Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes

Aims Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias....

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Autores: Aiba, Takeshi, Hesketh, Geoffrey G., Liu, Ting, Carlisle, Rachael, Villa Abrille, María Celeste, O'Rourke, Brian, Akar, Fadi G., Tomaselli, Gordon F.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:Argentina
Institución:Universidad Nacional de La Plata
Repositorio:SEDICI (UNLP)
Idioma:inglés
OAI Identifier:oai:sedici.unlp.edu.ar:10915/104334
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/104334
Access Level:acceso abierto
Palabra clave:Ciencias Médicas
Ca2+/cam-dependent protein kinase ii
Calcium
Calmodulin
Na-channel
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spelling Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytesAiba, TakeshiHesketh, Geoffrey G.Liu, TingCarlisle, RachaelVilla Abrille, María CelesteO'Rourke, BrianAkar, Fadi G.Tomaselli, Gordon F.Ciencias MédicasCa2+/cam-dependent protein kinase iiCalciumCalmodulinNa-channelAims Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias. However, the acute effects of Ca 2+/CaM and CaMKII on cardiac Na+ channels are not fully understood.Methods and results Purified NaV1.5-glutathione-S-transferase fusion peptides were phosphorylated in vitro by CaMKII predominantly on the I-II linker. Whole-cell voltage-clamp was used to measure Na+ current (INa) in isolated guinea-pig ventricular myocytes in the absence or presence of CaM or CaMKII in the pipette solution. CaMKII shifted the voltage dependence of Na+ channel availability by ≈+5 mV, hastened recovery from inactivation, decreased entry into intermediate or slow inactivation, and increased persistent (late) current, but did not change INa decay. These CaMKII-induced changes of Na+ channel gating were completely abolished by a specific CaMKII inhibitor, autocamtide-2-related inhibitory peptide (AIP). Ca2+/CaM alone reproduced the CaMKII-induced changes of INa availability and the fraction of channels undergoing slow inactivation, but did not alter recovery from inactivation or the magnitude of the late current. Furthermore, the CaM-induced changes were also completely abolished by AIP. On the other hand, cAMP-dependent protein kinase A inhibitors did not abolish the CaM/CaMKII-induced alterations of INa function.Conclusion Ca 2+/CaM and CaMKII have distinct effects on the inactivation phenotype of cardiac Na+ channels. The differences are consistent with CaM-independent effects of CaMKII on cardiac Na+ channel gating.Centro de Investigaciones Cardiovasculares2010-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf454-463http://sedici.unlp.edu.ar/handle/10915/104334enginfo:eu-repo/semantics/altIdentifier/url/http://hdl.handle.net/11336/61762info:eu-repo/semantics/altIdentifier/issn/0008-6363info:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvp324info:eu-repo/semantics/altIdentifier/hdl/11336/61762info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2024-05-08T13:00:35Zoai:sedici.unlp.edu.ar:10915/104334Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292024-05-08 13:00:35.736SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
title Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
spellingShingle Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
Aiba, Takeshi
Ciencias Médicas
Ca2+/cam-dependent protein kinase ii
Calcium
Calmodulin
Na-channel
title_short Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
title_full Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
title_fullStr Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
title_full_unstemmed Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
title_sort Na<SUP>+</SUP> channel regulation by Ca<SUP>2+</SUP>/calmodulin and Ca <SUP>2+</SUP>/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes
dc.creator.none.fl_str_mv Aiba, Takeshi
Hesketh, Geoffrey G.
Liu, Ting
Carlisle, Rachael
Villa Abrille, María Celeste
O'Rourke, Brian
Akar, Fadi G.
Tomaselli, Gordon F.
author Aiba, Takeshi
author_facet Aiba, Takeshi
Hesketh, Geoffrey G.
Liu, Ting
Carlisle, Rachael
Villa Abrille, María Celeste
O'Rourke, Brian
Akar, Fadi G.
Tomaselli, Gordon F.
author_role author
author2 Hesketh, Geoffrey G.
Liu, Ting
Carlisle, Rachael
Villa Abrille, María Celeste
O'Rourke, Brian
Akar, Fadi G.
Tomaselli, Gordon F.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
Ca2+/cam-dependent protein kinase ii
Calcium
Calmodulin
Na-channel
topic Ciencias Médicas
Ca2+/cam-dependent protein kinase ii
Calcium
Calmodulin
Na-channel
description Aims Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias. However, the acute effects of Ca 2+/CaM and CaMKII on cardiac Na+ channels are not fully understood.Methods and results Purified NaV1.5-glutathione-S-transferase fusion peptides were phosphorylated in vitro by CaMKII predominantly on the I-II linker. Whole-cell voltage-clamp was used to measure Na+ current (INa) in isolated guinea-pig ventricular myocytes in the absence or presence of CaM or CaMKII in the pipette solution. CaMKII shifted the voltage dependence of Na+ channel availability by ≈+5 mV, hastened recovery from inactivation, decreased entry into intermediate or slow inactivation, and increased persistent (late) current, but did not change INa decay. These CaMKII-induced changes of Na+ channel gating were completely abolished by a specific CaMKII inhibitor, autocamtide-2-related inhibitory peptide (AIP). Ca2+/CaM alone reproduced the CaMKII-induced changes of INa availability and the fraction of channels undergoing slow inactivation, but did not alter recovery from inactivation or the magnitude of the late current. Furthermore, the CaM-induced changes were also completely abolished by AIP. On the other hand, cAMP-dependent protein kinase A inhibitors did not abolish the CaM/CaMKII-induced alterations of INa function.Conclusion Ca 2+/CaM and CaMKII have distinct effects on the inactivation phenotype of cardiac Na+ channels. The differences are consistent with CaM-independent effects of CaMKII on cardiac Na+ channel gating.
publishDate 2010
dc.date.none.fl_str_mv 2010-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Articulo
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://sedici.unlp.edu.ar/handle/10915/104334
url http://sedici.unlp.edu.ar/handle/10915/104334
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://hdl.handle.net/11336/61762
info:eu-repo/semantics/altIdentifier/issn/0008-6363
info:eu-repo/semantics/altIdentifier/doi/10.1093/cvr/cvp324
info:eu-repo/semantics/altIdentifier/hdl/11336/61762
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
454-463
dc.source.none.fl_str_mv reponame:SEDICI (UNLP)
instname:Universidad Nacional de La Plata
instacron:UNLP
instname_str Universidad Nacional de La Plata
instacron_str UNLP
institution UNLP
reponame_str SEDICI (UNLP)
collection SEDICI (UNLP)
repository.name.fl_str_mv SEDICI (UNLP) - Universidad Nacional de La Plata
repository.mail.fl_str_mv alira@sedici.unlp.edu.ar
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