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 language | English (US) |
|---|---|
| Pages (from-to) | 923-933 |
| Number of pages | 11 |
| Journal | Journal of Cell Biology |
| Volume | 184 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 23 2009 |
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ASJC Scopus subject areas
- Cell Biology
- Medicine(all)
Cite this
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 journal › Article
}
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 -