KVLQT1 POTASSIUM CHANNEL BUT NOT ISK IS THE MOLECULAR TARGET FOR NYL-N-METHYLAMINO)-3-HYDROXY-2,2-DIMETHYL-CHROMANE

Mutations in the KvLQT1 gene are the cause for the long QT syndrome [C irculation 94:1996-2012 (1996)]. Coexpression of KvLQT1 in association with the channel regulator protein IsK produces a K+ current with cha racteristics reminiscent of the slow component of the delayed rectifie r in cardiac myocytes. We explored the pharmacological properties of o nyl-N-methylamino)-3-hydroxy-1,2-dimethylchromane (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 re corded by means of the whole-cell and cell-attached patch-clamp config urations under chloride-free conditions. Cells injected with KvLQT1 cD NA alone exhibited a fast-activating outward K+ current, whereas cells coinjected with KvLQT1 plus IsK cDNAs exhibited a time-dependent outw ard current with slower activation kinetics. The chromanol 293B blocke d the K+ current related to KvLQT1 expression in both the absence or p resence of IsK. The IC50 value for 293B to block KvLQT1-related curren t was not significantly modified by the presence of IsK (9.9 mu M in t he absence of IsK versus 9.8 mu M 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 co nstants for the drug to block the current were in the same order of ma gnitude as activation kinetics of the current. Kinetics for drug unblo ck at the holding potential were much faster, in the order of a few te nths of a msec. KvLQT1 currents recorded in the cell-attached configur ation were also blocked by externally applied 293B, suggesting that th e compound penetrated the cell to block the channel. Cromakalim, anoth er chromanol compound, also blocked KvLQT1 currents. Our results show that the chromanol compound 293B is targeted to KvLQT1 channels but no t to the IsK regulator.