title: Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Na(V)1.7 mutant channel.
abstract: Sodium channel Na(V)1.7 is critical for human pain signalling. Gain-of-function mutations produce pain syndromes including inherited erythromelalgia, which is usually resistant to pharmacotherapy, but carbamazepine normalizes activation of Na(V)1.7-V400M mutant channels from a family with carbamazepine-responsive inherited erythromelalgia. Here we show that structural modelling and thermodynamic analysis predict pharmacoresponsiveness of another mutant channel (S241T) that is located 159 amino acids distant from V400M. Structural modelling reveals that Na(v)1.7-S241T is ~2.4 Å apart from V400M in the folded channel, and thermodynamic analysis demonstrates energetic coupling of V400M and S241T during activation. Atomic proximity and energetic coupling are paralleled by pharmacological coupling, as carbamazepine (30 μM) depolarizes S214T activation, as previously reported for V400M. Pharmacoresponsiveness of S241T to carbamazepine was further evident at a cellular level, where carbamazepine normalized the hyperexcitability of dorsal root ganglion neurons expressing S241T. We suggest that this approach might identify variants that confer enhanced pharmacoresponsiveness on a variety of channels.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013816:Thermodynamics
chemical_list: D050505:Mutant Proteins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D002220:Carbamazepine; D004121:Dimethyl Sulfoxide