Resurgent current of voltage-gated Na⁺ channels

Resurgent Na⁺ current results from a distinctive form of Na⁺ channel gating, originally identified in cerebellar Purkinje neurons. In these neurons, the tetrodotoxin-sensitive voltage-gated Na⁺ channels responsible for action potential firing have specialized mechanisms that reduce the likelihood that they accumulate in fast inactivated states, thereby shortening refractory periods and permitting rapid, repetitive, and/or burst firing. Under voltage clamp, step depolarizations evoke transient Na⁺ currents that rapidly activate and quickly decay, and step repolarizations elicit slower channel reopening, or a 'resurgent' current. The generation of resurgent current depends on a factor in the Na⁺ channel complex, probably a subunit such as Na_Vß4 (Scn4b), which blocks open Na⁺ channels at positive voltages, competing with the fast inactivation gate, and unblocks at negative voltages, permitting recovery from an open channel block along with a flow of current. Following its initial discovery, resurgent Na⁺ current has been found in nearly 20 types of neurons. Emerging research suggests that resurgent current is preferentially increased in a variety of clinical conditions associated with altered cellular excitability. Here we review the biophysical, molecular and structural mechanisms of resurgent current and their relation to the normal functions of excitable cells as well as pathophysiology.