Author/Editor     Yang, Shi-Bing; Proks, Peter; Ashcroft, Frances M; Rupnik, Marjan
Title     Inhibition of ATP-sensitive potassium channels by haloperidol
Type     članek
Source     Br J Pharmacol
Vol. and No.     Letnik 143
Publication year     2004
Volume     str. 960-7
Language     eng
Abstract     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 (KATP) 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 KATP channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. 3 KATP 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 KATP 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 KATP 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 KATP current by haloperidol was 1.6 microM in 2 mM extracellular K+ concentration ([K+]o) and increased to 23.9 microM 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 KATP channels may contribute to the side effects of this drug when used therapeutically.
Descriptors     ADENOSINE TRIPHOSPHATE
HALOPERIDOL
POTASSIUM CHANNELS
MICE
DOSE-RESPONSE RELATIONSHIP, DRUG
CELL LINE
CELLS, CULTURED