Altered gating of HERG potassium channels by cobalt and lanthanum

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.