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| Item Type: | Article |
|---|---|
| Title: | Caveolin-3 and Caveolin-1 interaction decreases channel dysfunction due to Caveolin-3 mutations |
| Creators Name: | Benzoni, P. and Gazzerro, E. and Fiorillo, C. and Baratto, S. and Bartolucci, C. and Severi, S. and Milanesi, R. and Lippi, M. and Langione, M. and Murano, C. and Meoni, C. and Popolizio, V. and Cospito, A. and Baruscotti, M. and Bucchi, A. and Barbuti, A. |
| Abstract: | Caveolae constitute membrane microdomains where receptors and ion channels functionally interact. Caveolin-3 (cav-3) is the key structural component of muscular caveolae. Mutations in CAV3 lead to caveolinopathies, which result in both muscular dystrophies and cardiac diseases. In cardiomyocytes, cav-1 participates with cav-3 to form caveolae; skeletal myotubes and adult skeletal fibers do not express cav-1. In the heart, the absence of cardiac alterations in the majority of cases may depend on a conserved organization of caveolae thanks to the expression of cav-1. We decided to focus on three specific cav-3 mutations (Δ62-64YTT; T78K and W101C) found in heterozygosis in patients suffering from skeletal muscle disorders. We overexpressed both the WT and mutated cav-3 together with ion channels interacting with and modulated by cav-3. Patch-clamp analysis conducted in caveolin-free cells (MEF-KO), revealed that the T78K mutant is dominant negative, causing its intracellular retention together with cav-3 WT, and inducing a significant reduction in current densities of all three ion channels tested. The other cav-3 mutations did not cause significant alterations. Mathematical modelling of the effects of cav-3 T78K would impair repolarization to levels incompatible with life. For this reason, we decided to compare the effects of this mutation in other cell lines that endogenously express cav-1 (MEF-STO and CHO cells) and to modulate cav-1 expression with an shRNA approach. In these systems, the membrane localization of cav-3 T78K was rescued in the presence of cav-1, and the current densities of hHCN4, hKv1.5 and hKir2.1 were also rescued. These results constitute the first evidence of a compensatory role of cav-1 in the heart, justifying the reduced susceptibility of this organ to caveolinopathies. |
| Keywords: | Caveolin-3, Caveolin-1, Electrophysiology, HCN4, Kv1.5, Kir2.1, Caveolinopathies, Animals, Cricetinae, Cricetulus, Mice |
| Source: | International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| Publisher: | MDPI |
| Volume: | 25 |
| Number: | 2 |
| Page Range: | 980 |
| Date: | 2 January 2024 |
| Official Publication: | https://doi.org/10.3390/ijms25020980 |
| PubMed: | View item in PubMed |
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