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

Chia-Yen C Wu; Zhiheng Jia; Wei Wang; Lisa M Ballou; Ya-Ping Jiang; Biyi Chen; Richard T Mathias; Ira S Cohen; Long-Sheng Song; Emilia Entcheva; Richard Z Lin

doi:10.1371/journal.pone.0024404

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

Journal article

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

Chia-Yen C Wu, Zhiheng Jia, Wei Wang, Lisa M Ballou, Ya-Ping Jiang, Biyi Chen, Richard T Mathias, Ira S Cohen, Long-Sheng Song, Emilia Entcheva, …

PloS one, Vol.6(9), pp.e24404-e24404

2011

DOI: 10.1371/journal.pone.0024404

PMCID: PMC3166327

PMID: 21912691

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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 Ca2+ channels in the T-tubules with ryanodine receptors in the sarcoplasmic reticulum, and reduced Ca2+ 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 Ca2+-induced Ca2+ 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.

Myocytes, Cardiac - cytology

Muscle Contraction - genetics

Humans

Heart Failure - physiopathology

Heart Failure - genetics

Ryanodine Receptor Calcium Release Channel - metabolism

Heart Failure - metabolism

Phosphatidylinositol 3-Kinases - metabolism

Heart Failure - pathology

Gene Knockout Techniques

Protein Transport

Phosphatidylinositol 3-Kinases - genetics

Myocytes, Cardiac - pathology

Animals

Phosphatidylinositol 3-Kinases - deficiency

Sarcolemma - pathology

Gene Deletion

Myocytes, Cardiac - metabolism

Membrane Proteins - metabolism

Mice

Calcium Channels, L-Type - metabolism

Calcium Signaling - genetics

Sarcolemma - metabolism

Details

Title: Subtitle: PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes
Creators: Chia-Yen C Wu - Department of Physiology and Biophysics and Institute of Molecular Cardiology, Stony Brook University, Stony Brook, New York, United States of America
Zhiheng Jia
Wei Wang
Lisa M Ballou
Ya-Ping Jiang
Biyi Chen
Richard T Mathias
Ira S Cohen
Long-Sheng Song
Emilia Entcheva
Richard Z Lin
Resource Type: Journal article
Publication Details: PloS one, Vol.6(9), pp.e24404-e24404
DOI: 10.1371/journal.pone.0024404
PMID: 21912691
PMCID: PMC3166327
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science
Grant note: HL085221 / NHLBI NIH HHS HL090905 / NHLBI NIH HHS P50 GM071558 / NIGMS NIH HHS R01 CA136754 / NCI NIH HHS DK62722 / NIDDK NIH HHS R01 HL085221 / NHLBI NIH HHS GM071558 / NIGMS NIH HHS R01 DK062722 / NIDDK NIH HHS R01 HL090905 / NHLBI NIH HHS CA136754 / NCI NIH HHS
Language: English
Date published: 2011
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094637902771

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