Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function.
AIMS: We determined the contribution of the desmosomal cadherin desmoglein-2 to cell-cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junct...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2014
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| _version_ | 1826294960113057792 |
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| author | Schlipp, A Schinner, C Spindler, V Vielmuth, F Gehmlich, K Syrris, P Mckenna, W Dendorfer, A Hartlieb, E Waschke, J |
| author_facet | Schlipp, A Schinner, C Spindler, V Vielmuth, F Gehmlich, K Syrris, P Mckenna, W Dendorfer, A Hartlieb, E Waschke, J |
| author_sort | Schlipp, A |
| collection | OXFORD |
| description | AIMS: We determined the contribution of the desmosomal cadherin desmoglein-2 to cell-cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junctions. METHODS AND RESULTS: We studied intercalated discs of HL-1 cardiomyocytes by immunostaining of desmoglein-2 and N-cadherin. Cohesion was measured using a liberase-based dissociation-assay and compared with cell-free single-molecule atomic force microscopy measurements. L-tryptophan caused irregular desmoglein-2 condensation, weakened cell-cell cohesion and impaired both homophilic desmoglein-2 and N-cadherin trans-interaction, whereas l-phenylalanine had no effect. L-tryptophan did not affect N-cadherin localization and its inhibitory effect on cell-cohesion and desmoglein-2 binding, but not on N-cadherin interaction, was blocked by a desmoglein-specific tandem peptide. Moreover, Ca(2+)-depletion, desmoglein-2 knockdown, a desmoglein-specific single peptide and certain desmoglein-2 mutations associated with arrhythmogenic cardiomyopathy reduced cell-cell cohesion, whereas cell adhesion was strengthened by desmoglein-2 overexpression. Since single peptide did not interfere with N-cadherin trans-interaction, these data indicate that (i) desmoglein-2 binding is crucial for cardiomyocyte cohesion and (ii) L-tryptophan reduced both desmoglein-2 and N-cadherin binding, whereas single and tandem peptide can be used to specifically target desmoglein-2-mediated adhesion. L-tryptophan and single peptide also induced ultrastructural alterations of areae compositae. Functional analyses at the organ level revealed reduced cardiomyocyte function and inefficient response to adrenergic stimulation in both L-tryptophan- and single peptide-challenged murine Langendorff hearts paralleled by redistribution of connexin 43 in L-tryptophan-treated heart slices. CONCLUSION: Our data demonstrate that desmoglein-2 plays a critical role in cardiomyocyte cohesion and function. |
| first_indexed | 2024-03-07T03:53:45Z |
| format | Journal article |
| id | oxford-uuid:c2277cc3-137d-4232-958d-2d9d70b6dfbe |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:53:45Z |
| publishDate | 2014 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:c2277cc3-137d-4232-958d-2d9d70b6dfbe2022-03-27T06:06:52ZDesmoglein-2 interaction is crucial for cardiomyocyte cohesion and function.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c2277cc3-137d-4232-958d-2d9d70b6dfbeEnglishSymplectic Elements at OxfordOxford University Press2014Schlipp, ASchinner, CSpindler, VVielmuth, FGehmlich, KSyrris, PMckenna, WDendorfer, AHartlieb, EWaschke, JAIMS: We determined the contribution of the desmosomal cadherin desmoglein-2 to cell-cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junctions. METHODS AND RESULTS: We studied intercalated discs of HL-1 cardiomyocytes by immunostaining of desmoglein-2 and N-cadherin. Cohesion was measured using a liberase-based dissociation-assay and compared with cell-free single-molecule atomic force microscopy measurements. L-tryptophan caused irregular desmoglein-2 condensation, weakened cell-cell cohesion and impaired both homophilic desmoglein-2 and N-cadherin trans-interaction, whereas l-phenylalanine had no effect. L-tryptophan did not affect N-cadherin localization and its inhibitory effect on cell-cohesion and desmoglein-2 binding, but not on N-cadherin interaction, was blocked by a desmoglein-specific tandem peptide. Moreover, Ca(2+)-depletion, desmoglein-2 knockdown, a desmoglein-specific single peptide and certain desmoglein-2 mutations associated with arrhythmogenic cardiomyopathy reduced cell-cell cohesion, whereas cell adhesion was strengthened by desmoglein-2 overexpression. Since single peptide did not interfere with N-cadherin trans-interaction, these data indicate that (i) desmoglein-2 binding is crucial for cardiomyocyte cohesion and (ii) L-tryptophan reduced both desmoglein-2 and N-cadherin binding, whereas single and tandem peptide can be used to specifically target desmoglein-2-mediated adhesion. L-tryptophan and single peptide also induced ultrastructural alterations of areae compositae. Functional analyses at the organ level revealed reduced cardiomyocyte function and inefficient response to adrenergic stimulation in both L-tryptophan- and single peptide-challenged murine Langendorff hearts paralleled by redistribution of connexin 43 in L-tryptophan-treated heart slices. CONCLUSION: Our data demonstrate that desmoglein-2 plays a critical role in cardiomyocyte cohesion and function. |
| spellingShingle | Schlipp, A Schinner, C Spindler, V Vielmuth, F Gehmlich, K Syrris, P Mckenna, W Dendorfer, A Hartlieb, E Waschke, J Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title | Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title_full | Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title_fullStr | Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title_full_unstemmed | Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title_short | Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. |
| title_sort | desmoglein 2 interaction is crucial for cardiomyocyte cohesion and function |
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