Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function
- Francesca Rusconi 1, Paola Ceriotti 1, Michele Miragoli , Pierluigi Carullo , Nicolò Salvarani , Marcella Rocchetti , Elisa Di Pasquale , Stefano Rossi , Maddalena Tessari , Silvia Caprari , Magali Cazade , Paolo Kunderfranco , Jean Chemin , Marie-Louise Bang , Fabio Polticelli , Antonio Zaza , Giuseppe Faggian , Gianluigi Condorelli , Daniele Catalucci
- 1From Humanitas Clinical and Research Center, Rozzano, Milan, Italy (F.R., P. Ceriotti, M.M., P. Carullo, N.S., E.D.P., P.K., M.-L.B., G.C., D.C.); Institute of Genetic and Biomedical Research UOS Milan National Research Council, Milan, Italy (F.R., P. Carullo, N.S., E.D.P., M.-L.B., D.C.); Department of Biotechnologies and Biosciences, University of Milan-Bicocca, Milan, Italy (M.R., A.Z.); Departments of Life Sciences (S.R.) and Clinical and Experimental Medicine (M.M.), University of Parma, Parma, Italy; University Hospital of Verona, Division of Cardiac Surgery, Verona, Italy (M.T., G.F.); Department of Sciences, University of Roma Tre, Rome, Italy (S.C., F.P.); University of Montpellier, CNRS UMR 5203, INSERM, Department of Neuroscience, Institute for Functional Genomics, LabEx Ion Channel Science and Therapeutics, Montpellier, France (M.C., J.C.); and National Institute of Nuclear Physics, Rome Tre Section, Rome, Italy (F.P.).
- 0From Humanitas Clinical and Research Center, Rozzano, Milan, Italy (F.R., P. Ceriotti, M.M., P. Carullo, N.S., E.D.P., P.K., M.-L.B., G.C., D.C.); Institute of Genetic and Biomedical Research UOS Milan National Research Council, Milan, Italy (F.R., P. Carullo, N.S., E.D.P., M.-L.B., D.C.); Department of Biotechnologies and Biosciences, University of Milan-Bicocca, Milan, Italy (M.R., A.Z.); Departments of Life Sciences (S.R.) and Clinical and Experimental Medicine (M.M.), University of Parma, Parma, Italy; University Hospital of Verona, Division of Cardiac Surgery, Verona, Italy (M.T., G.F.); Department of Sciences, University of Roma Tre, Rome, Italy (S.C., F.P.); University of Montpellier, CNRS UMR 5203, INSERM, Department of Neuroscience, Institute for Functional Genomics, LabEx Ion Channel Science and Therapeutics, Montpellier, France (M.C., J.C.); and National Institute of Nuclear Physics, Rome Tre Section, Rome, Italy (F.P.).
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View abstract on PubMed
Summary
This summary is machine-generated.This study reveals how Akt-dependent Cavβ2 phosphorylation regulates L-type calcium channels (LTCCs) in the heart. A novel peptide targeting Cavβ2 was shown to restore cardiac function in a diabetic mouse model.
Area Of Science
- Cardiology
- Molecular Biology
- Biochemistry
Background
- L-type calcium channels (LTCCs) are crucial for cardiomyocyte function, with their cell surface density regulated by trafficking and stability.
- Dysregulation of LTCCs is implicated in various cardiac physiological and pathological conditions.
Purpose Of The Study
- To investigate the molecular mechanisms by which the LTCC Cavβ2 chaperone influences channel density at the plasma membrane.
- To explore the therapeutic potential of targeting Cavβ2 for cardiac conditions.
Main Methods
- Yeast 2-hybrid screenings, biochemical assays, protein interaction studies, fluorescence microscopy, molecular modeling, and functional assessments.
- Analysis of Cavα1.2 and Cavβ2 in a mouse model of diabetic cardiac disease and human patient samples.
Main Results
- Akt-dependent phosphorylation of Cavβ2 directly correlates with Cavα1.2 levels in diabetic cardiac disease and human patients.
- Phosphorylated Cavβ2 enhances LTCC density by reducing Cavα1.2 degradation and promoting its trafficking and transcription.
- A novel Cavβ2 mimetic peptide restored calcium balance and cardiac function in a mouse model of diabetic cardiac disease.
Conclusions
- Novel mechanisms for modulating LTCC trafficking and life cycle have been identified.
- Cavβ2 mimetic peptide shows promise as a therapeutic agent for cardiac conditions linked to LTCC dysfunction.
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