These three subpopulations of Na⁺ conductances are similar in their voltage dependence (activating with depolarization) and sensitivity to tetrodotoxin (TTX). However, each exerts a distinct influence on the behavior of membrane voltage. The fast (I-NaF) and persistent (I-NaP) Na⁺ conductances were previously identified in mature rat cerebellar granule cells (D’Angelo et al., 1998). The resurgent (NaR) conductance, also taken from D’Angelo et al. (2001), supports repetitive firing by virtue of its rapid transition from open to closed states via a blocked state (bypassing inactivation) following repolarization. I-NaR is likely carried by a subpopulation of NaF channels containing the NaV1.6 a subunit (Raman and Bean, 2001), which is thought to mediate the above-mentioned properties of the channel.

The fast Na⁺ current, I-NaF, is responsible for the classical depolarizing phase of the Hodgkin-Huxley (1952) action potential. Conceptually, the channel underlying this current can be thought of as occupying one of three states at any given time. The channel is closed at membrane potentials more hyperpolarized than around —40mV. In the closed state, no ions pass through the channel and the conductance appears to be at rest. It is possible to transition from the closed state to the open state by depolarizing the cell membrane to a threshold level. The inward Na⁺ current flowing through a single channel will cause additional depolarization, resulting in a chain-reaction type event wherein all NaF channels are opened and an action potential depolarizing spike is initiated. As the membrane potential approaches the reversal potential for Na⁺, the point at which the electrochemical gradient for Na⁺ ions switches to an outward direction (+87.39mV in this model), NaF channels transition from the open state into an inactivated state from which the open state cannot be directly reached. Hyperpolarization to beyond threshold levels allows the NaF channels to recover into the closed state, at which point they are primed for another depolarizing event.

Although the fast Na⁺ channel is effective at providing brief, large depolarizing currents in the spiking neuron, it cannot account for many of the complex current-voltage responses of neurons such as fast repetitive firing, bursting, and subthreshold resonance (D’Angelo et al., 2001). These more sophisticated electrical responses require the involvement of two other major classes of neurally expressed Na⁺ channels, NaP and NaR. The persistent sodium channel, NaP, activates more slowly than NaF and at a more hyperpolarized membrane potential. NaP also does not inactivate, which allows it to remain open for an extended period of time after initial depolarization. Importantly for this model, NaP has been shown to amplify ionotropic glutamatergic EPSPs below the threshold for spike generation (Berman, Dunn, and Maler, 2001), and to act in concert with the slow, muscarinic K⁺ channel, KM, to control the duration of bursting events during which spikes are rapidly generated from a plateau depolarization (D’Angelo et al., 2001).

During fast-repetitive firing, neurons can fire action potentials at rates upwards of 100Hz. This requires rapid recovery from the afterhyperpolarization following each spike, which may not be supported by the delay required for NaF channels to pass through the inactivated state to the closed state and finally reopen upon depolarization. The resurgent Na⁺ current, NaR, is carried by a subfamily of Na⁺ channels that inactivate and recover by two separate mechanisms depending on voltage dynamics (Raman and Bean, 2001). Following slow repolarization, NaR channels must pass through inactivated and closed states, similarly to NaF. However, brief, large depolarization followed by fast repolarization, such as that seen during an action potential waveform, causes NaR channels to transition into a temporary "blocked" state from which they reopen immediately upon reaching threshold (Raman and Bean, 2001). This property enables the generation of action potentials at high frequencies and sharpens the upstroke of each successive action potential by removing the inflection point caused by slow NaF recovery from inactivation.

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