Heart Failure Reviews (2019) 24:115–132 https://doi.org/10.1007/s10741-018-9743-7 Intercalated discs: cellular adhesion and signaling in heart health and diseases Guangze Zhao1,2 & Ye Qiu3 & Huifang M. Zhang 1,2 & Decheng Yang1,2 Published online: 5 October 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFATsignaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions. Keywords Intercalated disc . Desmosome . Adherens junction . Gap junction . Signaling . Cardiomyopathy Introduction cells; AJ and desmosome provide mechanical attachment be- tween two cardiomyocytes by anchoring the actin cytoskele- Normal heart function requires the synchronous mechanical ton and intermediate filaments (IF), respectively, which en- and electrical activity of individual cardiomyocytes to ensure hances the strength and stability of the myocardium. Studies the coordinated excitation and contractile performance of the have shown that these three complexes do not function inde- myocardium. The intercalated disc (ICD), a highly organized pendently but co-operate with each other via cross-talking cell-cell adhesion structure connecting a cardiomyocyte to one between mechanical and electrical junctions at the ICD. another, fulfills this important role [1, 2]. ICD is composed of Thus researchers have renamed the ICD protein interactions three major complexes, gap junction (GJ), desmosome, and into adhering junction, the so called area composita [3]. adherens junction (AJ). GJ connects the cytoplasm of adjacent Due to the important roles of ICD, it is not surprising that cardiomyocytes metabolically and electronically to enable the mutation or defect of ICD proteins causes a range of heart propagation of electrical stimuli throughout the heart muscle diseases, such as arrhythmogenic right ventricular cardiomy- opathy (ARVC), hypertrophy cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) [2, 4, 5]. In addition, recent * Decheng Yang studies provided a large amount of data showing that ICD [email protected] proteins are involved in regulating signal transduction path- ways leading to cardiac remodeling and diseases [6, 7]. In this 1 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada review, we will first discuss the recent progresses of research on structural organization and functions of ICD proteins as 2 Center for Heart Lung Innovation - St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, well as their mutations in causing heart diseases. Secondly, Canada we will also focus on the activation or suppression of the 3 College of Biology, Hunan Universsity, Changsha, China signaling pathways in various myocardial disorders caused 116 Heart Fail Rev (2019) 24:115–132 by the altered levels of these ICD component proteins. We catenin) and plakophilin (Pkp-2). Pkg is also found in AJ. notice that several reviews have been recently published [8, Pkg contains 12 arm repeats, which share 65% identity with 9]. However, our review is different from them by focusing on the one present in β-catenin, and are flanked by Pro-Lys-Gly- mutational causes of ICD-related inherited heart diseases and rich N- and C-terminal domains [14–16]. Pkg interacts with signal transduction pathways associated with ICD proteins. In desmosomal cadherins via its N-terminal domain, and the arm addition, wherever possible, we mention the virus-induced repeats near its C-terminus. Although it can interact with both ICD destruction and alteration of the cellular signaling. desmosomal and AJ cadherins, it has a higher affinity to Dsg- 2, supporting its main desmosomal localization [17]. In addi- tion, Pkg can also interact via its central arm repeats with ICD structural organization and function desmoplakin, which further binds to desmin-containing IFs. Plakophilin has four splicing products, but Pkp-2 is the most As mentioned above, ICDs, as highly organized units between prominent form in human cardiomyocytes. Pkp-2 binds to cardiomyocytes, maintain structural integrity and synchro- several desmosomal proteins via its N-terminal domain, in- nized function of the heart. The ICD is categorized into three cluding desmocollin, desmoplakin, and plakoglobin as well major junctional complexes (Fig. 1): the desmosome, which as actin and the IF proteins (desmin and keratin) [18]. functions as a cell anchor, the AJ, which provides cell Furthermore, Pkp-2 also interacts with Ankyrin-G, a sodium strength, and the GJ, which couples cells electrically and met- channel-anchoring protein, and with connexin 43 (Cx43) [19], abolically. For cellular communication, AJs and desmosomes a major component protein of GJ. Besides Ankyrin-G, Pkp-2 are tightly connected to the cytoskeleton. Furthermore, several interacts with PKCα, which is necessary for phosphorylation proteins that are not involved in direct cell-cell contact such as and recruitment of Dsp to newly forming desmosomes during ion channels also reside in the ICD. Here, we will only focus heart development or repair of heart injury [11]. on the discussion of the three major complexes: Desmoplakin and myozap Desmoplakin (Dsp) is a large Desmosome multi-domain protein that links the IF desmin and desmo- somes. It is the major plakin protein expressed in the heart, Desmosomes are intercellular adhesions and part of the ICDs. and its structure is characterized by a central α-helical coiled- Desmoglein and desmocollin, the two cadherin-type trans- coil rod domain, which is flanked by globular N- and C-ter- membrane adhesion molecules, build up the desmosomal core mini. Through its α-helical region, Dsp has been suggested to and are linked to the cytoskeleton via adapter proteins, such as form homodimers. Its N-terminus binds to Pkg and Pkp-2, plakoglobin, plakophilin, and desmoplakin. Four desmoglein targeting them to desmosomes [20], while its C-terminal tail isoforms and three desmocollin isoforms have been identified containing three plakin-repeat domains mediates binding to so far, and the expression of them shows a distinct tissue- desmin protein [21, 22]. Thus, like other desmosomal protein, specific distribution pattern [10], with desmoglein-2 (Dsg-2) Dsp-2 plays an important role in desmosome assembly. and desmocollin-2 (Dsc-2) being the main isoforms expressed Myozap (myocardium-enriched zonula occludens-1- in cardiomyocytes [11]. interacting protein) is a recently identified ICD protein, which is highly expressed in the heart. In ICD, it colocalizes with β- Dsg-2 and Dsc-2 Dsg-2 and Dsc-2 are members of the super- catenin, N-cadherin as well as Pkp-2 and directly binds to Dsp family of Ca2+-dependent desmosomal adhesion molecules, and zonula occludens 1 (ZO-1). Knockdown of myozap in which form dimers via heterophilic interactions to make up zebrafish results in cardiomyopathy with severe contractile the core of desmosomal junctions [12]. They are highly ho- dysfunction [23]. Overexpression of myozap in mice sensi- mologous and share ~ 30% identity in the amino acid se- tizes the animals to biomechanical stress and develops quence [13]. The majority of the homology is found within protein-aggregate-associated cardiomyopathy [24]. their extracellular domains, while their non-homologous re- gions are found within the C-termini. Within the desmosome, Adherens junction the intracellular tails of these desmosomal cadherins associate with armadillo (arm) proteins, plakoglobin, and plakophilin, N-cadherin AJ, also called fascia adherens, is the primary while their intercellular portions interact with the counterparts anchor for myofibrils and connects actin filaments from adja- of the desmosomal cadherins from the adjacent cent cardiomyocytes, which provides structural support for the cardiomyocytes. heart muscle cells. In addition, it transduces signals concerning actin cytoskeleton and senses mechanical forces Plakoglobin and plakophilin-2 Desmosomal cadherins form on the cells [25, 26]. N-cadherin (N-cad), also known as cytoplasmic connections with IFs partially via proteins of ar- cadherin-2,