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Vol. 52, Issue 6, 1131-1136, 1997
Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et
Moléculaires, Institut National de la Santé et de la
Recherche Médicale CJF96-01, Hôpital Hotel-Dieu, Nantes,
France (G.L., F.C., R.M-P, I.B., D.E.), and
Institute of Physiology,
Albert-Ludwigs-Universität, Freiburg, Germany (K.K.)
Mutations in the KvLQT1 gene are the cause for the
long QT syndrome [Circulation 94:1996-2012
(1996)]. Coexpression of KvLQT1 in association with the channel
regulator protein IsK produces a K+ current with
characteristics reminiscent of the slow component of the delayed
rectifier in cardiac myocytes. We explored the pharmacological
properties of
trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane (293B), a chromanol compound, on the K+ current produced by
direct intranuclear injection of KvLQT1 and IsK cDNA plasmids in COS-7
cells. Injected cells were recorded by means of the whole-cell and
cell-attached patch-clamp configurations under chloride-free
conditions. Cells injected with KvLQT1 cDNA alone exhibited a
fast-activating outward K+ current, whereas cells
coinjected with KvLQT1 plus IsK cDNAs exhibited a time-dependent
outward current with slower activation kinetics. The chromanol 293B
blocked the K+ current related to KvLQT1 expression in both
the absence or presence of IsK. The IC50 value for 293B to
block KvLQT1-related current was not significantly modified by the
presence of IsK (9.9 µM in the absence of IsK versus 9.8 µM in its presence). The block produced by 293B was
strongly voltage-dependent inasmuch as it was close to 0 at 
80 mV and
occurred during a depolarizing voltage step. The time constants for the
drug to block the current were in the same order of magnitude as
activation kinetics of the current. Kinetics for drug unblock at the
holding potential were much faster, in the order of a few tenths of a
msec. KvLQT1 currents recorded in the cell-attached configuration were
also blocked by externally applied 293B, suggesting that the compound
penetrated the cell to block the channel. Cromakalim, another chromanol
compound, also blocked KvLQT1 currents. Our results show that the
chromanol compound 293B is targeted to KvLQT1 channels but not to the
IsK regulator.
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