Activation of RyR2 by class I kinase inhibitors

A.D. Chakraborty, L.A. Gonano, M.L. Munro, L.J. Smith, C. Thekkedam, V. Staudacher, A.B. Gamble, N. Macquaide, A.F. Dulhunty, P.P. Jones*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)773-786
Number of pages14
JournalBritish Journal of Pharmacology
Volume176
Issue number6
Early online date30 Jan 2019
DOIs
Publication statusPublished - Mar 2019

Keywords

  • Animals
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Imidazoles/pharmacology
  • Ligands
  • Male
  • Muscle Cells/drug effects
  • Naphthyridines/pharmacology
  • Protein Kinase Inhibitors/pharmacology
  • Pyridazines/pharmacology
  • Pyrimidines/pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Ryanodine Receptor Calcium Release Channel/metabolism
  • Single-Cell Analysis
  • Structure-Activity Relationship
  • Sunitinib/pharmacology

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    Chakraborty, A. D., Gonano, L. A., Munro, M. L., Smith, L. J., Thekkedam, C., Staudacher, V., Gamble, A. B., Macquaide, N., Dulhunty, A. F., & Jones, P. P. (2019). Activation of RyR2 by class I kinase inhibitors. British Journal of Pharmacology, 176(6), 773-786. https://doi.org/10.1111/bph.14562