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Vol. 57, Issue 6, 1218-1223, June 2000
Departments of Physiology and Biophysics (H.-S.W., I.S.C) and
Neurobiology and Behavior (D.M.), Institute of Molecular Cardiology,
State University of New York, Stony Brook, New York; and Central
Nervous System Diseases Research, DuPont Pharmaceuticals,
Wilmington, Delaware (B.S.B.)
Channels formed by coassembly of the KCNQ1 (KvLQT1) subunit and the
minK subunit underlie slowly activating cardiac delayed rectifier
(IKs) in the heart, whereas two other members of the KCNQ
channel family, KCNQ2 and KCNQ3, coassemble to underlie the M current
in the nervous system. Because of their important physiological function, KCNQ channels have potential as drug targets, and an understanding of possible mechanisms that would enable tissue-specific targeting of these channels will be of significant value to drug development. In this study, we examined the role of the minK subunit in
determining the response of KCNQ1 channels to blockade by the cognitive
enhancer XE991. Coexpression with minK markedly decreased the
sensitivity of KCNQ1 to blockade by XE991. When measured at the end of
a 500-ms step, XE991 blockade of the KCNQ1+minK current had a
KD value of 11.1 ± 1.8 µM,
approximately 14-fold less sensitive than the block of the KCNQ1
current (KD = 0.78 ± 0.05 µM).
In addition, XE991 reduced activation and deactivation time constants and caused a rightward shift in the activation curve of KCNQ1+minK, but
affected none of these parameters for KCNQ1 alone. Also, XE991 block of
KCNQ1+minK, but not of KCNQ1, was time- and voltage-dependent. We
conclude that the presence of minK in the IKs channel
complex gives rise to differential sensitivity of KCNQ and
IKs channels to blockade by XE991. Our results have
implications for drug development by demonstrating the important
potential role of accessory subunits in determining the pharmacological
properties of KCNQ channels.
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