Publications

Authors:

Rusconi, Francesca; Ceriotti, Paola; Miragoli, Michele; Carullo, Pierluigi; Salvarani, Nicolò; Rocchetti, Marcella; Di Pasquale, Elisa; Rossi, Stefano; Tessari, Maddalena; Caprari, Silvia; Cazade, Magali; Kunderfranco, Paolo; Chemin, Jean; Bang, Marie louise; Polticelli, Fabio; Zaza, Antonio; Faggian, Giuseppe; Condorelli, Gianluigi; Catalucci, Daniele

Title:

Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function

Year:

2016

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

A Stampa

Referee:

Sì

Name of journal:

Circulation

ISSN of journal:

0009-7322

N° Volume:

134

Number or Folder:

7

Page numbers:

534-546

Keyword:

calcium; calcium channels; L-type; cardiovascular diseases; diabetic cardiomyopathies; drug therapy; peptides; protein transport

Short description of contents:

BACKGROUND: L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. METHODS: Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Ca-v beta 2 chaperone regulates channel density at the plasma membrane. RESULTS: On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Ca-v alpha 1.2 and the Akt-dependent phosphorylation status of Ca-v beta 2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Ca-v beta 2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Ca-v alpha 1.2 retrograde trafficking and protein degradation through the prevention of dynaminmediated LTCC endocytosis; promotion of Ca-v alpha 1.2 anterograde trafficking by blocking Kir/ Gem-dependent sequestration of Ca-v beta 2, thus facilitating the chaperoning of Ca-v alpha 1.2; and promotion of Ca-v alpha 1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Ca-v beta 2 to the nucleus, where it limits the transcription of Ca-v alpha 1.2 through recruitment of the heterochromatin protein 1. epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Ca-v beta 2, corrects LTCC lifecycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. CONCLUSIONS: We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Ca-v beta 2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function.

Product ID:

99790

Handle IRIS:

11562/971522

Last Modified:

November 14, 2022

Bibliographic citation:

Rusconi, Francesca; Ceriotti, Paola; Miragoli, Michele; Carullo, Pierluigi; Salvarani, Nicolò; Rocchetti, Marcella; Di Pasquale, Elisa; Rossi, Stefano; Tessari, Maddalena; Caprari, Silvia; Cazade, Magali; Kunderfranco, Paolo; Chemin, Jean; Bang, Marie louise; Polticelli, Fabio; Zaza, Antonio; Faggian, Giuseppe; Condorelli, Gianluigi; Catalucci, Daniele, Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function «Circulation» , vol. 134 , n. 7 , 2016 , pp. 534-546

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