PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes.
PLoS One
; 6(9): e24404, 2011.
Article
em En
| MEDLINE
| ID: mdl-21912691
ABSTRACT
BACKGROUND:
Phosphoinositide 3-kinases (PI3Ks) regulate numerous physiological processes including some aspects of cardiac function. Although regulation of cardiac contraction by individual PI3K isoforms has been studied, little is known about the cardiac consequences of downregulating multiple PI3Ks concurrently. METHODS ANDRESULTS:
Genetic ablation of both p110α and p110ß in cardiac myocytes throughout development or in adult mice caused heart failure and death. Ventricular myocytes from double knockout animals showed transverse tubule (T-tubule) loss and disorganization, misalignment of L-type Ca(2+) channels in the T-tubules with ryanodine receptors in the sarcoplasmic reticulum, and reduced Ca(2+) transients and contractility. Junctophilin-2, which is thought to tether T-tubules to the sarcoplasmic reticulum, was mislocalized in the double PI3K-null myocytes without a change in expression level.CONCLUSIONS:
PI3K p110α and p110ß are required to maintain the organized network of T-tubules that is vital for efficient Ca(2+)-induced Ca(2+) release and ventricular contraction. PI3Ks maintain T-tubule organization by regulating junctophilin-2 localization. These results could have important medical implications because several PI3K inhibitors that target both isoforms are being used to treat cancer patients in clinical trials.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sarcolema
/
Fosfatidilinositol 3-Quinases
/
Miócitos Cardíacos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article