Activation of RyR2 by class I kinase inhibitors

Autores
Chakraborty, A. D.; Gonano, Luis Alberto; Munro, M. L.; Smith, L. J.; Thekkedam, C.; Staudacher, V.; Gamble, A. B.; Macquaide, N.; Dulhunty, A. F.; Jones, P. P.
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. Key Results: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. Conclusions and Implications: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.
Fil: Chakraborty, A. D.. University of Otago; Nueva Zelanda
Fil: Gonano, Luis Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. University of Otago; Nueva Zelanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Munro, M. L.. University of Otago; Nueva Zelanda
Fil: Smith, L. J.. University of Otago; Nueva Zelanda
Fil: Thekkedam, C.. Australian National University; Australia
Fil: Staudacher, V.. University of Otago; Nueva Zelanda
Fil: Gamble, A. B.. University of Otago; Nueva Zelanda
Fil: Macquaide, N.. University of Glasgow; Reino Unido
Fil: Dulhunty, A. F.. Australian National University; Australia
Fil: Jones, P. P.. University of Otago; Nueva Zelanda
Materia
RyR2
Sunitinib
Nilotinib
ATP
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:11336/130302
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/130302
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of RyR2 by class I kinase inhibitorsChakraborty, A. D.Gonano, Luis AlbertoMunro, M. L.Smith, L. J.Thekkedam, C.Staudacher, V.Gamble, A. B.Macquaide, N.Dulhunty, A. F.Jones, P. P.RyR2SunitinibNilotinibATPhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background and Purpose: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. Key Results: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. Conclusions and Implications: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.Fil: Chakraborty, A. D.. University of Otago; Nueva ZelandaFil: Gonano, Luis Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. University of Otago; Nueva Zelanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Munro, M. L.. University of Otago; Nueva ZelandaFil: Smith, L. J.. University of Otago; Nueva ZelandaFil: Thekkedam, C.. Australian National University; AustraliaFil: Staudacher, V.. University of Otago; Nueva ZelandaFil: Gamble, A. B.. University of Otago; Nueva ZelandaFil: Macquaide, N.. University of Glasgow; Reino UnidoFil: Dulhunty, A. F.. Australian National University; AustraliaFil: Jones, P. P.. University of Otago; Nueva ZelandaWiley Blackwell Publishing, Inc2018-12-26info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/130302Chakraborty, A. D.; Gonano, Luis Alberto; Munro, M. L.; Smith, L. J.; Thekkedam, C.; et al.; Activation of RyR2 by class I kinase inhibitors; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 176; 6; 26-12-2018; 773-7860007-1188CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1111/bph.14562info:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14562info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:53:18Zoai:ri.conicet.gov.ar:11336/130302instacron: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:34982025-09-03 09:53:18.8CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of RyR2 by class I kinase inhibitors
title Activation of RyR2 by class I kinase inhibitors
spellingShingle Activation of RyR2 by class I kinase inhibitors
Chakraborty, A. D.
RyR2
Sunitinib
Nilotinib
ATP
title_short Activation of RyR2 by class I kinase inhibitors
title_full Activation of RyR2 by class I kinase inhibitors
title_fullStr Activation of RyR2 by class I kinase inhibitors
title_full_unstemmed Activation of RyR2 by class I kinase inhibitors
title_sort Activation of RyR2 by class I kinase inhibitors
dc.creator.none.fl_str_mv Chakraborty, A. D.
Gonano, Luis Alberto
Munro, M. L.
Smith, L. J.
Thekkedam, C.
Staudacher, V.
Gamble, A. B.
Macquaide, N.
Dulhunty, A. F.
Jones, P. P.
author Chakraborty, A. D.
author_facet Chakraborty, A. D.
Gonano, Luis Alberto
Munro, M. L.
Smith, L. J.
Thekkedam, C.
Staudacher, V.
Gamble, A. B.
Macquaide, N.
Dulhunty, A. F.
Jones, P. P.
author_role author
author2 Gonano, Luis Alberto
Munro, M. L.
Smith, L. J.
Thekkedam, C.
Staudacher, V.
Gamble, A. B.
Macquaide, N.
Dulhunty, A. F.
Jones, P. P.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RyR2
Sunitinib
Nilotinib
ATP
topic RyR2
Sunitinib
Nilotinib
ATP
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background and Purpose: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. Key Results: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. Conclusions and Implications: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.
Fil: Chakraborty, A. D.. University of Otago; Nueva Zelanda
Fil: Gonano, Luis Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. University of Otago; Nueva Zelanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Munro, M. L.. University of Otago; Nueva Zelanda
Fil: Smith, L. J.. University of Otago; Nueva Zelanda
Fil: Thekkedam, C.. Australian National University; Australia
Fil: Staudacher, V.. University of Otago; Nueva Zelanda
Fil: Gamble, A. B.. University of Otago; Nueva Zelanda
Fil: Macquaide, N.. University of Glasgow; Reino Unido
Fil: Dulhunty, A. F.. Australian National University; Australia
Fil: Jones, P. P.. University of Otago; Nueva Zelanda
description Background and Purpose: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. Key Results: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. Conclusions and Implications: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.
publishDate 2018
dc.date.none.fl_str_mv 2018-12-26
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/11336/130302
Chakraborty, A. D.; Gonano, Luis Alberto; Munro, M. L.; Smith, L. J.; Thekkedam, C.; et al.; Activation of RyR2 by class I kinase inhibitors; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 176; 6; 26-12-2018; 773-786
0007-1188
CONICET Digital
CONICET
url http://hdl.handle.net/11336/130302
identifier_str_mv Chakraborty, A. D.; Gonano, Luis Alberto; Munro, M. L.; Smith, L. J.; Thekkedam, C.; et al.; Activation of RyR2 by class I kinase inhibitors; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 176; 6; 26-12-2018; 773-786
0007-1188
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1111/bph.14562
info:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14562
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
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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 13.13397

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