Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function

Abstract Variants in the LMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peak INa in HEK‐293 cells expressing Nav1.5. Decreased pea...

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Autores principales:	Michael A. Olaopa, Tomohiko Ai, Bo Chao, Xiangshu Xiao, Matteo Vatta, Beth A. Habecker
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cardiac conduction disease Lamin phosphorylation Nav1.5 Physiology QP1-981
Acceso en línea:	https://doaj.org/article/7aaf40cbff3446268244b82cff02bd1c
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spelling	oai:doaj.org-article:7aaf40cbff3446268244b82cff02bd1c2021-11-27T15:48:30ZPhosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function2051-817X10.14814/phy2.15121https://doaj.org/article/7aaf40cbff3446268244b82cff02bd1c2021-11-01T00:00:00Zhttps://doi.org/10.14814/phy2.15121https://doaj.org/toc/2051-817XAbstract Variants in the LMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peak INa in HEK‐293 cells expressing Nav1.5. Decreased peak INa in the cardiac conduction system could account for patients’ atrioventricular block. We found that serine 22 (Ser 22) phosphorylation of Lamin A/C was decreased in the p.R545H variant and hypothesized that lamin phosphorylation modulated Nav1.5 activity. To test this hypothesis, we assessed Nav1.5 function in HEK‐293 cells co‐transfected with LMNA variants or treated with the small molecule LBL1 (lamin‐binding ligand 1). LBL1 decreased Ser 22 phosphorylation by 65% but did not affect Nav1.5 function. To test the complete loss of phosphorylation, we generated a version of LMNA with serine 22 converted to alanine 22 (S22A‐LMNA); and a version of mutant R545H‐LMNA that mimics phosphorylation via serine 22 to aspartic acid 22 substitution (S22D‐R545H‐LMNA). We found that S22A‐LMNA inhibited Lamin‐mediated activation of peak INa by 63% and shifted voltage‐dependency of steady‐state inactivation of Nav1.5. Conversely, S22D‐R545H‐LMNA abolished the effects of mutant R545H‐LMNA on voltage‐dependency but not peak INa. We conclude that Lamin A/C Ser 22 phosphorylation can modulate Nav1.5 function and contributes to the mechanism by which R545H‐LMNA alters Nav1.5 function. The differential impact of complete versus partial loss of Ser 22 phosphorylation suggests a threshold of phosphorylation that is required for full Nav1.5 modulation. This is the first study to link Lamin A/C phosphorylation to Nav1.5 function.Michael A. OlaopaTomohiko AiBo ChaoXiangshu XiaoMatteo VattaBeth A. HabeckerWileyarticlecardiac conduction diseaseLamin phosphorylationNav1.5PhysiologyQP1-981ENPhysiological Reports, Vol 9, Iss 22, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cardiac conduction disease Lamin phosphorylation Nav1.5 Physiology QP1-981
spellingShingle	cardiac conduction disease Lamin phosphorylation Nav1.5 Physiology QP1-981 Michael A. Olaopa Tomohiko Ai Bo Chao Xiangshu Xiao Matteo Vatta Beth A. Habecker Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
description	Abstract Variants in the LMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.A287Lfs*193, which were identified in CCD patients, decreased peak INa in HEK‐293 cells expressing Nav1.5. Decreased peak INa in the cardiac conduction system could account for patients’ atrioventricular block. We found that serine 22 (Ser 22) phosphorylation of Lamin A/C was decreased in the p.R545H variant and hypothesized that lamin phosphorylation modulated Nav1.5 activity. To test this hypothesis, we assessed Nav1.5 function in HEK‐293 cells co‐transfected with LMNA variants or treated with the small molecule LBL1 (lamin‐binding ligand 1). LBL1 decreased Ser 22 phosphorylation by 65% but did not affect Nav1.5 function. To test the complete loss of phosphorylation, we generated a version of LMNA with serine 22 converted to alanine 22 (S22A‐LMNA); and a version of mutant R545H‐LMNA that mimics phosphorylation via serine 22 to aspartic acid 22 substitution (S22D‐R545H‐LMNA). We found that S22A‐LMNA inhibited Lamin‐mediated activation of peak INa by 63% and shifted voltage‐dependency of steady‐state inactivation of Nav1.5. Conversely, S22D‐R545H‐LMNA abolished the effects of mutant R545H‐LMNA on voltage‐dependency but not peak INa. We conclude that Lamin A/C Ser 22 phosphorylation can modulate Nav1.5 function and contributes to the mechanism by which R545H‐LMNA alters Nav1.5 function. The differential impact of complete versus partial loss of Ser 22 phosphorylation suggests a threshold of phosphorylation that is required for full Nav1.5 modulation. This is the first study to link Lamin A/C phosphorylation to Nav1.5 function.
format	article
author	Michael A. Olaopa Tomohiko Ai Bo Chao Xiangshu Xiao Matteo Vatta Beth A. Habecker
author_facet	Michael A. Olaopa Tomohiko Ai Bo Chao Xiangshu Xiao Matteo Vatta Beth A. Habecker
author_sort	Michael A. Olaopa
title	Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
title_short	Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
title_full	Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
title_fullStr	Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
title_full_unstemmed	Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function
title_sort	phosphorylation of lamin a/c at serine 22 modulates nav1.5 function
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7aaf40cbff3446268244b82cff02bd1c
work_keys_str_mv	AT michaelaolaopa phosphorylationoflaminacatserine22modulatesnav15function AT tomohikoai phosphorylationoflaminacatserine22modulatesnav15function AT bochao phosphorylationoflaminacatserine22modulatesnav15function AT xiangshuxiao phosphorylationoflaminacatserine22modulatesnav15function AT matteovatta phosphorylationoflaminacatserine22modulatesnav15function AT bethahabecker phosphorylationoflaminacatserine22modulatesnav15function
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Phosphorylation of Lamin A/C at serine 22 modulates Nav1.5 function

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