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Cardiovascular Research 2003 58(1):46-54; doi:10.1016/S0008-6363(02)00831-3
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Drug- and mutagenesis-induced changes in the selectivity filter of a cardiac two-pore background K+ channel

Péter Hajdúa, Chris Ulensb, György Panyic and Jan Tytgatb,*

aCell Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, H-4012 Debrecen, Hungary
bLaboratory of Toxicology, Faculty of Pharmaceutical Sciences, Catholic University of Leuven, E. Van Evenstraat 4, B-3000 Leuven, Belgium chris.ulens{at}farm.kuleuven.ac.be jan.tytgat{at}farm.kuleuven.ac.be
cDepartment of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, H-4012 Debrecen, Hungary panyi{at}jaguar.dote.hu

* Corresponding author. Tel.: +32-16-323-403; fax: +32-16-323-405. hajdup{at}jaguar.dote.hu

Objective: As compared with voltage-gated K+ channels (Kv-type), our knowledge of the structure-function and pharmacology of two-pore background K+ channels is still very limited. Here we have used a drug- and mutagenesis-based approach to study the effect of the antidepressant fluoxetine (FL) and analgesic D-norpropoxyphene (NORP) on the cardiac two-pore background K+ channel. Methods: Whole-cell currents of the cTBAK-1 channel expressed in Xenopus laevis oocytes were investigated using conventional two-microelectrode voltage-clamp recording method combined with functional mutagenesis of the channel protein. Results: Both drugs inhibit cTBAK-1 current: FL proved to be a voltage-dependent pore-blocker, while NORP induced a change in the selectivity of cTBAK-1 giving rise to a shift in the reversal potential (Erev) toward more positive voltages due to an increased Na+ permeability. Mutations were introduced into the selectivity filter of the first (Y105F) and the second (F211Y) pore to mimic the P-region of HERG (GFGN) and Kv1.1 (GYGD) channels. Point mutations in the channel resulted in two distinct phenotypes of cTBAK-1: the mutant Y105F channel lost its selectivity and was unaffected by NORP, in contrast to the F211Y mutant. Conclusion: FL and NORP block the current of cTBAK-1 channels differently, the latter modified the selectivity of the channel pore. Our mutagenesis study revealed that NORP interacts with the selectivity filter of cTBAK-1. The significant role of the GYGD motif in this type of K+ channels is emphasized.

KEYWORDS Ion channels; K-channel; Membrane currents; Membrane permeability/physics; Myocytes


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