Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 2088K) PDF+supp data (3456K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Catalucci, D. Articles by Condorelli, G. Search for Related Content PubMed PubMed Citation Articles by Catalucci, D. Articles by Condorelli, G. Social Bookmarking                            What's this?

Akt regulates L-type Ca²⁺ channel activity by modulating Ca_v1 protein stability

¹ Division of Cardiology, Department of Medicine and ² Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
³ Istituto di Ricovero e Cura a Carattere Scientifico Multimedica, Milan 20138, Italy
⁴ Department of Pharmacology, School of Medicine and ⁵ Genome and Biomedical Sciences Facility, University of California, Davis, Davis, CA 95616
⁶ Physiopathologie Cardiovasculaire, Institut National de la Santé et de la Recherche Médicale Unité 637, Université Montpellier 1, Montpellier 34295, France
⁷ Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale Unité 661, Université Montpellier 2, Montpellier 34295, France
⁸ Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore Sanità, Rome 00161, Italy

Correspondence to Daniele Catalucci: daniele.catalucci{at}itb.cnr.it; or Gianluigi Condorelli: gcondorelli{at}ucsd.edu

The insulin IGF-1–PI3K–Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca²⁺ 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 Ca²⁺ channel (LTCC) protein density. The pore-forming channel subunit Ca_v1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca_v1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca_vβ2, the LTCC chaperone for Ca_v1, antagonizes Ca_v1 protein degradation by preventing Ca_v1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca²⁺ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca²⁺ entry, Ca²⁺ handling, and contractility.

Abbreviations used in this paper: AID, 1-interacting domain; ANOVA, analysis of variance; DN, dominant-negative; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; KO, knockout; LTCC, L-type Ca²⁺ channel; PLN, phospholamban; Ryr, ryanodine receptor; siAkt, small interfering Akt; SR, sarcoplasmic reticulum; TEA, tetraethylammonium; Tg, transgenic; WT, wild type.

© 2009 Catalucci et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Catalucci, D., Latronico, M. V. G., Ceci, M., Rusconi, F., Young, H. S., Gallo, P., Santonastasi, M., Bellacosa, A., Brown, J. H., Condorelli, G. (2009). Akt Increases Sarcoplasmic Reticulum Ca2+ Cycling by Direct Phosphorylation of Phospholamban at Thr17. J. Biol. Chem. 284: 28180-28187 [Abstract] [Full Text]  
• Catalucci, D., Zhang, D.-H., DeSantiago, J., Aimond, F., Barbara, G., Chemin, J., Bonci, D., Picht, E., Rusconi, F., Dalton, N. D., Peterson, K. L., Richard, S., Bers, D. M., Brown, J. H., Condorelli, G. (2009). Akt regulates L-type Ca2+ channel activity by modulating Cav{alpha}1 protein stability. JGP 133: i4-i4 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents