Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation

An increase in stimulation frequency causes an acceleration of myocardial relaxation (FDAR). Several mechanisms have been postulated to explain this effect, among which is the Ca²⁺–calmodulin-dependent protein kinase (CaMKII)-dependent phosphorylation of the Thr¹⁷ site of phospholamban (PLN). To gai...

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Autores: Valverde, Carlos Alfredo, Mundiña-Weilenmann, Cecilia, Said, María Matilde, Ferrero, Paola Viviana, Vittone, Leticia Beatriz, Salas, Margarita Ana, Palomeque, Julieta, Vila Petroff, Martín Gerardo, Mattiazzi, Alicia Ramona
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2005
País:Argentina
Recursos:Universidad Nacional de La Plata
Repositorio:SEDICI (UNLP)
Idioma:inglés
OAI Identifier:oai:sedici.unlp.edu.ar:10915/127258
Acesso em linha:http://sedici.unlp.edu.ar/handle/10915/127258
Access Level:acceso abierto
Palavra-chave:Medicina
myocardial relaxation
phosphorylation
isoprenaline
mammalian heart
phospholamban
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spelling Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylationValverde, Carlos AlfredoMundiña-Weilenmann, CeciliaSaid, María MatildeFerrero, Paola VivianaVittone, Leticia BeatrizSalas, Margarita AnaPalomeque, JulietaVila Petroff, Martín GerardoMattiazzi, Alicia RamonaMedicinamyocardial relaxationphosphorylationisoprenalinemammalian heartphospholambanAn increase in stimulation frequency causes an acceleration of myocardial relaxation (FDAR). Several mechanisms have been postulated to explain this effect, among which is the Ca²⁺–calmodulin-dependent protein kinase (CaMKII)-dependent phosphorylation of the Thr¹⁷ site of phospholamban (PLN). To gain further insights into the mechanisms of FDAR, we studied the FDAR and the phosphorylation of PLN residues in perfused rat hearts, cat papillary muscles and isolated cat myocytes. This allowed us to sweep over a wide range of frequencies, in species with either positive or negative force–frequency relationships, as well as to explore the FDAR under isometric (or isovolumic) and isotonic conditions. Results were compared with those produced by isoprenaline, an intervention known to accelerate relaxation (IDAR) via PLN phosphorylation. While IDAR occurs tightly associated with a significant increase in the phosphorylation of Ser¹⁶ and Thr¹⁷ of PLN, FDAR occurs without significant changes in the phosphorylation of PLN residues in the intact heart and cat papillary muscles. Moreover, in intact hearts, FDAR was not associated with any significant change in the CaMKII-dependent phosphorylation of sarcoplasmic/endoplasmic Ca²⁺ ATPase (SERCA2a), and was not affected by the presence of the CaMKII inhibitor, KN-93. In isolated myocytes, FDAR occurred associated with an increase in Thr¹⁷ phosphorylation. However, for a similar relaxant effect produced by isoprenaline, the phosphorylation of PLN (Ser¹⁶ and Thr¹⁷) was significantly higher in the presence of the β-agonist. Moreover, the time course of Thr¹⁷ phosphorylation was significantly delayed with respect to the onset of FDAR. In contrast, the time course of Ser¹⁶ phosphorylation, the first residue that becomes phosphorylated with isoprenaline, was temporally associated with IDAR. Furthermore, KN-93 significantly decreased the phosphorylation of Thr¹⁷ that was evoked by increasing the stimulation frequency, but failed to affect FDAR. Taken together, the results provide direct evidence indicating that CaMKII phosphorylation pathways are not involved in FDAR and that FDAR and IDAR do not share a common underlying mechanism. More likely, a CaMKII-independent mechanism could be involved, whereby increasing stimulation frequency would disrupt the SERCA2a–PLN interaction, leading to an increase in SR Ca²⁺ uptake and myocardial relaxation.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculares2005-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf801-813http://sedici.unlp.edu.ar/handle/10915/127258enginfo:eu-repo/semantics/altIdentifier/issn/0022-3751info:eu-repo/semantics/altIdentifier/issn/1469-7793info:eu-repo/semantics/altIdentifier/doi/10.1113/jphysiol.2004.075432info: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:UNLP2024-05-08T13:09:17Zoai:sedici.unlp.edu.ar:10915/127258Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292024-05-08 13:09:17.767SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
title Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
spellingShingle Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
Valverde, Carlos Alfredo
Medicina
myocardial relaxation
phosphorylation
isoprenaline
mammalian heart
phospholamban
title_short Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
title_full Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
title_fullStr Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
title_full_unstemmed Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
title_sort Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation
dc.creator.none.fl_str_mv Valverde, Carlos Alfredo
Mundiña-Weilenmann, Cecilia
Said, María Matilde
Ferrero, Paola Viviana
Vittone, Leticia Beatriz
Salas, Margarita Ana
Palomeque, Julieta
Vila Petroff, Martín Gerardo
Mattiazzi, Alicia Ramona
author Valverde, Carlos Alfredo
author_facet Valverde, Carlos Alfredo
Mundiña-Weilenmann, Cecilia
Said, María Matilde
Ferrero, Paola Viviana
Vittone, Leticia Beatriz
Salas, Margarita Ana
Palomeque, Julieta
Vila Petroff, Martín Gerardo
Mattiazzi, Alicia Ramona
author_role author
author2 Mundiña-Weilenmann, Cecilia
Said, María Matilde
Ferrero, Paola Viviana
Vittone, Leticia Beatriz
Salas, Margarita Ana
Palomeque, Julieta
Vila Petroff, Martín Gerardo
Mattiazzi, Alicia Ramona
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Medicina
myocardial relaxation
phosphorylation
isoprenaline
mammalian heart
phospholamban
topic Medicina
myocardial relaxation
phosphorylation
isoprenaline
mammalian heart
phospholamban
description An increase in stimulation frequency causes an acceleration of myocardial relaxation (FDAR). Several mechanisms have been postulated to explain this effect, among which is the Ca²⁺–calmodulin-dependent protein kinase (CaMKII)-dependent phosphorylation of the Thr¹⁷ site of phospholamban (PLN). To gain further insights into the mechanisms of FDAR, we studied the FDAR and the phosphorylation of PLN residues in perfused rat hearts, cat papillary muscles and isolated cat myocytes. This allowed us to sweep over a wide range of frequencies, in species with either positive or negative force–frequency relationships, as well as to explore the FDAR under isometric (or isovolumic) and isotonic conditions. Results were compared with those produced by isoprenaline, an intervention known to accelerate relaxation (IDAR) via PLN phosphorylation. While IDAR occurs tightly associated with a significant increase in the phosphorylation of Ser¹⁶ and Thr¹⁷ of PLN, FDAR occurs without significant changes in the phosphorylation of PLN residues in the intact heart and cat papillary muscles. Moreover, in intact hearts, FDAR was not associated with any significant change in the CaMKII-dependent phosphorylation of sarcoplasmic/endoplasmic Ca²⁺ ATPase (SERCA2a), and was not affected by the presence of the CaMKII inhibitor, KN-93. In isolated myocytes, FDAR occurred associated with an increase in Thr¹⁷ phosphorylation. However, for a similar relaxant effect produced by isoprenaline, the phosphorylation of PLN (Ser¹⁶ and Thr¹⁷) was significantly higher in the presence of the β-agonist. Moreover, the time course of Thr¹⁷ phosphorylation was significantly delayed with respect to the onset of FDAR. In contrast, the time course of Ser¹⁶ phosphorylation, the first residue that becomes phosphorylated with isoprenaline, was temporally associated with IDAR. Furthermore, KN-93 significantly decreased the phosphorylation of Thr¹⁷ that was evoked by increasing the stimulation frequency, but failed to affect FDAR. Taken together, the results provide direct evidence indicating that CaMKII phosphorylation pathways are not involved in FDAR and that FDAR and IDAR do not share a common underlying mechanism. More likely, a CaMKII-independent mechanism could be involved, whereby increasing stimulation frequency would disrupt the SERCA2a–PLN interaction, leading to an increase in SR Ca²⁺ uptake and myocardial relaxation.
publishDate 2005
dc.date.none.fl_str_mv 2005-02
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/10915/127258
url http://sedici.unlp.edu.ar/handle/10915/127258
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/issn/0022-3751
info:eu-repo/semantics/altIdentifier/issn/1469-7793
info:eu-repo/semantics/altIdentifier/doi/10.1113/jphysiol.2004.075432
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
801-813
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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score 15,812455

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