Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib
Autor: | Weng-Onn Lui, Robin Fröbom, Erik Berglund, Catharina Larsson, Robert Bränström, Inga Lena Nilsson, Craig A. Aspinwall |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Sunitinib Chemistry medicine.drug_class Biophysics Imatinib Cell Biology Pharmacology Biochemistry Tyrosine-kinase inhibitor 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Nilotinib 030220 oncology & carcinogenesis medicine Tyrosine Atp sensitive k channel Receptor Molecular Biology Tyrosine kinase medicine.drug |
Zdroj: | Biochemical and Biophysical Research Communications. 557:14-19 |
ISSN: | 0006-291X |
Popis: | The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic β-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 μM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs. |
Databáze: | OpenAIRE |
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