Summary
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 α-catenin family member αT-catenin, part of the N-cadherin–catenin adhesion complex in the heart, is the only α-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that αT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of αT-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding αT-catenin, in the mouse. The αT-catenin-null mice are viable and fertile; however, the animals exhibit progressive cardiomyopathy. Adherens junctional and desmosomal proteins were unaffected by loss of αT-catenin, with the exception of the desmosomal protein PKP2. Immunogold labeling at the ICD demonstrated in the αT-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 αT-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 αT-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.
Footnotes
-
↵‡ These authors contributed equally to this work
-
Funding
This work was supported by the Jefferson Kimmel Cancer Center [NIH Cancer Center Core grant number 5 P30 CA-56036]; American Heart Association Scientist Development [grant number N2080068 to J.L.]; National Institutes of Health [grant number HL081569 to G.R.]; the Research Foundation – Flanders (FWO) [grant number G.0104.09N to F.v.R.]; and the Concerted Research Actions – Ghent University (GOA) [grant number 01G01908 to F.v.R.]. S.G. is a postdoctoral fellow with the FWO, and K.T. is a predoctoral fellow with the Flemish Agency for Innovation by Science and Technology (IWT). Deposited in PMC for release after 12 months.
-
Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.098640/-/DC1
- Accepted October 4, 2011.
- © 2012.