title: A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons.
abstract: Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel Nav1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where Nav1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The selective presence, in sensory but not sympathetic neurons, of the Nav1.8 channel, which remains available for activation at depolarized membrane potentials, is a major determinant of these opposing effects. These results provide a molecular basis for the sympathetic dysfunction that has been observed in erythermalgia. Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed.
authors.affiliation: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
authors.forename: Joel A
authors.initials: JA
authors.lastname: Black
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000378:metabolism*; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000378:metabolism*; D009435:Synaptic Transmission; D013997:Time Factors; D014162:Transfection
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels