RT Journal Article
SR Electronic
T1 KvLQT1 Potassium Channel but Not IsK Is the Molecular Target fortrans-6-Cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1131
OP 1136
DO 10.1124/mol.52.6.1131
VO 52
IS 6
A1 Gildas Loussouarn
A1 Flavien Charpentier
A1 Raha Mohammad-Panah
A1 Karl Kunzelmann
A1 Isabelle Baró
A1 Denis Escande
YR 1997
UL http://molpharm.aspetjournals.org/content/52/6/1131.abstract
AB 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 oftrans-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.