TY - JOUR T1 - HIV Protease Inhibitors: Suppression of Insulin Secretion by Inhibition of Voltage-Dependent K<sup>+</sup> Currents and Anion Currents JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 106 LP - 112 DO - 10.1124/jpet.105.090589 VL - 316 IS - 1 AU - Yvonne Neye AU - Martina Düfer AU - Gisela Drews AU - Peter Krippeit-Drews Y1 - 2006/01/01 UR - http://jpet.aspetjournals.org/content/316/1/106.abstract N2 - We have shown before that the human immunodeficiency virus (HIV) protease inhibitors ritonavir and nelfinavir, but not indinavir, suppress insulin secretion from mouse pancreatic B-cells via reduction of the cytosolic free calcium concentration ([Ca2+]c). This was not because of an effect on ATP-dependent K+ channels (KATP channels) or L-type Ca2+ channels. The study was intended to elucidate the mechanisms by which distinct HIV protease inhibitors decrease [Ca2+]c and thus evoke their adverse side effect on insulin release. Membrane potential and whole-cell currents were measured with the patch-clamp technique, and [Ca2+]c was determined with a fluorescence dye. Ritonavir and nelfinavir both inhibited the same component(s) of voltage-dependent K+ currents with a concomitant change in action potential wave form, whereas indinavir was ineffective. Comparison with other blockers of voltage-dependent K+ currents revealed that suppression of distinct noninactivating current component(s) altered action potential wave form and decreased [Ca2+]c similar to ritonavir and nelfinavir, whereas blockage of inactivating component(s) was without effect. Complete inhibition of voltage-dependent K+ currents by 80 mM TEA+ drastically increased [Ca2+]c, demonstrating that voltage-dependent K+ channels are not the sole target of ritonavir and nelfinavir. Accordingly, the Ca2+-lowering effect of ritonavir was preserved in the presence of 80 mM TEA+. This effect was mimicked by the anion channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). Consequentially, ritonavir and nelfinavir inhibited a DIDS-sensitive anion current in B-cells. We suggest that ritonavir and nelfinavir decrease insulin secretion by inhibition of voltage-dependent K+ channels and anion channels, which are essential to provide counterion currents for Ca2+ influx across the plasma membrane. The American Society for Pharmacology and Experimental Therapeutics ER -