Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel

Yang Yang, Sulayman D. Dib-Hajj, Jian Zhang, Yang Zhang, Lynda Tyrrell, Mark Estacion and Stephen G. Waxman ()
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Yang Yang: Yale University School of Medicine
Sulayman D. Dib-Hajj: Yale University School of Medicine
Jian Zhang: Center for Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, Michigan 48109, USA.
Yang Zhang: Center for Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, Michigan 48109, USA.
Lynda Tyrrell: Yale University School of Medicine
Mark Estacion: Yale University School of Medicine
Stephen G. Waxman: Yale University School of Medicine

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract Sodium channel NaV1.7 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 NaV1.7-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 Nav1.7-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.

Date: 2012
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DOI: 10.1038/ncomms2184

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