Functional Properties and Toxin Pharmacology of a Dorsal Root Ganglion Sodium Channel Viewed through its Voltage Sensors

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Functional Properties and Toxin Pharmacology of a Dorsal Root Ganglion Sodium Channel Viewed through its Voltage Sensors

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Title: Functional Properties and Toxin Pharmacology of a Dorsal Root Ganglion Sodium Channel Viewed through its Voltage Sensors
Author: Bosmans, Frank; Puopolo, Michelino; Martin-Eauclaire, Marie-France; Swartz, Kenton J.; Bean, Bruce Palmer

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Citation: Bosmans, Frank, Michelino Puopolo, Marie-France Martin-Eauclaire, Bruce P. Bean, and Kenton J. Swartz. 2011. Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors. The Journal of General Physiology 138(1): 59-72.
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Abstract: The voltage-activated sodium (Nav) channel Nav1.9 is expressed in dorsal root ganglion (DRG) neurons where it is believed to play an important role in nociception. Progress in revealing the functional properties and pharmacological sensitivities of this non-canonical Nav channel has been slow because attempts to express this channel in a heterologous expression system have been unsuccessful. Here, we use a protein engineering approach to dissect the contributions of the four Nav1.9 voltage sensors to channel function and pharmacology. We define individual S3b–S4 paddle motifs within each voltage sensor, and show that they can sense changes in membrane voltage and drive voltage sensor activation when transplanted into voltage-activated potassium channels. We also find that the paddle motifs in Nav1.9 are targeted by animal toxins, and that these toxins alter Nav1.9-mediated currents in DRG neurons. Our results demonstrate that slowly activating and inactivating Nav1.9 channels have functional and pharmacological properties in common with canonical Nav channels, but also show distinctive pharmacological sensitivities that can potentially be exploited for developing novel treatments for pain.
Published Version: doi:10.1085/jgp.201110614
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135324/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10303290
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