The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy.
作者： Chongyang Han , Yang Yang , Bianca T. A. de Greef , Janneke G. J. Hoeijmakers , Monique M. Gerrits
DOI: 10.1007/S12017-015-8347-9
关键词: Nav1.9 、 Anesthesia 、 Missense mutation 、 Sodium channel 、 Chemistry 、 Cell biology 、 Gating 、 Dorsal root ganglion 、 Erythromelalgia 、 Point mutation 、 Membrane potential
摘要: Painful small fiber neuropathy is a challenging medical condition with no effective treatment. Non-genetic causes can be identified in one half of the subjects. Gain-of-function variants sodium channels Nav1.7 and Nav1.8 have recently been associated painful neuropathy. More recently, mutations channel Nav1.9 linked to human pain disorders, two gain-of-function found patients Here we report novel mutation, glycine 699 substitution by arginine (G699R) domain II S4-S5 linker, patient In this study, assayed mutant voltage-clamp superior cervical ganglion neurons, which do not produce endogenous or currents, provide platform where expressed at relatively high levels. Voltage-clamp analysis showed that mutation hyperpolarizes (−10.1 mV) activation, depolarizes (+6.3 mV) steady-state fast inactivation, slows deactivation, enhances ramp responses compared wild-type channels. Current-clamp G699R render dorsal root neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold increased evoked firing. These observations show linker plays an important role gating demonstrates common disorder.
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