Nav 1 . 3 ramp currents 1 The response of NaV 1 . 3 sodium channels to ramp stimuli : multiple components and 1 mechanisms

41 42 Nav1.3 voltage-gated sodium channels have been shown to be expressed at increased levels 43 within axotomized dorsal root ganglion (DRG) neurons and within injured axons within neuromas and 44 have been implicated in neuropathic pain. Like a number of other sodium channel isoforms, Nav1.3 45 channels produce a robust response to slow ramplike stimuli. Here we show that the response of Nav1.3 46 to ramp stimuli consists of two components: an early component, dependent upon ramp rate, that 47 corresponds to a window current that is dependent upon closed-state inactivation, and a second 48 component at more depolarized potentials that is correlated with persistent current which is detected for 49 many tens of milliseconds after the start of a depolarizing pulse. We also assessed the K354Q Nav1.3 50 epilepsy-associated mutant channel, which is known to display an enhanced persistent current, and 51 demonstrate a strong correlation with the second component of the ramp response. Our results show that 52 a single sodium channel isoform can produce a ramp response with multiple components, reflecting 53 multiple mechanisms, and suggest that the upregulatied expression of Nav1.3 in axotomized DRG 54 neurons and enhanced ramp current in K354Q mutant channels can contribute in several ways to 55 hyperexcitability and abnormal spontaneous firing that contribute to hyperexcitability disorders such as 56 epilepsy and neuropathic pain. 57