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Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2013 Aug 28; Vol. 33 (35), pp. 14087-97. - Publication Year :
- 2013
-
Abstract
- Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
- Subjects :
- Amino Acid Sequence
Animals
Cells, Cultured
Humans
Ion Channel Gating
Male
Membrane Potentials
Mice
Mice, Transgenic
Middle Aged
Molecular Sequence Data
NAV1.8 Voltage-Gated Sodium Channel metabolism
Peripheral Nervous System Diseases diagnosis
Peripheral Nervous System Diseases physiopathology
Rats
Rats, Sprague-Dawley
Action Potentials
Ganglia, Spinal physiopathology
Mutation, Missense
NAV1.8 Voltage-Gated Sodium Channel genetics
Neurons physiology
Peripheral Nervous System Diseases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 33
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 23986244
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.2710-13.2013