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      Evidence for a protein tether involved in somatic touch

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          Abstract

          The gating of ion channels by mechanical force underlies the sense of touch and pain. The mode of gating of mechanosensitive ion channels in vertebrate touch receptors is unknown. Here we show that the presence of a protein link is necessary for the gating of mechanosensitive currents in all low-threshold mechanoreceptors and some nociceptors of the dorsal root ganglia (DRG). Using TEM, we demonstrate that a protein filament with of length ∼100 nm is synthesized by sensory neurons and may link mechanosensitive ion channels in sensory neurons to the extracellular matrix. Brief treatment of sensory neurons with non-specific and site-specific endopeptidases destroys the protein tether and abolishes mechanosensitive currents in sensory neurons without affecting electrical excitability. Protease-sensitive tethers are also required for touch-receptor function in vivo. Thus, unlike the majority of nociceptors, cutaneous mechanoreceptors require a distinct protein tether to transduce mechanical stimuli.

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          Most cited references56

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          ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins.

          Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein-protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.
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            The neuronal background K2P channels: focus on TREK1.

            Two-pore-domain K(+) (K(2P)) channel subunits are made up of four transmembrane segments and two pore-forming domains that are arranged in tandem and function as either homo- or heterodimeric channels. This structural motif is associated with unusual gating properties, including background channel activity and sensitivity to membrane stretch. Moreover, K(2P) channels are modulated by a variety of cellular lipids and pharmacological agents, including polyunsaturated fatty acids and volatile general anaesthetics. Recent in vivo studies have demonstrated that TREK1, the most thoroughly studied K(2P) channel, has a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain and depression.
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              Molecular basis of mechanosensory transduction.

              Mechanotransduction - a cell's conversion of a mechanical stimulus into an electrical signal - reveals vital features of an organism's environment. From hair cells and skin mechanoreceptors in vertebrates, to bristle receptors in flies and touch receptors in worms, mechanically sensitive cells are essential in the life of an organism. The scarcity of these cells and the uniqueness of their transduction mechanisms have conspired to slow molecular characterization of the ensembles that carry out mechanotransduction. But recent progress in both invertebrates and vertebrates is beginning to reveal the identities of proteins essential for transduction.
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                Author and article information

                Journal
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                17 February 2010
                14 January 2010
                14 January 2010
                : 29
                : 4
                : 855-867
                Affiliations
                [1 ]Department of Neuroscience, Max-Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Berlin-Buch, Germany
                [2 ]Center for Biochemistry, Department of Dermatology, and Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany
                Author notes
                [a ]Molecular Physiology of Somatic Sensation, Department of Neuroscience, Max-Delbrueck-Centrum, Robert-Rössle-Strasse 10, Berlin D-13125, Germany. Tel.: +49 30 9406 2430; Fax: +49 30 9406 2793; E-mail: glewin@ 123456mdc-berlin.de
                [b ]Center for Integrative Neuroscience (CIN), Paul-Ehrlich-Strasse 15-17, Tubingen 72076, Germany. Tel.: +49 7071 2989181; Fax: +49 7071 294697; E-mail: jing.hu@ 123456cin.uni-tuebingen.de
                [*]

                These authors contributed equally to this work

                [†]

                Present address: Center for Integrative Neuroscience (CIN), Paul-Ehrlich-Strasse 15-17, Tübingen 72076, Germany

                Article
                emboj2009398
                10.1038/emboj.2009.398
                2810375
                20075867
                a9c2af5b-3246-457d-819d-ae862e859768
                Copyright © 2010, European Molecular Biology Organization

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.

                Page count
                Pages: 13
                Categories
                Article

                Molecular biology
                ion channels,extracellular matrix,mechanotransduction,proteases,laminin
                Molecular biology
                ion channels, extracellular matrix, mechanotransduction, proteases, laminin

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