Nonlinear effects of hyperpolarizing shifts in activation of mutant Nav1.7 channels on resting membrane potential.
The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation in a hyperpolarizing direction. When expressed within DRG neurons, these mutations produce a depolarization of resting membrane potential (RMP). The biophysical basis for the depolarized RMP has to date not been established. To explore the effect on RMP of the shift in activation associated with a prototypical IEM mutation (L858H), we used dynamic-clamp models that represent graded shifts that fractionate the effect of the mutation on activation voltage dependence. Dynamic-clamp recording from DRG neurons using a before-and-after protocol for each cell made it possible, even in the presence of cell-to-cell variation in starting RMP, to assess the effects of these graded mutant models. Our results demonstrate a nonlinear, progressively larger effect on RMP as the shift in activation voltage dependence becomes more hyperpolarized. The observed differences in RMP were predicted by the "late" current of each mutant model. Since the depolarization of RMP imposed by IEM mutant channels is known, in itself, to produce hyperexcitability of DRG neurons, the development of pharmacological agents that normalize or partially normalize activation voltage dependence of IEM mutant channels merits further study.NEW & NOTEWORTHYInherited erythromelalgia (IEM), the first human pain disorder linked to a sodium channel, is widely regarded as a genetic model of neuropathic pain. IEM is produced by Nav1.7 mutations that hyperpolarize activation. These mutations produce a depolarization of resting membrane potential (RMP) in dorsal root ganglion neurons. Using dynamic clamp to explore the effect on RMP of the shift in activation, we demonstrate a nonlinear effect on RMP as the shift in activation voltage dependence becomes more hyperpolarized.
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut; and.|Rehabilitation Research Center, Department of Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
Mark
M
Estacion
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut; and stephen.waxman@yale.edu.|Rehabilitation Research Center, Department of Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
Stephen G
SG
Waxman
D000818:Animals; D001703:Biophysics; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics*; D008959:Models, Neurological; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques
D062556:NAV1.7 Voltage-Gated Sodium Channel
Nav1.7; dynamic clamp; persistent current