The response of Na(V)1.3 sodium channels to ramp stimuli: multiple components and mechanisms

Na(V)1.3 voltage-gated sodium channels have been shown to be expressed at increased levels within axotomized dorsal root ganglion neurons and within injured axons within neuromas and have been implicated in neuropathic pain. Like a number of other sodium channel isoforms, Na(V)1.3 channels produce a robust response to slow ramplike stimuli. Here we show that the response of Na(V)1.3 to ramp stimuli consists of two components: an early component, dependent upon ramp rate, that corresponds to a window current that is dependent upon closed-state inactivation; and a second component at more depolarized potentials that is correlated with persistent current which is detected for many tens of milliseconds after the start of a depolarizing pulse. We also assessed the K354Q Na(V)1.3 epilepsy-associated mutant channel, which is known to display an enhanced persistent current and demonstrate a strong correlation with the second component of the ramp response. Our results show that a single sodium channel isoform can produce a ramp response with multiple components, reflecting multiple mechanisms, and suggest that the upregulated expression of Na(V)1.3 in axotomized dorsal root ganglion neurons and enhanced ramp current in K354Q mutant channels can contribute in several ways to hyperexcitability and abnormal spontaneous firing that contribute to hyperexcitability disorders, such as epilepsy and neuropathic pain.