PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Myocytes, Cardiac/*cytology ; Phosphatidylinositol 3-Kinases/*metabolism ; Sarcolemma/*metabolism; Animals ; Calcium Channels, L-Type/metabolism ; Calcium Signaling/genetics ; Gene Deletion ; Gene Knockout Techniques ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/pathology ; Heart Failure/physiopathology ; Humans ; Membrane Proteins/metabolism ; Mice ; Muscle Contraction/genetics ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Phosphatidylinositol 3-Kinases/deficiency ; Phosphatidylinositol 3-Kinases/genetics ; Protein Transport ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcolemma/pathology
    • 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 and 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.
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    • Grant Information:
      CA136754 United States CA NCI NIH HHS; R01 DK062722 United States DK NIDDK NIH HHS; P50 GM071558 United States GM NIGMS NIH HHS; R01 HL085221 United States HL NHLBI NIH HHS; R01 CA136754 United States CA NCI NIH HHS; GM071558 United States GM NIGMS NIH HHS; HL085221 United States HL NHLBI NIH HHS; HL090905 United States HL NHLBI NIH HHS; DK62722 United States DK NIDDK NIH HHS; R01 HL090905 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (CACNA1C protein, mouse)
      0 (Calcium Channels, L-Type)
      0 (Membrane Proteins)
      0 (Ryanodine Receptor Calcium Release Channel)
      0 (junctophilin)
      EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
    • Publication Date:
      Date Created: 20110914 Date Completed: 20111229 Latest Revision: 20211020
    • Publication Date:
      20231215
    • Accession Number:
      PMC3166327
    • Accession Number:
      10.1371/journal.pone.0024404
    • Accession Number:
      21912691