title: Kinetic modeling of Nav1.7 provides insight into erythromelalgia-associated F1449V mutation.
abstract: Gain-of-function mutations of the voltage-gated sodium channel (VGSC) Na(v)1.7 have been linked to human pain disorders. The mutation F1449V, located at the intracellular end of transmembrane helix S6 of domain III, induces the inherited pain syndrome erythromelalgia. A kinetic model of wild-type (WT) and F1449V Na(v)1.7 may provide a basis for predicting putative intraprotein interactions. We semiautomatically constrained a Markov model using stochastic search algorithms and whole cell patch-clamp recordings from human embryonic kidney cells transfected with Na(v)1.7 and its F1449V mutation. The best models obtained simulated known differences in action potential thresholds and firing patterns in spinal sensory neurons expressing WT and F1449V. The most suitable Markov model consisted of three closed, one open, and two inactivated states. The model predicted that the F1449V mutation shifts occupancy of the closed states closer to the open state, making it easier for the channel pore to open. It also predicted that F1449V's second inactivated state is more than four times more likely to be occupied than the equivalent state in WT at hyperpolarized potentials, although the mutation still lowered the firing threshold of action potentials. The differences between WT and F1449V were not limited to a single transition. Thus a point mutation in position F1449, while phenotypically most probably affecting the activation gate, may also modify channel functions mediated by structures in more distant areas of the channel protein.
authors.affiliation: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel. gurkiewicz@gmail.com
authors.forename: Meron
authors.initials: M
authors.lastname: Gurkiewicz
authors.forename: Alon
authors.initials: A
authors.lastname: Korngreen
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D004916:Erythromelalgia / Q000235:genetics* / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology; D008390:Markov Chains; D008954:Models, Biological; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D062556:NAV1.7 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013269:Stochastic Processes; D014162:Transfection
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels