 

  • Dorian P, Zhong J, So PSS, Debicki D, Hennan JK (2005) Increasing gap junction conductance with ZP123 improves defibrillation success in experimental cardiac arrest [abstract]. Circulation 112:II-115

    Google Scholar 

  • Duffy HS, Delmar M, Spray DC (2002a) Formation of the gap junction nexus: binding partners for connexins. J Physiol Paris 96:243–249

    Google Scholar 

  • Duffy HS, Sorgen PL, Girvin ME, O’Donnell P, Coombs W, Taffet SM, Delmar M, Spray DC (2002b) pH-dependent intramolecular binding and structure involving Cx43 cytoplasmic domains. J Biol Chem 277:36706–36714

  • Ek-Vitorin JF, Calero G, Morley GE, Coombs W, Taffet SM, Delmar M (1996) pH regulation of connexin43: molecular analysis of the gating particle. Biophys J 71:1273–1284

    PubMed  CAS  Google Scholar 

  • Eloff BC, Gilat E, Wan X, Rosenbaum DS (2003) Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy. Circulation 108:3157–3163

    Article  PubMed  CAS  Google Scholar 

  • Eloff BC, Lerner DL, Yamada KA, Schuessler RB, Saffitz JE, Rosenbaum DS (2001) High resolution optical mapping reveals conduction slowing in connexin43 deficient mice. Cardiovasc Res 51:681–690

    Article  PubMed  CAS  Google Scholar 

  • Evans WH, Boitano S (2001) Connexin mimetic peptides: specific inhibitors of gap-junctional intercellular communication. Biochem Soc Trans 29:606–612

    Article  PubMed  Google Scholar 

  • Garcia-Dorado D, Inserte J, Ruiz-Meana M, Gonzalez MA, Solares J, Julia M, Barrabes JA, Soler-Soler J (1997) Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. Circulation 96:3579–3586

    PubMed  CAS  Google Scholar 

  • Garcia-Dorado D, Rodriguez-Sinovas A, Ruiz-Meana M (2004) Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovasc Res 61:386–401

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Dorado D, Theroux P, Duran JM, Solares J, Alonso J, Sanz E, Munoz R, Elizaga J, Botas J, Fernandez-Aviles F (1992) Selective inhibition of the contractile apparatus. A new approach to modification of infarct size, infarct composition, and infarct geometry during coronary artery occlusion and reperfusion. Circulation 85:1160–1174

    PubMed  CAS  Google Scholar 

  • Gluhak-Heinrich J, Gu S, Pavlin D, Jiang JX (2006) Mechanical loading stimulates expression of connexin 43 in alveolar bone cells in the tooth movement model. Cell Commun Adhes 13:115–125

    Article  PubMed  CAS  Google Scholar 

  • Guerra JM, Everett TH, Lee KW, Wilson E, Olgin JE (2006) Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation 114:110–118

    Article  PubMed  CAS  Google Scholar 

  • Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE (1997) Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J Clin Invest 99:1991–1998

    Article  PubMed  CAS  Google Scholar 

  • Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339

    PubMed  CAS  Google Scholar 

  • Gysembergh A, Kloner RA, Przyklenk K (2001) Pretreatment with the gap junction uncoupler heptanol does not limit infarct size in rabbit heart. Cardiovasc Pathol 10:13–17

    Article  PubMed  CAS  Google Scholar 

  • Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke K (1999) Conduction disturbances and increased atrial vulnerability in connexin40-deficient mice analyzed by transesophageal stimulation. Circulation 99:1508–1515

    PubMed  CAS  Google Scholar 

  • Haugan K, Lam HR, Knudsen CB, Petersen JS (2004) Atrial fibrillation in rats induced by rapid transesophageal atrial pacing during brief episodes of asphyxia: a new in vivo model. J Cardiovasc Pharmacol 44:125–135

    Article  PubMed  CAS  Google Scholar 

  • Haugan K, Marcussen N, Kjolbye AL, Nielsen MS, Hennan JK, Petersen JS (2006a) Treatment with the gap junction modifier rotigaptide (ZP123) reduces infarct size in rats with chronic myocardial infarction. J Cardiovasc Pharmacol 47:236–242

    Google Scholar 

  • Haugan K, Miyamoto T, Takeishi Y, Kubota I, Nakayama J, Shimojo H, Hirose M (2006b) Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria. Basic Clin Pharmacol Toxicol 99:71–79

    Google Scholar 

  • Haugan K, Olsen KB, Hartvig L, Petersen JS, Holstein-Rathlou NH, Hennan JK, Nielsen MS (2005) The antiarrhythmic peptide analog ZP123 prevents atrial conduction slowing during metabolic stress. J Cardiovasc Electrophysiol 16:537–545

    Article  PubMed  Google Scholar 

  • Hayashi H, Wang C, Miyauchi Y, Omichi C, Pak HN, Zhou S, Ohara T, Mandel WJ, Lin SF, Fishbein MC, Chen PS, Karagueuzian HS (2002) Aging-related increase to inducible atrial fibrillation in the rat model. J Cardiovasc Electrophysiol 13:801–808

    Article  PubMed  Google Scholar 

  • Hennan JK, Swillo RE, Morgan GA, Keith JC Jr, Schaub RG, Smith RP, Feldman HS, Haugan K, Kantrowitz J, Wang PJ, bu-Qare A, Butera J, Larsen BD, Crandall DL (2006) Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs. J Pharmacol Exp Ther 317:236–243

    Article  PubMed  CAS  Google Scholar 

  • Huelsing DJ, Spitzer KW, Pollard AE (2000) Electrotonic suppression of early afterdepolarizations in isolated rabbit Purkinje myocytes. Am J Physiol 279:H250-H259

    CAS  Google Scholar 

  • Ilvesaro J, Vaananen K, Tuukkanen J (2000) Bone-resorbing osteoclasts contain gap-junctional connexin-43. J Bone Miner Res 15:919–926

    Article  PubMed  CAS  Google Scholar 

  • Iovine MK, Higgins EP, Hindes A, Coblitz B, Johnson SL (2005) Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins. Dev Biol 278:208–219

    Article  PubMed  CAS  Google Scholar 

  • Jain SK, Schuessler RB, Saffitz JE (2003) Mechanisms of delayed electrical uncoupling induced by ischemic preconditioning. Circ Res 92:1138–1144

    Article  PubMed  CAS  Google Scholar 

  • Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C (1993) The incidence and size of gap junctions between the bone cells in rat calvaria. Anat Embryol (Berl) 187:343–352

    CAS  Google Scholar 

  • Jørgensen NR, Teilmann SC, Henriksen Z, Meier E, Hansen SS, Jensen JE, Sørensen OH, Petersen JS (2005) The antiarrhythmic peptide analog rotigaptide (ZP123) stimulates gap junction intercellular communication in human osteoblasts and prevents decrease in femoral trabecular bone strength in ovariectomized rats. Endocrinology 146:4745–4754

    Article  PubMed  CAS  Google Scholar 

  • Kagiyama Y, Hill JL, Gettes LS (1982) Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in guinea pig ventricular muscle. Circ Res 51:614–623

    PubMed  CAS  Google Scholar 

  • Kanno S, Kovacs A, Yamada KA, Saffitz JE (2003) Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice. J Am Coll Cardiol 41:681–686

    Article  PubMed  CAS  Google Scholar 

  • Kanno Y, Loewenstein WR (1964) Low-resistance coupling between gland cells. Some observations on intercellular contact membranes and intercellular space. Nature 201:194–195

    Article  PubMed  CAS  Google Scholar 

  • Keevil VL, Huang CL, Chau PL, Sayeed RA, Vandenberg JI (2000) The effect of heptanol on the electrical and contractile function of the isolated, perfused rabbit heart. Pfluegers Arch 440:275–282

    CAS  Google Scholar 

  • King TJ, Bertram JS (2005) Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta 1719:146–160

    Article  PubMed  CAS  Google Scholar 

  • Kirchhoff S, Kim JS, Hagendorff A, Thonnissen E, Kruger O, Lamers WH, Willecke K (2000) Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice. Circ Res 87:399–405

    PubMed  CAS  Google Scholar 

  • Kitamura H, Ohnishi Y, Yoshida A, Okajima K, Azumi H, Ishida A, Galeano EJ, Kubo S, Hayashi Y, Itoh H, Yokoyama M (2002) Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J Cardiovasc Electrophysiol 13:865–870

    Article  PubMed  Google Scholar 

  • Kjølbye AL, Knudsen CB, Jepsen T, Larsen BD, Petersen JS (2003) Pharmacological characterization of the new stable antiarrhythmic peptide analog Ac-d-Tyr-d-Pro-d-Hyp-Gly-d-Ala-Gly-NH2 (ZP123): in vivo and in vitro studies. J Pharmacol Exp Ther 306:1191–1199

    Article  PubMed  CAS  Google Scholar 

  • Kohama Y, Kuwahara S, Yamamoto K, Okabe M, Mimura T, Fukaya C, Watanabe M, Yokoyama K (1988) Effect of N-3-(4-hydroxyphenyl)propionyl Pro-Pro-Gly-Ala-Gly on calcium-induced arrhythmias. Chem Pharm Bull (Tokyo) 36:4597–4599

    CAS  Google Scholar 

  • Kohama Y, Okimoto N, Mimura T, Fukaya C, Watanabe M, Yokoyama K (1987) A new antiarrhythmic peptide, N-3-(4-hydroxyphenyl)propionyl Pro-Hyp- Gly-Ala-Gly. Chem Pharm Bull (Tokyo) 35:3928–3930

    CAS  Google Scholar 

  • Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J (2002) Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 54:361–379

    Article  PubMed  CAS  Google Scholar 

  • Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394:527–543

    Article  PubMed  CAS  Google Scholar 

  • Lampe PD, Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol 36:1171–1186

    Article  PubMed  CAS  Google Scholar 

  • Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R (2000) Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 151:931–944

    Article  PubMed  CAS  Google Scholar 

  • Lerner DL, Yamada KA, Schuessler RB, Saffitz JE (2000) Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101:547–552

    PubMed  CAS  Google Scholar 

  • Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95

    PubMed  CAS  Google Scholar 

  • Li G, Whittaker P, Yao M, Kloner RA, Przyklenk K (2002) The gap junction uncoupler heptanol abrogates infarct size reduction with preconditioning in mouse hearts. Cardiovasc Pathol 11:158–165

    Article  PubMed  CAS  Google Scholar 

  • Loewenstein WR, Kanno Y (1966) Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature 209:1248–1249

    Article  PubMed  CAS  Google Scholar 

  • Matchkov VV, Rahman A, Peng H, Nilsson H, Aalkjaer C (2004) Junctional and nonjunctional effects of heptanol and glycyrrhetinic acid derivates in rat mesenteric small arteries. Br J Pharmacol 142:961–972

    Article  PubMed  CAS  Google Scholar 

  • Moreno AP, Chanson M, Elenes S, Anumonwo J, Scerri I, Gu H, Taffet SM, Delmar M (2002) Role of the carboxyl terminal of connexin43 in transjunctional fast voltage gating. Circ Res 90:450–457

    Article  PubMed  CAS  Google Scholar 

  • Moreno AP, Rook MB, Fishman GI, Spray DC (1994a) Gap junction channels: distinct voltage-sensitive and -insensitive conductance states. Biophys J 67:113–119

    Google Scholar 

  • Moreno AP, Saez JC, Fishman GI, Spray DC (1994b) Human connexin43 gap junction channels. Regulation of unitary conductances by phosphorylation. Circ Res 74:1050–1057

    Google Scholar 

  • Müller A, Gottwald M, Tudyka T, Linke W, Klaus W, Dhein S (1997a) Increase in gap junction conductance by an antiarrhythmic peptide. Eur J Pharmacol 327:65–72

    Google Scholar 

  • Müller A, Schaefer T, Linke W, Tudyka T, Gottwald M, Klaus W, Dhein S (1997b) Actions of the antiarrhythmic peptide AAP10 on intercellular coupling. Naunyn Schmiedebergs Arch Pharmacol 356:76–82

    Google Scholar 

  • Nao T, Ohkusa T, Hisamatsu Y, Inoue N, Matsumoto T, Yamada J, Shimizu A, Yoshiga Y, Yamagata T, Kobayashi S, Yano M, Hamano K, Matsuzaki M (2003) Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol 91:678–683

    Article  PubMed  CAS  Google Scholar 

  • Nattel S (2004) The clinical relevance of connexin gating: how to control communication in the heart. Heart Rythm 1:234

    Article  Google Scholar 

  • Nelson WL, Makielski JC (1991) Block of sodium current by heptanol in voltage-clamped canine cardiac Purkinje cells. Circ Res 68:977–983

    PubMed  CAS  Google Scholar 

  • Ohara T, Qu Z, Lee MH, Ohara K, Omichi C, Mandel WJ, Chen PS, Karagueuzian HS (2002) Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol. Am J Physiol 283:H1116-H1122

    CAS  Google Scholar 

  • Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW (2003) Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408–418

    Article  PubMed  CAS  Google Scholar 

  • Peters NS, Coromilas J, Severs NJ, Wit AL (1997) Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 95:988–996

    PubMed  CAS  Google Scholar 

  • Qi X, Varma P, Newman D, Dorian P (2001) Gap junction blockers decrease defibrillation thresholds without changes in ventricular refractoriness in isolated rabbit hearts. Circulation 104:1544–1549

    PubMed  CAS  Google Scholar 

  • Quan W, Rudy Y (1990) Unidirectional block and reentry of cardiac excitation: a model study. Circ Res 66:367–382

    PubMed  CAS  Google Scholar 

  • Ren Y, Zhang CT, Wu J, Ruan YF, Pu J, He L, Wu W, Chen BD, Wang WG, Wang L (2006) The effects of antiarrhythmic peptide AAP10 on ventricular arrhythmias in rabbits with healed myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi 34:825–828

    PubMed  CAS  Google Scholar 

  • Robinson JA, Chatterjee-Kishore M, Yaworsky PJ, Cullen DM, Zhao W, Li C, Kharode Y, Sauter L, Babij P, Brown EL, Hill AA, Akhter MP, Johnson ML, Recker RR, Komm BS, Bex FJ (2006) Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem 281:31720–31728

    Article  PubMed  CAS  Google Scholar 

  • Rohr S, Kucera JP, Kleber AG (1998) Slow conduction in cardiac tissue. I: Effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circ Res 83:781–794

    PubMed  CAS  Google Scholar 

  • Ronsberg MA, Saunders TK, Chan PS, Cervoni P (1986) The antiarrhythmic effect of antiarrhythmic peptide (Gly-Pro-4Hyp-Gly-Ala-Gly) and its analog on chemically-induced arrhythmias in mice. Med Sci 14:350–351

    CAS  Google Scholar 

  • Saltman AE, Aksehirli TO, Valiunas V, Gaudette GR, Matsuyama N, Brink P, Krukenkamp IB (2002) Gap junction uncoupling protects the heart against ischemia. J Thorac Cardiovasc Surg 124:371–376

    Article  PubMed  CAS  Google Scholar 

  • Schiller PC, Mehta PP, Roos BA, Howard GA (1992) Hormonal regulation of intercellular communication: parathyroid hormone increases connexin 43 gene expression and gap-junctional communication in osteoblastic cells. Mol Endocrinol 6:1433–1440

    Article  PubMed  CAS  Google Scholar 

  • Schirrmacher K, Schmitz I, Winterhager E, Traub O, Brummer F, Jones D, Bingmann D (1992) Characterization of gap junctions between osteoblast-like cells in culture. Calcif Tissue Int 51:285–290

    Article  PubMed  CAS  Google Scholar 

  • Schlack W, Preckel B, Barthel H, Obal D, Thamer V (1997) Halothane reduces reperfusion injury after regional ischaemia in the rabbit heart in vivo. Br J Anaesth 79:88–96

    PubMed  CAS  Google Scholar 

  • Schlack W, Uebing A, Schafer M, Bier F, Schafer S, Piper HM, Thamer V (1994) Regional contractile blockade at the onset of reperfusion reduces infarct size in the dog heart. Pfluegers Arch 428:134–141

    Article  CAS  Google Scholar 

  • Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G (2002) No ischemic preconditioning in heterozygous connexin43-deficient mice. Am J Physiol 283:H1740-H1742

    CAS  Google Scholar 

  • Sebbag L, Verbinski SG, Reimer KA, Jennings RB (2003) Protection of ischemic myocardium in dogs using intracoronary 2,3-butanedione monoxime (BDM). J Mol Cell Cardiol 35:165–176

    Article  PubMed  CAS  Google Scholar 

  • Seki A, Duffy HS, Coombs W, Spray DC, Taffet SM, Delmar M (2004) Modifications in the biophysical properties of connexin43 channels by a peptide of the cytoplasmic loop region. Circ Res 95:e22–e28

    Article  PubMed  CAS  Google Scholar 

  • Shibayama J, Lewandowski R, Kieken F, Coombs W, Shah S, Sorgen PL, Taffet SM, Delmar M (2006) Identification of a novel peptide that interferes with the chemical regulation of connexin43. Circ Res 98:1365–1372

    Article  PubMed  CAS  Google Scholar 

  • Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S (2007) Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation 115:310–318

    Article  PubMed  CAS  Google Scholar 

  • Sims JJ, Schoff KL, Loeb JM, Wiegert NA (2003) Regional gap junction inhibition increases defibrillation thresholds. Am J Physiol 285:H10–H16

    CAS  Google Scholar 

  • Stahlhut M, Petersen JS, Hennan JK, Ramirez MT (2006) The antiarrhythmic peptide rotigaptide (ZP123) increases connexin 43 protein expression in neonatal rat ventricular cardiomyocytes. Cell Commun Adhes 13:21–27

    Article  PubMed  CAS  Google Scholar 

  • van der Heyden MA, Rook MB, Hermans MM, Rijksen G, Boonstra J, Defize LH, Destree OH (1998) Identification of connexin43 as a functional target for Wnt signalling. J Cell Sci 111(Pt 12):1741–1749

    PubMed  Google Scholar 

  • Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJ (1999) Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol 10:1380–1389

    Article  PubMed  CAS  Google Scholar 

  • Weingart R, Bukauskas FF (1993) Gap junction channels of insects exhibit a residual conductance. Pfluegers Arch 424:192–194

    Article  CAS  Google Scholar 

  • Weng S, Lauven M, Schaefer T, Polontchouk L, Grover R, Dhein S (2002) Pharmacological modification of gap junction coupling by an antiarrhythmic peptide via protein kinase C activation. FASEB J 16:1114–1116

    PubMed  CAS  Google Scholar 

  • Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, Doll N, Hindricks G, Dhein S, Kottkamp H (2005) Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 91:166–170

    Article  PubMed  CAS  Google Scholar 

  • Wilders R, Wagner MB, Golod DA, Kumar R, Wang YG, Goolsby WN, Joyner RW, Jongsma HJ (2000) Effects of anisotropy on the development of cardiac arrhythmias associated with focal activity. Pfluegers Arch 441:301–312

    Article  CAS  Google Scholar 

  • Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Guldenagel M, Deutsch U, Sohl G (2002) Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem 383:725–737

    Article  PubMed  CAS  Google Scholar 

  • Xing D, Kjølbye AL, Nielsen MS, Petersen JS, Harlow KW, Holstein-Rathlou NH, Martins JB (2003) ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol 14:510–520

    Article  PubMed  Google Scholar 

  • Xing D, Kjolbye AL, Petersen JS, Martins JB (2005) Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs. Am J Physiol 288:H511–H516

    CAS  Google Scholar 

  • Yasui K, Kada K, Hojo M, Lee JK, Kamiya K, Toyama J, Opthof T, Kodama I (2000) Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes. Cardiovasc Res 48:68–76

    Article  PubMed  CAS  Google Scholar 

  • Yellowley CE, Li Z, Zhou Z, Jacobs CR, Donahue HJ (2000) Functional gap junctions between osteocytic and osteoblastic cells. J Bone Miner Res 15:209–217

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Naber N, Cooke R (1995) Muscle cross-bridges bound to actin are disordered in the presence of 2,3-butanedione monoxime. Biophys J 68:1980–1990

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

N-.H. H-.R. and M. S. N. were supported by grants from the Danish National Research Foundation, The John and Birthe Meyer Foundation, The Danish Heart Association and The A. P. Møller Foundation.

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Correspondence to Morten Schak Nielsen.

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Axelsen, L.N., Haugan, K., Stahlhut, M. et al. Increasing Gap Junctional Coupling: A Tool for Dissecting the Role of Gap Junctions. J Membrane Biol 216, 23–35 (2007). https://doi.org/10.1007/s00232-007-9026-z

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  • DOI: https://doi.org/10.1007/s00232-007-9026-z

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