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Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca 2+ channel Ca V 1.2
Ca 1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through G -coupled AT1 receptors, angiotensin II trigge...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (14), p.e2221242120 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Ca
1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through G
-coupled AT1 receptors, angiotensin II triggers a decrease in PIP
, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP
depletion suppresses Ca
1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that Ca
1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP
stabilizes Ca
1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP
depletion and destabilization of Ca
1.2 expression. We tested this hypothesis and report that Ca
1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP
depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular Ca
1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP
supplementation. Functional data revealed acute angiotensin II reduced Ca
1.2 currents and Ca
transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP
are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP
stabilizes Ca
1.2 membrane lifetimes, and angiotensin II-induced PIP
depletion destabilizes sarcolemmal Ca
1.2, triggering their removal, and the acute reduction of Ca
1.2 currents and contractility. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.2221242120 |