N-Cadherin/Catenin Complex as a Master Regulator of Intercalated Disc Function

Figures & data

Figure 1. Transmission electron microscopy of a cross section through intercalated disc of a mouse heart. TEM image showing the intercalated disc with a large mixed-type junction (area composita) surrounded by two dense desmosome structures (black arrows).

Figure 2. Molecular organization of area composita vs. desmosome in the heart. (a) Immunoelectron microscopic images of the myocardium of a mouse heart showing the co-localization of PKP2 and αT-catenin at the area composita. Note the absence of αT-catenin in the desmosome. These images were originally published in a study by Goossens et al. (2007). (b) Model for cadherin-based cell–cell adhesion in the heart. This model represents the composition of a hybrid junction compared to a desmosome. αT-Catenin recruits desmosomal proteins through its interaction with plakophilin-2 (PKP2), forming a hybrid junction (named area composita), reinforcing the intercalated discs resistance. (αE: αE-catenin; αT: αT-catenin; β-cat: β-catenin; PG: plakoglobin; PKP2: plakophillin-2; IF: intermediate filaments).

Table 1. Genetic manipulation of adherens junction proteins in the adult myocardium.

Mouse model	Stress	Cardiac phenotype	References
N-Cadherin LOF	None	Cardiomyopathy, GJ and ion channel remodeling, arrhythmia, SCD	Li et al. (2005), Kostetskii et al. (2005), Cheng et al. (2011)
N-Cadherin HET	PS	Normal cardiac function, GJ remodeling, inducible arrhythmia	Li et al. (2008)
β-Catenin LOF	None	Normal cardiac function, increase PG	Zhou et al. (2007)
β-Catenin LOF	TAC	Block hypertrophy, decrease Wnt genes	Chen et al. (2006)
β-catenin LOF	AngII	No change in hypertrophy response	Baurand et al. (2007)
β-Catenin LOF	MI	Improve LV function, increase cpc	Zelarayan et al. (2008)
β-Catenin HET	TAC	Block hypertrophy, increase fetal genes	Qu et al. (2007)
β-Catenin^Δex3 GOF	None	Cardiomyopathy, no change Wnt genes	Hirschy et al. (2010)
β-Catenin^Δex3 GOF	MI	No improvement in LV function, decrease cpc differentiation	Zelarayan et al. (2008)
β-Catenin^Δex3 GOF	AngII	Block hypertrophy, decrease cardiac function	Baurand et al. (2007)
PG LOF	None	AC-like pathology except adipocytes	Li et al. (2011a, 2011b)
PG hypomorph	None	Normal cardiac function, increase β-catenin	Swope et al. (2012)
PG GOF	None	AC-like pathology including adipocytes	Lombardi et al. (2011)
PG^Naxos GOF	None	AC-like pathology including adipocytes	Lombardi et al. (2011)
αE-Catenin LOF	None	Cardiomyopathy late onset	Sheikh et al. (2006)
αE-Catenin LOF	MI	Ventricular wall rupture	Sheikh et al. (2006)
αT-Catenin LOF	None	Cardiomyopathy early onset, GJ remodeling	Li et al. (2012)
αT-Catenin LOF	I/R	Arrhythmia	Li et al. (2012)

LOF, loss-of-function; GOF, gain-of-function; HET, heterozygous; SCD, sudden cardiac death; PS; program stimulation; GJ, gap junction; TAC, transverse aortic constriction; AngII, angiotensinII; MI, myocardial infarction; cpc, cardiac progenitor cells; I/R, ischemia/reperfusion.

Figure 3. Functional hierarchy at the intercalated disc. Scheme depicts the relationship between the different junctions and cardiac dysfunction.

Figure 4. Junctional proteins interactome. The intercalated disc protein–protein interaction network is based on STRING v9.1 analysis (http://www.string-db.org/) using the default settings (Franceschini et al., 2013). Black lines represent direct interactions, while dotted lines represent assumed interactions based on the studies of the structures homology. (Ncad: N-cadherin; B-cat: β-catenin; p120ctn: p120-catenin; αE-cat: αE-catenin; αT-cat: αT-catenin; PG: plakoglobin; PKP2: plakophillin-2; DSG2: desmoglein-2; DSC2: desmocollin-2; DSP: desmoplakin; Cx43: connexin-43; AnkG: ankyrin G; Kv: potassium channels; kChiP2: Kv channel-interacting protein 2; ACTN: actinin).

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