期刊
JOURNAL OF CELL SCIENCE
卷 125, 期 4, 页码 1058-1067出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.098640
关键词
Cardiac intercalated disc; Adherens junction; Desmosome; Plakophilin-2; Gap junction; Connexin43; alpha-catenin
类别
资金
- Jefferson Kimmel Cancer Center [NIH Cancer Center] [5 P30 CA-56036]
- American Heart Association [N2080068]
- National Institutes of Health [HL081569]
- Research Foundation - Flanders (FWO) [G.0104.09N]
- Concerted Research Actions - Ghent University (GOA) [01G01908]
It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a 'hybrid adhering junction' or 'area composita'. The alpha-catenin family member alpha T-catenin, part of the N-cadherin-catenin adhesion complex in the heart, is the only alpha-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that alpha T-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of alpha T-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding alpha T-catenin, in the mouse. The alpha T-catenin-null mice are viable and fertile; however, the animals exhibit progressive cardiomyopathy. Adherens junctional and desmosomal proteins were unaffected by loss of alpha T-catenin, with the exception of the desmosomal protein PKP2. Immunogold labeling at the ICD demonstrated in the alpha T-catenin-null heart a preferential reduction of PKP2 at the area composita compared with the desmosome. Furthermore, gap junction protein Cx43 was reduced at the ICD, including its colocalization with N-cadherin. Gap junction remodeling in alpha T-catenin-knockout hearts was associated with an increased incidence of ventricular arrhythmias after acute ischemia. This novel animal model demonstrates for the first time how perturbation in alpha T-catenin can affect both PKP2 and Cx43 and thereby highlights the importance of understanding the crosstalk between the junctional proteins of the ICD and its implications for arrhythmogenic cardiomyopathy.
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