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.