Erythromelalgia is an autosomal dominant disorder characterized by burning pain in response to warm stimuli or moderate exercise. We describe a novel mutation in a family with erythromelalgia in SCN9A, the gene that encodes the Na(v)1.7 sodium channel. Na(v)1.7 produces threshold currents and is selectively expressed within sensory neurons including nociceptors. We demonstrate that this mutation, which produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowers thresholds for single action potentials and high frequency firing in dorsal root ganglion neurons. Erythromelalgia is the first inherited pain disorder in which it is possible to link a mutation with an abnormality in ion channel function and with altered firing of pain signalling neurons.

Dorsal root ganglion neurons express an array of sodium channel isoforms allowing precise control of excitability. An increasing body of literature indicates that regulation of firing behaviour in these cells is linked to their patterns of expression of specific sodium channel isoforms, which have been discovered to possess distinct biophysical characteristics. The pattern of expression of sodium channels differs in different subclasses of DRG neurons and is not fixed but, on the contrary, changes in response to a variety of disease insults. Moreover, modulation of channels by their environment has been found to play an important role in the response of these neurons to stimuli. In this review we illustrate how excitability can be finely tuned to provide contrasting firing templates in different subclasses of DRG neurons by selective deployment of various sodium channel isoforms, by plasticity of expression of these proteins, and by interactions of these sodium channel isoforms with each other and with other modulatory molecules.

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...

Nature employs a variety of tactics to precisely time and execute the processes and mechanics of life, relying on sequential sense and response cascades to transduce signaling events over multiple length and time scales. Many of these tactics, such as the activation of a zymogen, involve the direct manipulation of a material by a stimulus. Similarly, effective therapeutics and diagnostics require the selective and efficient homing of material to specific tissues and biomolecular targets with appropriate temporal resolution. These systems must also avoid undesirable or toxic side effects and evade unwanted removal by endogenous clearing mechanisms. Nanoscale delivery vehicles have been developed to package materials with the hope of delivering them to select locations with rates of accumulation and clearance governed by an interplay between the carrier and its cargo. Many modern approaches to drug delivery have taken inspiration from natural activatable materials like zymogens, membrane proteins, and metabolites, whereby stimuli initiate transformations that are required for cargo release, prodrug activation, or selective transport. This Perspective describes key advances in the field of stimuli-responsive nanomaterials while highlighting some of the many challenges faced and opportunities for development. Major hurdles include the increasing need for powerful new tools and strategies for characterizing the dynamics, morphology, and behavior of advanced delivery systems in situ and the perennial problem of identifying truly specific and useful physical or molecular biomarkers that allow a material to autonomously distinguish diseased from normal tissue.

Sodium channels Na v 1.2 and Na v 1.6 are both normally expressed along premyelinated and myelinated axons at different stages of maturation and are also expressed in a subset of demyelinated axons, where coexpression of Na v 1.6 together with the Na + /Ca 2+ exchanger is associated with axonal injury. It has been difficult to distinguish the currents produced by Na v 1.2 and Na v 1.6 in native neurones, and previous studies have not compared these channels within neuronal expression systems. In this study, we have characterized and directly compared Na v 1.2 and Na v 1.6 in a mammalian neuronal cell background and demonstrate differences in their properties that may affect neuronal behaviour. The Na v 1.2 channel displays more depolarized activation and availability properties that may permit conduction of action potentials, even with depolarization. However, Na v 1.2 channels show a greater accumulation of inactivation at higher frequencies of stimulation (20-100 Hz) than Na v 1.6 and thus are likely to generate lower frequencies of firing. Na v 1.6 channels produce a larger persistent current that may play a role in triggering reverse Na + /Ca 2+ exchange, which can injure demyelinated axons where Na v 1.6 and the Na + /Ca 2+ exchanger are colocalized, while selective expression of Na v 1.2 may support action potential electrogenesis, at least at lower frequencies, while producing a smaller persistent current.