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Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

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      Abstract

      The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.

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      Most cited references 423

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      Lipid rafts and signal transduction.

       D Toomre,  K Simons (2000)
      Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.
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        Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins.

        In neural systems, information is often carried by ensembles of cells rather than by individual units. Optical indicators provide a powerful means to reveal such distributed activity, particularly when protein-based and encodable in DNA: encodable probes can be introduced into cells, tissues, or transgenic organisms by genetic manipulation, selectively expressed in anatomically or functionally defined groups of cells, and, ideally, recorded in situ, without a requirement for exogenous cofactors. Here we describe sensors for secretion and neurotransmission that fulfil these criteria. We have developed pH-sensitive mutants of green fluorescent protein ('pHluorins') by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles to monitor vesicle exocytosis and recycling. When linked to a vesicle membrane protein, pHluorins were sorted to secretory and synaptic vesicles and reported transmission at individual synaptic boutons, as well as secretion and fusion pore 'flicker' of single secretory granules.
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          SNAREs--engines for membrane fusion.

          Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.
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            Author and article information

            Affiliations
            Department of Biomedical Sciences, University of Padova, Italy (M.P., O.R., C.M.); Neurologic Department, University-Hospital S. Maria della Misericordia, Udine, Italy (R.E.); and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Italy (C.M.)
            Author notes
            Address correspondence to: Cesare Montecucco, Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35131 Padova, Italy. E-mail: cesare.montecucco@ 123456gmail.com
            Contributors
            Role: ASSOCIATE EDITOR
            Journal
            Pharmacol Rev
            Pharmacol. Rev
            pharmrev
            Pharmacol Rev
            PharmRev
            Pharmacological Reviews
            The American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD )
            0031-6997
            1521-0081
            April 2017
            April 2017
            April 2017
            : 69
            : 2
            : 200-235
            28356439
            5394922
            PHARMREV_012658
            10.1124/pr.116.012658
            (ASSOCIATE EDITOR)
            Copyright © 2017 by The Author(s)

            This is an open access article distributed under the CC BY-NC Attribution 4.0 International license .

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            Figures: 5, Tables: 6, Equations: 0, References: 425, Pages: 36
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