Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352.

Abstract

The compound BMS-204352 has been targeted for use against acute ischemic stroke, due to its activation of the large-conductance Ca2+-activated K-channel (BK). We have previously described that the racemate (+/-)BMS-204352 reversibly modulates KCNQ4 voltage dependency. Here we show that (+/-)BMS-204352 also induces a voltage-independent KCNQ4 current. The channels were stably expressed in human embryonic kidney cells (HEK293), and investigated by use of the whole-cell mode of the patch-clamp technique. (+/-)BMS-204352 was applied extracellularly (10 microM) in order to precipitate the robust appearance of the voltage-independent current. The voltage-independent KCNQ4 currents were recorded as instantaneous increases in currents upon hyperpolarizing or depolarizing voltage steps elicited from holding potentials of -90 or -110 mV. The voltage-independent current reversed at the equilibrium potential for potassium ( E(K)), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine. Similar results were obtained with KCNQ4 channels transiently transfected into Chinese hamster ovary cells (CHO). When (+/-)BMS-204352 was applied to stably expressed BK channels, only the voltage dependency was modulated. Retigabine, the classic activator of KCNQ channels, did not induce voltage-independent currents. Our data indicate that KCNQ4 channels may conduct voltage-dependent and voltage-independent currents in the presence of (+/-)BMS-204352.

• Authors: Rikke Louise Schrøder, Dorte Strøbaek, Søren-Peter Olesen, Palle Christophersen
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 446 Issue 5 Pg. 607-16 (Aug 2003) ISSN: 0031-6768 [Print] Germany
• PMID: 12851819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMS204352
• Calcium Channel Agonists
• Indoles
• KCNQ Potassium Channels
• KCNQ4 protein, human
• Potassium Channels
• Potassium Channels, Voltage-Gated

Topics

• Animals
• CHO Cells
• Calcium Channel Agonists (pharmacology)
• Cricetinae
• Humans
• Indoles (pharmacology)
• Ion Channel Gating (drug effects, physiology)
• KCNQ Potassium Channels
• Kidney (cytology)
• Membrane Potentials (drug effects, physiology)
• Patch-Clamp Techniques
• Potassium Channels (physiology)
• Potassium Channels, Voltage-Gated