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      Voltage-gated Na + currents in human dorsal root ganglion neurons

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          Abstract

          Available evidence indicates voltage-gated Na + channels (VGSCs) in peripheral sensory neurons are essential for the pain and hypersensitivity associated with tissue injury. However, our understanding of the biophysical and pharmacological properties of the channels in sensory neurons is largely based on the study of heterologous systems or rodent tissue, despite evidence that both expression systems and species differences influence these properties. Therefore, we sought to determine the extent to which the biophysical and pharmacological properties of VGSCs were comparable in rat and human sensory neurons. Whole cell patch clamp techniques were used to study Na + currents in acutely dissociated neurons from human and rat. Our results indicate that while the two major current types, generally referred to as tetrodotoxin (TTX)-sensitive and TTX-resistant were qualitatively similar in neurons from rats and humans, there were several differences that have important implications for drug development as well as our understanding of pain mechanisms.

          DOI: http://dx.doi.org/10.7554/eLife.23235.001

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          The Na(V)1.7 sodium channel: from molecule to man.

          The voltage-gated sodium channel Na(V)1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. Na(V)1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that Na(V)1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant Na(V)1.7 that causes pain.
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            Currents carried by sodium and potassium ions through the membrane of the giant axon ofLoligo

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              Presynaptic activity regulates Na(+) channel distribution at the axon initial segment.

              Deprivation of afferent inputs in neural circuits leads to diverse plastic changes in both pre- and postsynaptic elements that restore neural activity. The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. However, none of the plasticity currently known involves the AIS. We report here that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated Na(+) channels and the AIS anchoring protein, increased by 1.7 times in seven days after auditory input deprivation. This was accompanied by an increase in the whole-cell Na(+) current, membrane excitability and spontaneous firing. Our work demonstrates homeostatic regulation of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation.
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                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                16 May 2017
                2017
                : 6
                : e23235
                Affiliations
                [1 ]deptDepartment of Urology , The Second Hospital of Shandong University , Jinan Shi, China
                [2 ]Lilly Research Laboratories , Indianapolis, United States
                [3 ]deptOffice of Research on Women’s Health , National Institutes of Health , Bethesda, United States
                [4 ]deptDepartment of Neurobiology , University of Pittsburgh School of Medicine , Pittsburgh, United States
                Northwestern University , United States
                Northwestern University , United States
                Author notes
                Author information
                http://orcid.org/0000-0002-2083-6206
                Article
                23235
                10.7554/eLife.23235
                5433841
                28508747
                dcc3bfb9-d32d-4600-938e-16c87819ef7d

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 12 November 2016
                : 11 April 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01DE018252
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                2.5
                Human sensory neurons may not only bridge a critical gap between drug discovery and clinical trials, but force a re-evaluation of basic assumptions about the mechanisms controlling primary afferent excitability.

                Life sciences
                nav1.8,nav1.7,local anesthetics,cell culture,human
                Life sciences
                nav1.8, nav1.7, local anesthetics, cell culture, human

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