J. Kiehn et al., CLONED HUMAN INWARD RECTIFIER K-III METHANESULFONANILIDES( CHANNEL ASA TARGET FOR CLASS), Circulation research, 77(6), 1995, pp. 1151-1155
Methanesulfonanilide derivatives such as dofetilide are members of the
widely used Class III group of cardiac antiarrhythmic drugs. A methan
esulfonanilide-sensitive cardiac current has been identified as I-Kr,
the rapidly activating component of the repolarizing outward cardiac K
+ current, I-K.I-Kr may be encoded by the human ether-related gene (hE
RG), which belongs to the family of voltage-dependent K+ (K-v) channel
s having six putative transmembrane segments. The hERG also expresses
an inwardly rectifying, methanesulfonanilide-sensitive K+ current. Her
e we show that hIRK, a member of the two-transmembrane-segment family
of inward K+ rectifiers that we have cloned from human heart, is a tar
get for dofetilide. hIRK currents, expressed heterologously in Xenopus
oocytes, are blocked by dofetilide at submicromolar concentrations (I
C50=533 nmol/L at 40 mV and 20 degrees C). The drug has no significant
blocking effect on the human cardiac K, channels hK(v)1.2, hK(v)1.4,
hK(v)1.5, or hK(v)2.1. The block is voltage dependent, use dependent,
and shortens open times in a manner consistent with open-channel block
. While steady state block is strongest at depolarized potentials, rec
overy from block is very slow even at hyperpolarized potentials (tau=1
.17 seconds at -80 mV). Thus, block of hIRK may persist during diastol
e and might thereby affect cardiac excitability.