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dc.contributor.author
Chakraborty, A. D.
dc.contributor.author
Gonano, Luis Alberto
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dc.contributor.author
Munro, M. L.
dc.contributor.author
Smith, L. J.
dc.contributor.author
Thekkedam, C.
dc.contributor.author
Staudacher, V.
dc.contributor.author
Gamble, A. B.
dc.contributor.author
Macquaide, N.
dc.contributor.author
Dulhunty, A. F.
dc.contributor.author
Jones, P. P.
dc.date.available
2021-04-19T04:57:43Z
dc.date.issued
2018-12-26
dc.identifier.citation
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
dc.identifier.issn
0007-1188
dc.identifier.uri
http://hdl.handle.net/11336/130302
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Wiley Blackwell Publishing, Inc
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
RyR2
dc.subject
Sunitinib
dc.subject
Nilotinib
dc.subject
ATP
dc.subject.classification
Farmacología y Farmacia
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Activation of RyR2 by class I kinase inhibitors
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-11-19T22:01:30Z
dc.journal.volume
176
dc.journal.number
6
dc.journal.pagination
773-786
dc.journal.pais
Reino Unido
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dc.journal.ciudad
Londres
dc.description.fil
Fil: Chakraborty, A. D.. University of Otago; Nueva Zelanda
dc.description.fil
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
dc.description.fil
Fil: Munro, M. L.. University of Otago; Nueva Zelanda
dc.description.fil
Fil: Smith, L. J.. University of Otago; Nueva Zelanda
dc.description.fil
Fil: Thekkedam, C.. Australian National University; Australia
dc.description.fil
Fil: Staudacher, V.. University of Otago; Nueva Zelanda
dc.description.fil
Fil: Gamble, A. B.. University of Otago; Nueva Zelanda
dc.description.fil
Fil: Macquaide, N.. University of Glasgow; Reino Unido
dc.description.fil
Fil: Dulhunty, A. F.. Australian National University; Australia
dc.description.fil
Fil: Jones, P. P.. University of Otago; Nueva Zelanda
dc.journal.title
British Journal of Pharmacology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/bph.14562
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14562
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