Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations

Medientyp: E-Artikel

Titel: Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations

Beteiligte: Benzoni, Patrizia; Gazzerro, Elisabetta; Fiorillo, Chiara; Baratto, Serena; Bartolucci, Chiara; Severi, Stefano; Milanesi, Raffaella; Lippi, Melania; Langione, Marianna; Murano, Carmen; Meoni, Clarissa; Popolizio, Vera; Cospito, Alessandro; Baruscotti, Mirko; Bucchi, Annalisa; Barbuti, Andrea

Erschienen: MDPI AG, 2024

Sprache: Englisch

DOI: 10.3390/ijms25020980

ISSN: 1422-0067

Schlagwörter: Inorganic Chemistry ; Organic Chemistry ; Physical and Theoretical Chemistry ; Computer Science Applications ; Spectroscopy ; Molecular Biology ; General Medicine ; Catalysis

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Beschreibung: 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.

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