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The Journal of Neuroscience, September 22, 2004, 24(38):8232-8236; doi:10.1523/JNEUROSCI.2695-04.2004
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BRIEF COMMUNICATION
Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy
Theodore R. Cummins,1 Sulayman D. Dib-Hajj,2,3,4 andStephen G. Waxman2,3,4 1Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, 2Department of Neurology and 3Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, and 4Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516
Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of Nav1.7, a sodium channel that produces a tetrodotoxin-sensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. Nav1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from inactivation and by slow closed-state inactivation that results in relatively large responses to small, subthreshold depolarizations. Here we show that these mutations in Nav1.7 produce a hyperpolarizing shift in activation and slow deactivation. We also show that these mutations cause an increase in amplitude of the current produced by Nav1.7 in response to slow, small depolarizations. These observations provide the first demonstration of altered sodium channel function associated with an inherited painful neuropathy and suggest that these physiological changes, which confer hyperexcitability on peripheral sensory and sympathetic neurons, contribute to symptom production in hereditary erythermalgia.
Key words: dorsal root ganglion; hyperpolarization; voltage clamp; tetrodotoxin sensitive; neuropathic pain; skeletal sodium channel
Received July 7, 2004; revised August 6, 2004; accepted August 10, 2004.
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