Inhibition of ATP-sensitive potassium channels by haloperidol

1 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 beta cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. 2 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. 3 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. 4 Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2DeltaC36 K-ATP channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. 5 The IC50 for inhibition of the K-ATP current by haloperidol was 1.6 muM in 2 mM extracellular K+ concentration ([K+](o)) and increased to 23.9 muM 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. 6 Haloperidol block of K-ATP channels may contribute to the side effects of this drug when used therapeutically.