The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins

Franke, Werner W.; Borrmann, Carola M.; Gründ, Christine; Pieperhoff, Sebastian

doi:10.1016/j.ejcb.2005.11.003

Cited by 211 publications

(221 citation statements)

References 105 publications

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“…In intercalated discs of cardiomyocytes, plakophilin 2 and desmoplakin (a plakin; see 3. Plakins, below) colocalization was evident in both desmosomes and adherens junctions (Franke et al, 2006). In this same in vivo system, plakophilin 2 interacted specifically with ␣T-catenin (Goossens et al, 2007a), seemingly suggesting that desmosomes and adherens junctions are mixed in cardiac intercalated discs.…”

Section: Anchoring Junctions and Male Contraceptionmentioning

confidence: 71%

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

2008

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Section: Anchoring Junctions and Male Contraceptionmentioning

confidence: 71%

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

2008

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“…1A). The structural integrity of the cardiomyocytes is maintained by the intercalated discs, which contain various junctional complexes including desmosomes, adherens junctions, and gap junctions (19). Desmoplakin is a constituent of the desmosomal plaque; it binds the intermediate filament protein desmin and connects the cytoskeleton to the sarcolemmal membrane in myocytes in vivo (20,21).…”

Section: Results Iaspp Anchors Desmoplakin and Desmin At Intercalatedmentioning

confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPPdeficient mice with exon 8 deletion (Ppp1r13l Δ8/Δ8 ) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.ARVC | sudden death | desmosome | iASPP | cell-cell junctions

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“…Desmoglein and desmocollin, also members of the cadherin superfamily, are found in the desmosome where they interact with linker proteins such as plakoglobin and desmoplakin. Recent data indicate a hybrid junctional complex exists in the heart referred to as area composita where a combination of components from the adherens junction and desmosome colocalize and interact (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

Levin

Xiong

et al. 2008

Journal of Molecular and Cellular Cardiology

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Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, Ncadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.

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The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins

Cited by 211 publications

References 105 publications

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

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