Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib

Abstract

The ATP-regulated K⁺ channel (K_ATP) 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 K_ATP channel activity in isolated membrane patches, using a pancreatic β-cell line as a K_ATP channel source. In excised inside-out patches, the activity of the K_ATP 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 (K_BK) or the small (K_SK) 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 K_ATP 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 K_ATP channel. Possibly, this might explain some of the side effects seen with TKIs.

Keywords: ATP-Sensitive K(+) channel; Tyrosine kinase inhibitor.