Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia

Abstract

For electromechanical coupling of cardiomyocytes, intercalated discs (ICDs) are pivotal as highly specialized intercellular contact areas. ICD consists of adhesive contacts, such as desmosomes and adherens junctions (AJs) that are partially intermingled and thereby form an area composita to provide mechanical strength, as well as gap junctions (GJ) and sodium channels for excitation propagation. In contrast, in epithelia, mixed junctions with features of desmosomes and AJs are regarded as transitory primarily during the formation of desmosomes. The anatomy of desmosomes is defined by a typical ultrastructure with dense intracellular plaques anchoring the cadherin‐type adhesion molecules to the intermediate filament cytoskeleton. Desmosomal diseases characterized by impaired adhesive and signalling functions of desmosomal contacts lead to arrhythmogenic cardiomyopathy when affecting cardiomyocytes and cause pemphigus when manifesting in keratinocytes or present as cardiocutaneous syndromes when both cell types are targeted by the disease, which underscores the high biomedical relevance of these cell contacts. Therefore, comparative analyses regarding the structure and regulation of desmosomal contacts in cardiomyocytes and epithelial cells are helpful to better understand disease pathogenesis. In this brief review, we describe the structural properties of ICD compared to epithelial desmosomes and suggest that mechanisms regulating adhesion may at least in part be comparable. Also, we discuss whether phenomena such as hyperadhesion or the bidirectional regulation of desmosomes to serve as signalling hubs in epithelial cells may also be relevant for ICD.

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

“…However, to our knowledge in cardiomyocytes this complex was not known before. It has been very well demonstrated that desmosomes in the epithelia or ICDs in the cardiomyocytes not only provide cellular cohesion but can also be part of a signaling hub (Broussard et al, 2015, Najor et al, 2017, Muller et al, 2021, Yeruva and Waschke, 2022), thus disrupting EGFR signaling in this context might lead to changes at the desmosome.…”

“…Furthermore, there is increasing evidence that desmosomes not only provide cellular cohesion, but also act as signaling hubs (Waschke, 2019, Muller et al, 2021), meaning that desmosomes can influence, but are also influenced by cellular signaling processes. Recent advancement in research suggests that similar molecular mechanisms are present in AC and pemphigus, an autoimmune skin disease, as well as inflammatory bowel diseases (Waschke, 2019, Shoykhet et al, 2020, Schmitt and Waschke, 2021, Yeruva and Waschke, 2022).…”

Role of ADAM10 and ADAM17 in the Regulation of Keratinocyte Adhesion in Pemphigus Vulgaris

“…Interestingly, ADAM10 inhibition shifted keratinocyte adhesion towards a hyperadhesive state, which is suggested to be required for keratinocytes and cardiomyocytes to acquire a very strong adhesive state in order to resist a high mechanical stress and probably reduce susceptibility for diseases ( 38 , 49 , 50 ). This is in line with the finding that ADAM10 is more active at high Ca 2+ ( 23 , 28 ).…”

Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin

“…Mutations in Dsg2 and Dsc2 are known to cause arrhythmogenic right ventricular cardiomyopathy whereas those in Pg and Dp cause cardiomyopathy as well as various cardio-cutaneous syndromes (62)(63)(64)(65). Some aspects in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy may be similar to pemphigus due to common aspects in the structure and regulation of desmosomal contacts in cardiac intercalated discs and desmosomes of the epidermis (66). Moreover, mutations in desmosomal proteins have been shown to affect skin appendages.…”