Activation of the rapid, delayed rectifier K current (I-Kr) is important fo
r normal repolarization of cardiac action potentials, especially in mammali
an ventricular muscle. The study of this current has been greatly aided by
the discovery that the human ether-a-go-go-related gene (HERG) encodes the
pore-forming alpha subunits of these channels. As for other voltage-activat
ed K+ channels, divalent and trivalent cations affect the gating of HERG ch
annels by screening negative membrane surface charges or by direct interact
ion with the channel gating mechanism. Previous studies have reported that
I-Kr Of myocytes, and HERG channels heterologously expressed in Xenopus ooc
ytes, are reduced by external Co2+ and La3+. We have reinvestigated the "bl
ocking" effect of Co2+ and La3+ on HERG channels expressed in Xenopus oocyt
es. At concentrations previously reported to block I-Kr or HERG current (I-
HERG), Co2+ (10 mM) and La3+ (10 CIM) had only small effects on the magnitu
de of fully activated I-HERG The apparent block results from altered kineti
cs and voltage dependence of gating, similar to the effects of Ca2+ on HERG
channels. Under control conditions, the half-points for voltage-dependent
activation and inactivation of HERG were -35+/-2.1 and -76.3+/-1.7 mV, resp
ectively. Co2+ and La3+ accelerated the rate of deactivation, decreased the
rate of current activation, and shifted the half-point of the HERG channel
activation curve by +53 and +65 mV, respectively. Co2+ Shifted the voltage
dependence of inactivation by +14 mV, whereas La3+ had no effect. Co2+ als
o slowed the onset of I-HERG inactivation and accelerated the rate of recov
ery from inactivation. These results indicate that reduction of IHERG by Co
2+ (10 mM) and La3+ (10 mu M) during depolarizing pulses is caused by a pos
itive shift in the voltage dependence of activation, and does not result fr
om pore block.