EN
Adhesive junctional microdomains and the interplay with gap junctions and cAMP/PKA signaling in arrhythmogenic cardiomyopathy (RP8)
Principial Investigators
Project Summary and Goals
The intercalated disc (ICD) is a highly specialized cell-cell interface that ensures mechanical and electrical coupling between cardiomyocytes through interconnected junctional complexes (gap junctions, adherens junctions, and desmosomes). Disruption of desmosomal integrity is a hallmark of Arrhythmogenic Cardiomyopathy (ACM), a hereditary heart disease in which impaired cell-cell adhesion represents an early pathogenic event. ACM is initially characterized by life-threatening ventricular arrhythmias and later progresses to fibrosis and cardiac dysfunction. Here, the mechanisms linking defective mechanical adhesion to impaired electrical conduction and arrhythmogenesis remain poorly understood.
We hypothesize that disruption of mechanical junctional microdomains and their respective crosstalk with electrical and signaling components contributes to the development of an early arrhythmogenic phenotype. Therefore, the functional interplay and signalling network of the ICD microdomains will be characterized, especially in early phases of the disease prior to structural changes, with a focus on gap junctions and cAMP/PKA signaling.
Aims Addressed by the Doctoral Candidates
- Morphological characterization of adhesive junctional microdomains and interactions at different stages of disease.
- Functional characterization of the interactions of adhesive and gap junctional microdomains.
- Analysis of the interactome and signalosome of gap and adhesive junctions in ACM.
Key Techniques
- Murine and 3D-stem cell derived models of Arrhythmogenic Cardiomyopathy
- 3D electron microscopy imaging
- Proteomics and Interactome analysis
- Förster resonance energy transfer (FRET) biosensors
- Live cell imaging
- Gap junction measurements
Publications
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Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-alphaVbeta6/TGF-beta Signaling Cascade. Schinner C, Xu L, Franz H, Zimmermann A, Wanuske MT, Rathod M, Hanns P, Geier F, Pelczar P, Liang Y, Lorenz V, Studle C, Maly PI, Kauferstein S, Beckmann BM, Sheikh F, Kuster GM, Spindler V (2022). Circulation. 146:1610-1626. -
Screening for pro-adhesive compounds and their relevance as therapeutic approach in Arrhythmogenic Cardiomyopathy. Hanns P, Colpaert R, Castellanos- Martinez R, Weidner F, Beensen S, Matthias F, Xu L, Kuster GM, Schinner C (2025). bioRxiv 2025.03.23.643549; doi: https://doi.org/10.1101/2025.03.23.643549 -
Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy. Schinner C, Erber BM, Yeruva S, Schlipp A, Rötzer V, Kempf E, Kant S, Leube RE, Mueller TD, Waschke J (2020). JCI Insight. 5:e130141. -
Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion. Schinner C, Erber BM, Yeruva S, Waschke J (2019). Acta Physiol. 226:e13242. -
Adrenergic Signaling Strengthens Cardiac Myocyte Cohesion. Schinner C, Vielmuth F, Rotzer V, Hiermaier M, Radeva MY, Co TK, Hartlieb E, Schmidt A, Imhof A, Messoudi A, Horn A, Schlipp A, Spindler V, Waschke J (2017). Circ Res. 120:1305-1317. -
Ezrin-anchored PKA phosphorylates serine 369 and 373 on connexin 43 to enhance gap junction assembly, communication, and cell fusion. Dukic AR, Gerbaud P, Guibourdenche J, Thiede B, Taskén K, Pidoux G (2018). Biochem J. 475:455-476.