Abstract
The Hodgkin-Huxley model of delayed repolarization of the sodium-dependent action potential assigns a voltage-dependent delayed rectifier K+ current for repolarization. However, here we show that one of the largest components of the delayed rectifier current in many mammalian neurons has gone unnoticed and is due to a Na+-activated-K+-current/Persistent-Na+-current coupled system. Previous studies of potassium conductances in mammalian neurons may have overlooked this large outward component because the sodium channel blocker TTX is typically used in such studies; we find that, in addition to blocking sodium currents, TTX also eliminates this delayed rectifier component as a secondary consequence. We unexpectedly found that the activity of the persistent inward sodium current (persistent INa) at cell resting potentials is the essential factor in activating the Na+-dependent (TTX-sensitive) delayed rectifier current. The persistent INa apparently maintains Na+-activated K+ channels in a “primed” state so that, upon depolarization, they carry a delayed outward conductance. Persistent INa appears to raise the local concentration of Na+ in the vicinity of Na+-activated K+ channels to higher levels than that of the bulk cytosol, possibly because of a submembrane diffusion-restricted space variously referred to in the literature as an “unstirred” layer” or “fuzzy” space”. We showed that “depleting” or “filling” this diffusion-restricted space by the action of persistent INa requires several seconds at cell resting potentials. Using siRNA techniques we identified SLO2.2 (Slack) channels as carriers of the Na+-dependent delayed rectifier current. These findings of a previously unseen K+ conductance involving a finely tuned partnership linking persistent INa and Na+-activated K+ channels, have far reaching implications for many neurons of the mammalian brain. Studies of “up-down” states of neuronal excitability, spike adaptation, synaptic integration, and other aspects of neuronal physiology may have to be reexamined taking this system into account.
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