Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7.
BACKGROUND
The disabling chronic pain syndrome erythromelalgia (also termed erythermalgia) is characterized by attacks of burning pain in the extremities induced by warmth. Pharmacological treatment is often ineffective, but the pain can be alleviated by cooling of the limbs. Inherited erythromelalgia has recently been linked to mutations in the gene SCN9A, which encodes the voltage-gated sodium channel Nav1.7. Nav1.7 is preferentially expressed in most nociceptive DRG neurons and in sympathetic ganglion neurons. It has recently been shown that several disease-causing erythromelalgia mutations alter channel-gating behavior in a manner that increases DRG neuron excitability.


RESULTS
Here we tested the effects of temperature on gating properties of wild type Nav1.7 and mutant L858F channels. Whole-cell voltage-clamp measurements on wild type or L858F channels expressed in HEK293 cells revealed that cooling decreases current density, slows deactivation and increases ramp currents for both mutant and wild type channels. However, cooling differentially shifts the midpoint of steady-state activation in a depolarizing direction for L858F but not for wild type channels.


CONCLUSIONS
The cooling-dependent shift of the activation midpoint of L858F to more positive potentials brings the threshold of activation of the mutant channels closer to that of wild type Nav1.7 at lower temperatures, and is likely to contribute to the alleviation of painful symptoms upon cooling in affected limbs in patients with this erythromelalgia mutation.
Han
Chongyang
C
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. HanChy@imm.ac.cn <HanChy@imm.ac.cn>
Lampert
Angelika
A
Rush
Anthony M
AM
Dib-Hajj
Sulayman D
SD
Wang
Xiaoliang
X
Yang
Yong
Y
Waxman
Stephen G
SG
D000704:Analysis of Variance; D002461:Cell Line, Transformed; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004916:Erythromelalgia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008564:Membrane Potentials / Q000502:physiology / Q000528:radiation effects; D009154:Mutation; D018408:Patch-Clamp Techniques / Q000379:methods; D010649:Phenylalanine / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D013696:Temperature; D014162:Transfection / Q000379:methods
D015222:Sodium Channels; D010649:Phenylalanine; D007930:Leucine