QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.090589v1 316/1/106    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Neye, Y. Articles by Krippeit-Drews, P. Search for Related Content PubMed PubMed Citation Articles by Neye, Y. Articles by Krippeit-Drews, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL CLOTRIMAZOLE

CELLULAR AND MOLECULAR

HIV Protease Inhibitors: Suppression of Insulin Secretion by Inhibition of Voltage-Dependent K⁺ Currents and Anion Currents

Pharmazeutisches Institut, Tübingen, Germany

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 (K_ATP 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.

Address correspondence to: Dr. Peter Krippeit-Drews, Pharmazeutisches Institut, Auf der Morgenstelle 8, D-72076 Tübingen, Germany. E-mail: peter.krippeit-drews{at}uni-tuebingen.de