Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation

Autores
Vila Petroff, Martin Gerarde; Mundiña, Cecilia Beatriz; Lezcano, Noelia Ariana; Snabaitis, Andrew K.; Huergo, María Ana Cristina; Valverde, Carlos Alfredo; Avkiran, Metin; Mattiazzi, Ramona Alicia
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The Na+/H+ exchanger (NHE-1) plays a key role in pHi recovery from acidosis and is regulated by pHi and the ERK1/2-dependent phosphorylation pathway. Since acidosis increases the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cardiac muscle, we examined whether CaMKII activates the exchanger by using pharmacological tools and highly specific genetic approaches. Adult rat cardiomyocytes, loaded with the pHi indicator SNARF-1/AM were subjected to different protocols of intracellular acidosis. The rate of pHi recovery from the acid load (dpHi/dt)—an index of NHE-1 activity in HEPES buffer or in NaHCO3 buffer in the presence of inhibition of anion transporters—was significantly decreased by the CaMKII inhibitors KN-93 or AIP. pHi recovery from acidosis was faster in CaMKII-overexpressing myocytes than in overexpressing β-galactosidase myocytes (dpHi/dt: 0.195 ± 0.04 vs. 0.045 ± 0.010 min− 1, respectively, n = 8) and slower in myocytes from transgenic mice with chronic cardiac CaMKII inhibition (AC3-I) than in controls (AC3-C). Inhibition of CaMKII and/or ERK1/2 indicated that stimulation of NHE-1 by CaMKII was independent of and additive to the ERK1/2 cascade. In vitro studies with fusion proteins containing wild-type or mutated (Ser/Ala) versions of the C-terminal domain of NHE-1 indicate that CaMKII phosphorylates NHE-1 at residues other than the canonical phosphorylation sites for the kinase (Ser648, Ser703, and Ser796). These results provide new mechanistic insights and unequivocally demonstrate a role of the already multifunctional CaMKII on the regulation of the NHE-1 activity. They also prove clinically important in multiple disorders which, like ischemia/reperfusion injury or hypertrophy, are associated with increased NHE-1 and CaMKII.
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Mundiña, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Lezcano, Noelia Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Snabaitis, Andrew K.. Kings College London;
Fil: Huergo, María Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Valverde, Carlos Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Avkiran, Metin. Kings College London;
Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Materia
Intracellular pH
Na+/H+ exchanger
Calcium/calmodulin-dependent protein kinase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/280483
Acceder
id CONICETDig_782019bdd51719da8b1e588c1fbd2957
oai_identifier_str oai:ri.conicet.gov.ar:11336/280483
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activationVila Petroff, Martin GerardeMundiña, Cecilia BeatrizLezcano, Noelia ArianaSnabaitis, Andrew K.Huergo, María Ana CristinaValverde, Carlos AlfredoAvkiran, MetinMattiazzi, Ramona AliciaIntracellular pHNa+/H+ exchangerCalcium/calmodulin-dependent protein kinasehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The Na+/H+ exchanger (NHE-1) plays a key role in pHi recovery from acidosis and is regulated by pHi and the ERK1/2-dependent phosphorylation pathway. Since acidosis increases the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cardiac muscle, we examined whether CaMKII activates the exchanger by using pharmacological tools and highly specific genetic approaches. Adult rat cardiomyocytes, loaded with the pHi indicator SNARF-1/AM were subjected to different protocols of intracellular acidosis. The rate of pHi recovery from the acid load (dpHi/dt)—an index of NHE-1 activity in HEPES buffer or in NaHCO3 buffer in the presence of inhibition of anion transporters—was significantly decreased by the CaMKII inhibitors KN-93 or AIP. pHi recovery from acidosis was faster in CaMKII-overexpressing myocytes than in overexpressing β-galactosidase myocytes (dpHi/dt: 0.195 ± 0.04 vs. 0.045 ± 0.010 min− 1, respectively, n = 8) and slower in myocytes from transgenic mice with chronic cardiac CaMKII inhibition (AC3-I) than in controls (AC3-C). Inhibition of CaMKII and/or ERK1/2 indicated that stimulation of NHE-1 by CaMKII was independent of and additive to the ERK1/2 cascade. In vitro studies with fusion proteins containing wild-type or mutated (Ser/Ala) versions of the C-terminal domain of NHE-1 indicate that CaMKII phosphorylates NHE-1 at residues other than the canonical phosphorylation sites for the kinase (Ser648, Ser703, and Ser796). These results provide new mechanistic insights and unequivocally demonstrate a role of the already multifunctional CaMKII on the regulation of the NHE-1 activity. They also prove clinically important in multiple disorders which, like ischemia/reperfusion injury or hypertrophy, are associated with increased NHE-1 and CaMKII.Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Mundiña, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Lezcano, Noelia Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Snabaitis, Andrew K.. Kings College London;Fil: Huergo, María Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Valverde, Carlos Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Avkiran, Metin. Kings College London;Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaAcademic Press Ltd - Elsevier Science Ltd2010-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/280483Vila Petroff, Martin Gerarde; Mundiña, Cecilia Beatriz; Lezcano, Noelia Ariana; Snabaitis, Andrew K.; Huergo, María Ana Cristina; et al.; Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular and Cellular Cardiology; 49; 1; 7-2010; 106-1120022-2828CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0022282809005173info:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2009.12.007info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:23:54Zoai:ri.conicet.gov.ar:11336/280483instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-02-26 10:23:55.009CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
title Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
spellingShingle Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
Vila Petroff, Martin Gerarde
Intracellular pH
Na+/H+ exchanger
Calcium/calmodulin-dependent protein kinase
title_short Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
title_full Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
title_fullStr Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
title_full_unstemmed Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
title_sort Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation
dc.creator.none.fl_str_mv Vila Petroff, Martin Gerarde
Mundiña, Cecilia Beatriz
Lezcano, Noelia Ariana
Snabaitis, Andrew K.
Huergo, María Ana Cristina
Valverde, Carlos Alfredo
Avkiran, Metin
Mattiazzi, Ramona Alicia
author Vila Petroff, Martin Gerarde
author_facet Vila Petroff, Martin Gerarde
Mundiña, Cecilia Beatriz
Lezcano, Noelia Ariana
Snabaitis, Andrew K.
Huergo, María Ana Cristina
Valverde, Carlos Alfredo
Avkiran, Metin
Mattiazzi, Ramona Alicia
author_role author
author2 Mundiña, Cecilia Beatriz
Lezcano, Noelia Ariana
Snabaitis, Andrew K.
Huergo, María Ana Cristina
Valverde, Carlos Alfredo
Avkiran, Metin
Mattiazzi, Ramona Alicia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Intracellular pH
Na+/H+ exchanger
Calcium/calmodulin-dependent protein kinase
topic Intracellular pH
Na+/H+ exchanger
Calcium/calmodulin-dependent protein kinase
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The Na+/H+ exchanger (NHE-1) plays a key role in pHi recovery from acidosis and is regulated by pHi and the ERK1/2-dependent phosphorylation pathway. Since acidosis increases the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cardiac muscle, we examined whether CaMKII activates the exchanger by using pharmacological tools and highly specific genetic approaches. Adult rat cardiomyocytes, loaded with the pHi indicator SNARF-1/AM were subjected to different protocols of intracellular acidosis. The rate of pHi recovery from the acid load (dpHi/dt)—an index of NHE-1 activity in HEPES buffer or in NaHCO3 buffer in the presence of inhibition of anion transporters—was significantly decreased by the CaMKII inhibitors KN-93 or AIP. pHi recovery from acidosis was faster in CaMKII-overexpressing myocytes than in overexpressing β-galactosidase myocytes (dpHi/dt: 0.195 ± 0.04 vs. 0.045 ± 0.010 min− 1, respectively, n = 8) and slower in myocytes from transgenic mice with chronic cardiac CaMKII inhibition (AC3-I) than in controls (AC3-C). Inhibition of CaMKII and/or ERK1/2 indicated that stimulation of NHE-1 by CaMKII was independent of and additive to the ERK1/2 cascade. In vitro studies with fusion proteins containing wild-type or mutated (Ser/Ala) versions of the C-terminal domain of NHE-1 indicate that CaMKII phosphorylates NHE-1 at residues other than the canonical phosphorylation sites for the kinase (Ser648, Ser703, and Ser796). These results provide new mechanistic insights and unequivocally demonstrate a role of the already multifunctional CaMKII on the regulation of the NHE-1 activity. They also prove clinically important in multiple disorders which, like ischemia/reperfusion injury or hypertrophy, are associated with increased NHE-1 and CaMKII.
Fil: Vila Petroff, Martin Gerarde. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Mundiña, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Lezcano, Noelia Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Snabaitis, Andrew K.. Kings College London;
Fil: Huergo, María Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Valverde, Carlos Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
Fil: Avkiran, Metin. Kings College London;
Fil: Mattiazzi, Ramona Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina
description The Na+/H+ exchanger (NHE-1) plays a key role in pHi recovery from acidosis and is regulated by pHi and the ERK1/2-dependent phosphorylation pathway. Since acidosis increases the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in cardiac muscle, we examined whether CaMKII activates the exchanger by using pharmacological tools and highly specific genetic approaches. Adult rat cardiomyocytes, loaded with the pHi indicator SNARF-1/AM were subjected to different protocols of intracellular acidosis. The rate of pHi recovery from the acid load (dpHi/dt)—an index of NHE-1 activity in HEPES buffer or in NaHCO3 buffer in the presence of inhibition of anion transporters—was significantly decreased by the CaMKII inhibitors KN-93 or AIP. pHi recovery from acidosis was faster in CaMKII-overexpressing myocytes than in overexpressing β-galactosidase myocytes (dpHi/dt: 0.195 ± 0.04 vs. 0.045 ± 0.010 min− 1, respectively, n = 8) and slower in myocytes from transgenic mice with chronic cardiac CaMKII inhibition (AC3-I) than in controls (AC3-C). Inhibition of CaMKII and/or ERK1/2 indicated that stimulation of NHE-1 by CaMKII was independent of and additive to the ERK1/2 cascade. In vitro studies with fusion proteins containing wild-type or mutated (Ser/Ala) versions of the C-terminal domain of NHE-1 indicate that CaMKII phosphorylates NHE-1 at residues other than the canonical phosphorylation sites for the kinase (Ser648, Ser703, and Ser796). These results provide new mechanistic insights and unequivocally demonstrate a role of the already multifunctional CaMKII on the regulation of the NHE-1 activity. They also prove clinically important in multiple disorders which, like ischemia/reperfusion injury or hypertrophy, are associated with increased NHE-1 and CaMKII.
publishDate 2010
dc.date.none.fl_str_mv 2010-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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://hdl.handle.net/11336/280483
Vila Petroff, Martin Gerarde; Mundiña, Cecilia Beatriz; Lezcano, Noelia Ariana; Snabaitis, Andrew K.; Huergo, María Ana Cristina; et al.; Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular and Cellular Cardiology; 49; 1; 7-2010; 106-112
0022-2828
CONICET Digital
CONICET
url http://hdl.handle.net/11336/280483
identifier_str_mv Vila Petroff, Martin Gerarde; Mundiña, Cecilia Beatriz; Lezcano, Noelia Ariana; Snabaitis, Andrew K.; Huergo, María Ana Cristina; et al.; Ca2+/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na+/H+ exchanger activation; Academic Press Ltd - Elsevier Science Ltd; Journal of Molecular and Cellular Cardiology; 49; 1; 7-2010; 106-112
0022-2828
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0022282809005173
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2009.12.007
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
publisher.none.fl_str_mv Academic Press Ltd - Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.176822

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