title: Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders.
abstract: BACKGROUND
  Two groups of gain-of-function mutations in sodium channel NaV1.7, which are expressed in dorsal root ganglion (DRG) neurons, produce two clinically-distinct pain syndromes - inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is characterized by intermittent burning pain and skin redness in the feet or hands, triggered by warmth or mild exercise, while PEPD is characterized by episodes of rectal, ocular and mandibular pain accompanied with skin flushing, triggered by bowel movement and perianal stimulation. Most of the IEM mutations are located within channel domains I and II, while most of the PEPD mutations are located within domains III and IV. The structural dichotomy parallels the biophysical effects of the two types of mutations, with IEM mutations shifting voltage-dependence of NaV1.7 activation in a hyperpolarized direction, and PEPD mutations shifting fast-inactivation of NaV1.7 in a depolarized direction. While four IEM and four PEPD mutations are located within cytoplasmic linkers joining segments 4 and 5 (S4-S5 linkers) in the different domains (IEM: domains I and II; PEPD: domains III and IV), no S4-S5 linker has been reported to house both IEM and PEPD mutations thus far.
  
  
  RESULTS
  We have identified a new IEM mutation P1308L within the C-terminus of the DIII/S4-S5 linker of NaV1.7, ten amino acids from a known PEPD mutation V1298F which is located within the N-terminus of this linker. We used voltage-clamp to compare the biophysical properties of the two mutant channels and current-clamp to study their effects on DRG neuron excitability. We confirm that P1308L and V1298F behave as prototypical IEM and PEPD mutations, respectively. We also show that DRG neurons expressing either P1308L or V1298F become hyperexcitable, compared to DRG neurons expressing wild-type channels.
  
  
  CONCLUSIONS
  Our results provide evidence for differential roles of the DIII/S4-S5 linker N- and C-termini in channel inactivation and activation, and demonstrate the cellular basis for pain in patients carrying these mutations.
authors.affiliation: Department of Neurology and Center for Neuroscience & Regeneration Research, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Dowain A
authors.initials: DA
authors.lastname: Wright
authors.forename: Tanya Z
authors.initials: TZ
authors.lastname: Fischer
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004594:Electrophysiology; D004916:Erythromelalgia / Q000235:genetics*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D006801:Humans; D008297:Male; D009154:Mutation; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013001:Somatoform Disorders / Q000235:genetics*
chemical_list: D015222:Sodium Channels