Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability

Daniele Catalucci, Deng Hong Zhang, Jaime Desantiago, Franck Aimond, Guillaume Barbara, Jean Chemin, Désiré Bonci, Eckard Picht, Francesca Rusconi, Nancy D. Dalton, Kirk L. Peterson, Sylvain Richard, Donald M Bers, Joan Heller Brown, Gianluigi Condorelli

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The insulin IGF-1 -PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca 2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca 2+ channel (LTCC) protein density. The pore-forming channel subunit Ca vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca vβ2, the LTCC chaperone for Ca vα1, antagonizes Ca vα1 protein degradation by preventing Ca vα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca 2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myo- cyte Ca 2+ entry, Ca 2+ handling, and contractility.

Original languageEnglish (US)
Pages (from-to)923-933
Number of pages11
JournalJournal of Cell Biology
Volume184
Issue number6
DOIs
StatePublished - Mar 23 2009

Fingerprint

Protein Stability
Proteolysis
Myocardial Contraction
Conserved Sequence
Sequence Deletion
Phosphatidylinositol 3-Kinases
Insulin-Like Growth Factor I
Cardiac Myocytes
Protein Kinases
Proteins
Phosphorylation
Insulin

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Catalucci, D., Zhang, D. H., Desantiago, J., Aimond, F., Barbara, G., Chemin, J., ... Condorelli, G. (2009). Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability. Journal of Cell Biology, 184(6), 923-933. https://doi.org/10.1083/jcb.200805063

Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability. / Catalucci, Daniele; Zhang, Deng Hong; Desantiago, Jaime; Aimond, Franck; Barbara, Guillaume; Chemin, Jean; Bonci, Désiré; Picht, Eckard; Rusconi, Francesca; Dalton, Nancy D.; Peterson, Kirk L.; Richard, Sylvain; Bers, Donald M; Brown, Joan Heller; Condorelli, Gianluigi.

In: Journal of Cell Biology, Vol. 184, No. 6, 23.03.2009, p. 923-933.

Research output: Contribution to journalArticle

Catalucci, D, Zhang, DH, Desantiago, J, Aimond, F, Barbara, G, Chemin, J, Bonci, D, Picht, E, Rusconi, F, Dalton, ND, Peterson, KL, Richard, S, Bers, DM, Brown, JH & Condorelli, G 2009, 'Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability', Journal of Cell Biology, vol. 184, no. 6, pp. 923-933. https://doi.org/10.1083/jcb.200805063
Catalucci D, Zhang DH, Desantiago J, Aimond F, Barbara G, Chemin J et al. Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability. Journal of Cell Biology. 2009 Mar 23;184(6):923-933. https://doi.org/10.1083/jcb.200805063
Catalucci, Daniele ; Zhang, Deng Hong ; Desantiago, Jaime ; Aimond, Franck ; Barbara, Guillaume ; Chemin, Jean ; Bonci, Désiré ; Picht, Eckard ; Rusconi, Francesca ; Dalton, Nancy D. ; Peterson, Kirk L. ; Richard, Sylvain ; Bers, Donald M ; Brown, Joan Heller ; Condorelli, Gianluigi. / Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability. In: Journal of Cell Biology. 2009 ; Vol. 184, No. 6. pp. 923-933.
@article{92efb53d691c40f790e19c192806d3d3,
title = "Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability",
abstract = "The insulin IGF-1 -PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca 2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca 2+ channel (LTCC) protein density. The pore-forming channel subunit Ca vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca vβ2, the LTCC chaperone for Ca vα1, antagonizes Ca vα1 protein degradation by preventing Ca vα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca 2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myo- cyte Ca 2+ entry, Ca 2+ handling, and contractility.",
author = "Daniele Catalucci and Zhang, {Deng Hong} and Jaime Desantiago and Franck Aimond and Guillaume Barbara and Jean Chemin and D{\'e}sir{\'e} Bonci and Eckard Picht and Francesca Rusconi and Dalton, {Nancy D.} and Peterson, {Kirk L.} and Sylvain Richard and Bers, {Donald M} and Brown, {Joan Heller} and Gianluigi Condorelli",
year = "2009",
month = "3",
day = "23",
doi = "10.1083/jcb.200805063",
language = "English (US)",
volume = "184",
pages = "923--933",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "6",

}

TY - JOUR

T1 - Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability

AU - Catalucci, Daniele

AU - Zhang, Deng Hong

AU - Desantiago, Jaime

AU - Aimond, Franck

AU - Barbara, Guillaume

AU - Chemin, Jean

AU - Bonci, Désiré

AU - Picht, Eckard

AU - Rusconi, Francesca

AU - Dalton, Nancy D.

AU - Peterson, Kirk L.

AU - Richard, Sylvain

AU - Bers, Donald M

AU - Brown, Joan Heller

AU - Condorelli, Gianluigi

PY - 2009/3/23

Y1 - 2009/3/23

N2 - The insulin IGF-1 -PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca 2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca 2+ channel (LTCC) protein density. The pore-forming channel subunit Ca vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca vβ2, the LTCC chaperone for Ca vα1, antagonizes Ca vα1 protein degradation by preventing Ca vα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca 2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myo- cyte Ca 2+ entry, Ca 2+ handling, and contractility.

AB - The insulin IGF-1 -PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca 2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca 2+ channel (LTCC) protein density. The pore-forming channel subunit Ca vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca vβ2, the LTCC chaperone for Ca vα1, antagonizes Ca vα1 protein degradation by preventing Ca vα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca 2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myo- cyte Ca 2+ entry, Ca 2+ handling, and contractility.

UR - http://www.scopus.com/inward/record.url?scp=64049105965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64049105965&partnerID=8YFLogxK

U2 - 10.1083/jcb.200805063

DO - 10.1083/jcb.200805063

M3 - Article

C2 - 19307602

AN - SCOPUS:64049105965

VL - 184

SP - 923

EP - 933

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 6

ER -