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

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