Section Days abstract book 2010.indd - RUB Research School ...

LS_19
Inhibition of IKs channels by JNJ-303
Eva Wrobel 1,2 , Rob Towart 3 , Joannes TM Linders 3 and Guiscard Seebohm 1
1
Department of Biochemistry I, Ruhr-University Bochum, 44780 Bochum, Germany
2
Graduate School of Chemistry and Biochemistry, Ruhr-University Bochum Research
School
3
Center of Excellence for Cardiovascular Safety Research & Mechanistic Pharmacology,
Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen
Pharmaceutica N.V., B-2340, Beerse, Belgium
e-mail: Eva.Wrobel@rub.de
Cardiac potassium channels are membrane proteins that enable controlled ion passage through
cellular membranes to allow electrical control of the cardiac cell. In a variety of acquired as
well as inherited channelopathies, the function of these channels is altered. Thus, channel
modulators that restore normal channel function are promising candidates for the treatment of
these potentially fatal diseases. However, to date only a limited set of channel inhibitors and
few channel activators are known. In cardiac myocytes the repolarizing potassium current
results from the two currents IKr (Kv11.1) and IKs (Kv7.1+KCNE1). The concerted activity of
these currents is crucial for the precise timing and efficiency of cardiac repolarization,
indicating a functional interaction of these two channels. Furthermore, recent studies
suggested that there might be a more direct modulation of IKr and IKs. A novel compound
reported to inhibit cardiac IKs channels is JNJ-303. Consistently, binding of 3 H-JNJ-303 could
be detected in a binding assay. Here, we report that JNJ-303 modulates IKs channel gating.
Further, we want to clarify if co-expression of Kv11.1 α-subunits alters the effective
inhibiting concentration of JNJ-303 on IKs channels. Finally, we have started to gain insights
into the molecular mechanisms underlying these effects by 3D-homology modeling, drug
docking and all-atoms-mobile molecular dynamic calculations.
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