title: PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes.
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.
  
  
  RESULTS
  Genetic ablation of both p110α and p110β 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 p110β 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.
authors.affiliation: Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Chia-Yen C
authors.initials: CY
authors.lastname: Wu
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Jia
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ballou
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Jiang
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Richard T
authors.initials: RT
authors.lastname: Mathias
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Emilia
authors.initials: E
authors.lastname: Entcheva
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D008565:Membrane Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C412507:junctophilin; D019869:Phosphatidylinositol 3-Kinases