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14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering.

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Title: 14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering.
Authors: Spooner, Heather C.1, Costa, Alexandre D.1, Westhoff, Maartje1, Hernández-González, Adriana1, Ibrahimkhail, Husna1, Yarov-Yarovoy, Vladimir1,2, Horne, Mary C.3, Dickson, Eamonn J.1, Dixon, Rose E.1 redickson@ucdavis.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/4/2025, Vol. 122 Issue 5, p1-24. 36p.
Subjects: Ion channels, Potassium channels, Calcium channels, High resolution imaging, Isoproterenol
Abstract: The L-type Ca2+ channel (CaV1.2) is essential for cardiac excitation-contraction coupling. To contribute to the inward Ca2+ flux that drives Ca2+-induced- Ca2+- release, CaV1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune CaV1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3- 3 has been proposed to affect Ca2+ channel trafficking in nonmyocytes; however, whether 14-3- 3 has similar effects on CaV1.2 in cardiomyocytes is unknown. 14-3- 3 preferentially binds phospho-serine/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including NaV1.5 and the human ether-à- go- go- related gene (hERG) potassium channel. Altered 14-3- 3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3- 3 interacts with CaV1.2 in a phosphorylation-dependent manner and regulates cardiac CaV1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, superresolution imaging, and coimmunoprecipitation revealed a population of 14-3- 3 colocalized and closely associated with CaV1.2. The degree of 14-3- 3/CaV1.2 colocalization increased upon stimulation of β-adrenergic receptors with isoproterenol. Notably, only the 14-3- 3- associated CaV1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3- 3 as a nucleation factor that directs CaV1.2 superclustering. Isoproterenol-stimulated augmentation of sarcolemmal CaV1.2 expression, Ca2+ currents, and Ca2+ transients in ventricular myocytes were strengthened by 14-3- 3 overexpression and attenuated by 14-3- 3 inhibition. These data support a model where 14-3- 3 interacts with CaV1.2 in a phosphorylation-dependent manner to promote enhanced trafficking/recycling, clustering, and activity during β-adrenergic stimulation. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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PubType: Academic Journal
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  Data: 14-3-3 promotes sarcolemmal expression of cardiac Ca<subscript>V</subscript>1.2 and nucleates isoproterenol-triggered channel superclustering.
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  Data: The L-type Ca2+ channel (CaV1.2) is essential for cardiac excitation-contraction coupling. To contribute to the inward Ca2+ flux that drives Ca2+-induced- Ca2+- release, CaV1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune CaV1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3- 3 has been proposed to affect Ca2+ channel trafficking in nonmyocytes; however, whether 14-3- 3 has similar effects on CaV1.2 in cardiomyocytes is unknown. 14-3- 3 preferentially binds phospho-serine/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including NaV1.5 and the human ether-à- go- go- related gene (hERG) potassium channel. Altered 14-3- 3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3- 3 interacts with CaV1.2 in a phosphorylation-dependent manner and regulates cardiac CaV1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, superresolution imaging, and coimmunoprecipitation revealed a population of 14-3- 3 colocalized and closely associated with CaV1.2. The degree of 14-3- 3/CaV1.2 colocalization increased upon stimulation of β-adrenergic receptors with isoproterenol. Notably, only the 14-3- 3- associated CaV1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3- 3 as a nucleation factor that directs CaV1.2 superclustering. Isoproterenol-stimulated augmentation of sarcolemmal CaV1.2 expression, Ca2+ currents, and Ca2+ transients in ventricular myocytes were strengthened by 14-3- 3 overexpression and attenuated by 14-3- 3 inhibition. These data support a model where 14-3- 3 interacts with CaV1.2 in a phosphorylation-dependent manner to promote enhanced trafficking/recycling, clustering, and activity during β-adrenergic stimulation. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2413308122
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        Text: English
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        PageCount: 36
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      – SubjectFull: Ion channels
        Type: general
      – SubjectFull: Potassium channels
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      – SubjectFull: Calcium channels
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      – SubjectFull: High resolution imaging
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      – SubjectFull: Isoproterenol
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      – TitleFull: 14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel superclustering.
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              Text: 2/4/2025
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