Inhibition of ATP-sensitive potassium channels by haloperidol

Abstract

Chronic haloperidol treatment has been associated with an increased incidence of glucose intolerance and type-II diabetes mellitus. We studied the effects of haloperidol on native ATP-sensitive potassium (K ATP) channels in mouse pancreatic β cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. The inhibitory effect of haloperidol on the K ATP channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. K ATP currents were studied using the patch-clamp technique in whole-cell and outside-out patch configurations. Addition of haloperidol to the extracellular solution inhibited the K ATP conductance immediately, in a reversible and voltage-independent manner. Haloperidol did not block the channel when applied intracellularly in whole-cell recordings. Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2ΔC36 K ATP channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. The IC 50 for inhibition of the K ATP current by haloperidol was 1.6 μM in 2 mM extracellular K + concentration ([K +] o) and increased to 23.9 μM in 150 mM [K +] o. The Hill coefficient was close to unity, suggesting that the binding of a single molecule of haloperidol is sufficient to close the channel. Haloperidol block of K ATP channels may contribute to the side effects of this drug when used therapeutically.