A high-Na+ conduction state during recovery from inactivation in the K+ channel Kv1.5

Na+ conductance through cloned K+ channels has previously allowed character ization of inactivation and K+ binding within the pore, and here we have us ed Na+ permeation to study recovery from C-type inactivation in human Kv1.5 channels. Replacing K+ in the solutions with Na+ allows complete Kv1.5 ina ctivation and alters the recovery. The inactivated state is nonconducting f or K+ but has a Na+ conductance of 13% of the open state. During recovery, inactivated channels progress to a higher Na+ conductance state (R) in a vo ltage-dependent manner before deactivating to closed-inactivated states. Ch annels finally recover from inactivation in the closed configuration. In th e R state channels can be reactivated and exhibit supernormal Na+ currents with a slow biexponential inactivation. Results suggest two pathways for en try to the inactivated state and a pore conformation, perhaps with a higher Na+ affinity than the open state. The rate of recovery from inactivation i s modulated by Na-o(+) such that 135 mM Na-o(+) promotes the recovery to no rmal closed, rather than closed-inactivated states. A kinetic model of reco very that assumes a highly Na+-permeable state and deactivation to closed-i nactivated and normal closed states at negative voltages can account for th e results. Thus these data offer insight into how Kv1.5 channels recover th eir resting conformation after inactivation and how ionic conditions can mo dify recovery rates and pathways.