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J. Biol. Chem., Vol. 281, Issue 47, 36029-36035, November 24, 2006

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Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating^*

From the Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510 and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut 06516

The Nav1.7 sodium channel is preferentially expressed in most nociceptive dorsal root ganglion neurons and in sympathetic neurons. Inherited erythromelalgia (IEM, also known as erythermalgia), an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth, has been linked to mutations in Nav1.7. Recently, a substitution of Ser-241 by threonine (S241T) in the domain I S4-S5 linker of Nav1.7 was identified in a family with IEM. To investigate the possible causative role of this mutation in the pathophysiology of IEM, we used whole-cell voltage-clamp analysis to study the effects of S241T on Nav1.7 gating in HEK293 cells. We found a hyperpolarizing shift of activation midpoint by 8.4 mV, an accelerated time to peak, slowing of deactivation, and an increase in the current in response to small, slow depolarizations. Additionally, S241T produced an enhancement of slow inactivation, shifting the midpoint by -12.3 mV. Because serine and threonine have similar biochemical properties, the S241T substitution suggested that the size of the side chain at this position affected channel gating. To test this hypothesis, we investigated the effect of S241A and S241L substitutions on the gating properties of Nav1.7. Although S241A did not alter the properties of the channel, S241L mimicked the effects of S241T. We conclude that the linker between S4 and S5 in domain I of Nav1.7 modulates gating of this channel, and that a larger side chain at position 241 interferes with its gating mechanisms.

Received for publication, August 10, 2006 , and in revised form, September 27, 2006.

^* This work was supported in part by the Medical Research Service and Rehabilitation Research Service, Department of Veterans Administration Rehabilitation Research and Development Service, the National Multiple Sclerosis Society, and the Erythromelalgia Association. The Center for Neuroscience and Regeneration Research is a collaboration of the Paralyzed Veterans of America and the United Spinal Association with Yale University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Postdoctoral Research Training Fellowship of the Epilepsy Foundation of America and UCB Pharma, Inc.

² To whom correspondence should be addressed: Dept. of Neurology, Yale Medical School, LCI 707, P. O. Box 208018, New Haven, CT 06520. Tel.: 203-785-6351; Fax: 203-785-2239; E-mail: Stephen.Waxman{at}yale.edu.

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