Arrhythmogenic Cardiomyopathy and Brugada Syndrome: Diseases of the Connexome

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 2014 Feb 20

PMID 24548564

Citations 66

Authors

Esperanza Agullo-Pascual

Marina Cerrone

Mario Delmar

Affiliations

Soon will be listed here.

Abstract

This review summarizes data in support of the notion that the cardiac intercalated disc is the host of a protein interacting network, called "the connexome", where molecules classically defined as belonging to one particular structure (e.g., desmosomes, gap junctions, sodium channel complex) actually interact with others, and together, control excitability, electrical coupling and intercellular adhesion in the heart. The concept of the connexome is then translated into the understanding of the mechanisms leading to two inherited arrhythmia diseases: arrhythmogenic cardiomyopathy, and Brugada syndrome. The cross-over points in these two diseases are addressed to then suggest that, though separate identifiable clinical entities, they represent "bookends" of a spectrum of manifestations that vary depending on the effect that a particular mutation has on the connexome as a whole.

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References

McNair W, Sinagra G, Taylor M, Lenarda A, Ferguson D, Salcedo E . SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol. 2011; 57(21):2160-8. PMC: 9689753. DOI: 10.1016/j.jacc.2010.09.084. View

Rizzo S, Lodder E, Verkerk A, Wolswinkel R, Beekman L, Pilichou K . Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes. Cardiovasc Res. 2012; 95(4):409-18. DOI: 10.1093/cvr/cvs219. View

Weidmann S . The electrical constants of Purkinje fibres. J Physiol. 1952; 118(3):348-60. PMC: 1392495. DOI: 10.1113/jphysiol.1952.sp004799. View

Akar F, Nass R, Hahn S, Cingolani E, Shah M, Hesketh G . Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 2007; 293(2):H1223-30. DOI: 10.1152/ajpheart.00079.2007. View

Noorman M, Hakim S, Kessler E, Groeneweg J, Cox M, Asimaki A . Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. Heart Rhythm. 2012; 10(3):412-9. PMC: 3608196. DOI: 10.1016/j.hrthm.2012.11.018. View

Kucera J, Rohr S, Rudy Y . Localization of sodium channels in intercalated disks modulates cardiac conduction. Circ Res. 2002; 91(12):1176-82. PMC: 1888562. DOI: 10.1161/01.res.0000046237.54156.0a. View

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

SJOSTRAND F, ANDERSSON-CEDERGREN E, DEWEY M . The ultrastructure of the intercalated discs of frog, mouse and guinea pig cardiac muscle. J Ultrastruct Res. 1958; 1(3):271-87. DOI: 10.1016/s0022-5320(58)80008-8. View

van Tintelen J, Entius M, Bhuiyan Z, Jongbloed R, Wiesfeld A, Wilde A . Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006; 113(13):1650-8. DOI: 10.1161/CIRCULATIONAHA.105.609719. View

10.

Frustaci A, Priori S, Pieroni M, Chimenti C, Napolitano C, Rivolta I . Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005; 112(24):3680-7. DOI: 10.1161/CIRCULATIONAHA.105.520999. View

11.

Desplantez T, McCain M, Beauchamp P, Rigoli G, Rothen-Rutishauser B, Parker K . Connexin43 ablation in foetal atrial myocytes decreases electrical coupling, partner connexins, and sodium current. Cardiovasc Res. 2012; 94(1):58-65. PMC: 3307380. DOI: 10.1093/cvr/cvs025. View

12.

Danik S, Rosner G, Lader J, Gutstein D, Fishman G, Morley G . Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. FASEB J. 2007; 22(4):1204-12. PMC: 2726820. DOI: 10.1096/fj.07-8974com. View

13.

Meyer R, Laird D, REVEL J, Johnson R . Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. J Cell Biol. 1992; 119(1):179-89. PMC: 2289623. DOI: 10.1083/jcb.119.1.179. View

14.

Hartshorne R, Catterall W . Purification of the saxitoxin receptor of the sodium channel from rat brain. Proc Natl Acad Sci U S A. 1981; 78(7):4620-4. PMC: 319845. DOI: 10.1073/pnas.78.7.4620. View

15.

Marsman R, Bezzina C, Freiberg F, Verkerk A, Adriaens M, Podliesna S . Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia. J Am Coll Cardiol. 2013; 63(6):549-59. PMC: 3926969. DOI: 10.1016/j.jacc.2013.10.062. View

16.

Dzhashiashvili Y, Zhang Y, Galinska J, Lam I, Grumet M, Salzer J . Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J Cell Biol. 2007; 177(5):857-70. PMC: 2064285. DOI: 10.1083/jcb.200612012. View

17.

Malhotra J, Thyagarajan V, Chen C, Isom L . Tyrosine-phosphorylated and nonphosphorylated sodium channel beta1 subunits are differentially localized in cardiac myocytes. J Biol Chem. 2004; 279(39):40748-54. DOI: 10.1074/jbc.M407243200. View

18.

Ruan Y, Liu N, Priori S . Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 2009; 6(5):337-48. DOI: 10.1038/nrcardio.2009.44. View

19.

Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S . Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013; 494(7435):105-10. PMC: 3753229. DOI: 10.1038/nature11799. View

20.

Bellett G, Carter J, Keynton J, Goldspink D, James C, Moss D . Microtubule plus-end and minus-end capture at adherens junctions is involved in the assembly of apico-basal arrays in polarised epithelial cells. Cell Motil Cytoskeleton. 2009; 66(10):893-908. DOI: 10.1002/cm.20393. View