Modelling of voltage-dependent gating and sodium currents in the Kv1.5 potassium channel

Activation gating in voltage-gated potassium channels involves multiple closed-closed transitions prior to channel opening. We have examined various voltage-dependent properties of activation gating in the human Kvl.5 potassium channel heterologously expressed in HEK-293 cells. Two gating charge systems have been described in another voltage-gated potassium channel, Shaker, and the analogous charge systems in Kvl.5 share similar features with Shaker. These two charge systems, Ql and Q2, had characteristic voltage-dependence and sensitivity with Wi values of-29.6 ± 1.6 mV, and -2.19 ± 2.09 mV, and effective valences of 1.87 ±0.15 and 5.53 ± 0.27 (e⁻) respectively. The contribution to total gating charge was 0.20 ± 0.04 for Q l , and 0.80 ±0.04 (n=5) for Q2. Using the drug 4-AP to isolate early gating transitons, Ql and Q2 were found to move in a sequential manner during activation. Gating currents resulting from the movement of these two charge systems were modelled with a simple linear sequential scheme and activation gating was considered with respect to gating in other voltage-gated potassium channels and compared with other kinetic models of channel activation. A concerted opening transition was added to this gating current model and the model was used to simulate sodium ionic currents through Kvl.5 channels. C-type inactivated Kvl.5 channels were found to conduct small Na+ ionic currents, while remaining K ⁺ impermeant. Experimental observations and modelling of this ionic current revealed a high Na+ conducting state during recovery from inactivation and a role for external NA ⁺ in the modulation of fast recovery from inactivation was uncovered.Medicine, Faculty ofCellular and Physiological Sciences, Department ofGraduat