A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons

Abstract

Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel Nav1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where Nav1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The selective presence, in sensory but not sympathetic neurons, of the Nav1.8 channel, which remains available for activation at depolarized membrane potentials, is a major determinant of these opposing effects. These results provide a molecular basis for the sympathetic dysfunction that has been observed in erythermalgia. Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed.inherited erythermalgia ͉ neuropathic pain ͉ primary erythromelalgia ͉ sodium channelopathy M utations in voltage-gated sodium channels have been associated with a number of neurological disorders including inherited epilepsy, muscle disorders, and primary erythermalgia, an autosomal dominant neuropathy characterized by pain of the extremities in response to mild warmth. Recent studies have demonstrated mutations in primary erythermalgia in Na v 1.7 (1), a sodium channel that is preferentially expressed within primary sensory [such as nociceptive dorsal root ganglion (DRG)] and sympathetic ganglion [e.g., superior cervical ganglion (SCG)] neurons (2-6). The Na v 1.7 mutations characterized to date produce changes in channel physiology that include hyperpolarizing shifts in activation, depolarizing shifts in steadystate inactivation, slowing of deactivation, and an increase in the ''ramp'' current evoked by slow, small depolarizations, all augmenting the response of Na v 1.7 channels to small stimuli (3, 6, 7). One of these mutations, F1449V, has been assessed at the level of cell function within DRG neurons, where it produces hyperexcitability (3). However, the effects on cell function of Na v 1.7 mutations have not been assessed in sympathetic ganglion neurons, where Na v 1.7 is also present.Because different ensembles of channels are present within DRG and SCG neurons, we hypothesized that the same sodium channel mutation might have different effects on excitability in these two neuronal types. Here we test this hypothesis for one of the first Na v 1.7 erythermalgia mutations to be characterized, L858H (2, 7). We show that although the L858H mutation produces a depolarizing shift in resting membrane potential (RMP) in both cell types, it renders DRG neurons hyperexcitable and SCG neurons hypoexcitable. We demonstrate that the opposing functi...

Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

“…Na v 1.7's role in electrogenesis in DRG neurons is thought to be to sense such transducer currents and amplify them into a signal that activates other VGSCs and that is capable of triggering an action potential (Cummins et al, 1998;Rush et al, 2007). Thus, any hyperpolarizing shift in Na v 1.7 activation will reduce the amount of transducer current necessary to generate firing activity, effectively lowering the neuron's threshold, as has been demonstrated in DRG neurons expressing mutant Na v 1.7 channels with hyperpolarized activation Rush et al, 2006;Han et al, 2009).…”

“…Thus, single amino acid substitutions demonstrated to alter the biophysical gating properties of Na v 1.7 channels and to render DRG neurons hyperexcitable in culture manifest in these patients as a recurrent and debilitating pain syndrome triggered by exposure to warmth and usually described as "burning" (Cummins et al, 2004;DibHajj et al, 2005DibHajj et al, , 2008Han et al, 2006Han et al, , 2009Harty et al, 2006;Rush et al, 2006;Estacion et al, 2008;Lampert et al, 2008;Choi et al, 2010;Cheng et al, 2011). Whether Na v 1.7 contributes similarly to pain following burn injury has thus far remained unexplored.…”

Inherited Pain

“…It may be possible that differences in the degree or distri- bution of the mosaicism may play a role. However, the electrophysiological phenotype of Nav mutations also depends on the cellular expression background, and some effects may be hidden in transfected HEK cells or DRG neurons (21).…”

Intense Isolectin-B4 Binding in Rat Dorsal Root Ganglion Neurons Distinguishes C-Fiber Nociceptors with Broad Action Potentials and High Nav1.9 Expression

“…The likely influence of this on excitability is unclear. Hyperpolarized Ems should reduce resting inactivation of Na ϩ channels (other than Nav1.8) that are present in IB4ϩ C-nociceptors, e.g., Nav1.7 and Nav1.9 Fang et al, 2002;Djouhri et al, 2003a;Rush et al, 2006).…”