Activation of RyR2 by class I kinase inhibitors.

Autor: Chakraborty AD; Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand., Gonano LA; Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand.; Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina., Munro ML; Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand., Smith LJ; Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand., Thekkedam C; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Staudacher V; School of Pharmacy, University of Otago, Dunedin, New Zealand., Gamble AB; School of Pharmacy, University of Otago, Dunedin, New Zealand., Macquaide N; Institute of Cardiovascular and Medical Sciences and School of Life Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK., Dulhunty AF; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Jones PP; Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2019 Mar; Vol. 176 (6), pp. 773-786. Date of Electronic Publication: 2019 Jan 30.
DOI: 10.1111/bph.14562
Abstrakt: 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 Ca 2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca 2+ 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 Ca 2+ 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.
(© 2018 The British Pharmacological Society.)
Databáze: MEDLINE
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