A new perspective on intercalated disc organization: implications for heart disease

Abstract

Adherens junctions and desmosomes are intercellular adhesive junctions and essential for the morphogenesis, differentiation, and maintenance of tissues that are subjected to high mechanical stress, including heart and skin. The different junction complexes are organized at the termini of the cardiomyocyte called the intercalated disc. Disruption of adhesive integrity via mutations in genes encoding desmosomal proteins causes an inherited heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides plakoglobin, which is shared by adherens junctions and desmosomes, other desmosomal components, desmoglein-2, desmocollin-2, plakophilin-2, and desmoplakin are also present in ultrastructurally defined fascia adherens junctions of heart muscle, but not other tissues. This mixed-type of junctional structure is termed hybrid adhering junction or area composita. Desmosomal plakophilin-2 directly interacts with adherens junction protein alphaT-catenin, providing a new molecular link between the cadherin-catenin complex and desmosome. The area composita only exists in the cardiac intercalated disc of mammalian species suggesting that it evolved to strengthen mechanical coupling in the heart of higher vertebrates. The cross-talk among different junctions and their implication in the pathogenesis of ARVC are discussed in this review.

Figure 1

(A) Transmission electron microscopy of intercalated disc in the normal mouse heart, showing the plasma membranes of the adjacent cardiomyocytes with a region structurally resembling a desmosome (arrow) anchoring intermediate filaments, and fascia adhaerens-like structure anchoring predominantly bundles of actin filaments (arrowheads). (B) and (C) Immunoelectron microscopy of the myocardium of mouse heart, showing desmoplakin (DP) antibody labeling with silver amplification at cell-cell junctions. Note that DP immunogold label is enriched in plaques of the junctions. Higher label intensity of DP is desmosome-like structure (the right hand junction in Figure 1(B)), and the fascia adhaerens-like junction is shown in less intensity of DP labeling (the left hand junction in Figure 1(B)). A continuous and equal intensity of DP labeling shows the hybrid junctions (Figure 1(C)) [16]. Figures 1(B) and 1(C) was originally published in “The Journal of Cell Biology, Grossman et al., 2004. doi:10.1083/jcb.200402096” [16].

Figure 2

Model for cadherin-based area composita in the heart. αT-catenin recruits desmosomal protein, plakophilin- (PKP-) 2 to hybrid adhering junction (left drawing), thereby forming, together with desmosome (right drawing), an area composita, which is an enforced, mixed-type junctional structure attached to both the actin cytoskeleton and the intermediate filament (PG: plakoglobin; DP: desmoplakin).