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Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles
Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501363/ https://www.ncbi.nlm.nih.gov/pubmed/26023088 http://dx.doi.org/10.1091/mbc.E14-11-1564 |
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author | Cavolo, Samantha L. Zhou, Chaoming Ketcham, Stephanie A. Suzuki, Matthew M. Ukalovic, Kresimir Silverman, Michael A. Schroer, Trina A. Levitan, Edwin S. |
author_facet | Cavolo, Samantha L. Zhou, Chaoming Ketcham, Stephanie A. Suzuki, Matthew M. Ukalovic, Kresimir Silverman, Michael A. Schroer, Trina A. Levitan, Edwin S. |
author_sort | Cavolo, Samantha L. |
collection | PubMed |
description | Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense-core vesicles (DCVs) containing a neuropeptide or brain-derived neurotrophic factor shows that the F-actin depolymerizing macrolide toxin mycalolide B (MB) rapidly and selectively abolishes retrograde, but not anterograde, transport in the axon and the nerve terminal. Latrunculin A does not mimic MB, demonstrating that F-actin depolymerization is not responsible for unidirectional transport inhibition. Given that dynactin initiates retrograde transport and that amino acid sequences implicated in macrolide toxin binding are found in the dynactin component actin-related protein 1, we examined dynactin integrity. Remarkably, cell extract and purified protein experiments show that MB induces disassembly of the dynactin complex. Thus imaging selective retrograde transport inhibition led to the discovery of a small-molecule dynactin disruptor. The rapid unidirectional inhibition by MB suggests that dynactin is absolutely required for retrograde DCV transport but does not directly facilitate ongoing anterograde DCV transport in the axon or nerve terminal. More generally, MB's effects bolster the conclusion that anterograde and retrograde axonal transport are not necessarily interdependent. |
format | Online Article Text |
id | pubmed-4501363 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-45013632015-09-30 Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles Cavolo, Samantha L. Zhou, Chaoming Ketcham, Stephanie A. Suzuki, Matthew M. Ukalovic, Kresimir Silverman, Michael A. Schroer, Trina A. Levitan, Edwin S. Mol Biol Cell Articles Axonal transport is critical for maintaining synaptic transmission. Of interest, anterograde and retrograde axonal transport appear to be interdependent, as perturbing one directional motor often impairs movement in the opposite direction. Here live imaging of Drosophila and hippocampal neuron dense-core vesicles (DCVs) containing a neuropeptide or brain-derived neurotrophic factor shows that the F-actin depolymerizing macrolide toxin mycalolide B (MB) rapidly and selectively abolishes retrograde, but not anterograde, transport in the axon and the nerve terminal. Latrunculin A does not mimic MB, demonstrating that F-actin depolymerization is not responsible for unidirectional transport inhibition. Given that dynactin initiates retrograde transport and that amino acid sequences implicated in macrolide toxin binding are found in the dynactin component actin-related protein 1, we examined dynactin integrity. Remarkably, cell extract and purified protein experiments show that MB induces disassembly of the dynactin complex. Thus imaging selective retrograde transport inhibition led to the discovery of a small-molecule dynactin disruptor. The rapid unidirectional inhibition by MB suggests that dynactin is absolutely required for retrograde DCV transport but does not directly facilitate ongoing anterograde DCV transport in the axon or nerve terminal. More generally, MB's effects bolster the conclusion that anterograde and retrograde axonal transport are not necessarily interdependent. The American Society for Cell Biology 2015-07-15 /pmc/articles/PMC4501363/ /pubmed/26023088 http://dx.doi.org/10.1091/mbc.E14-11-1564 Text en © 2015 Cavolo et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Cavolo, Samantha L. Zhou, Chaoming Ketcham, Stephanie A. Suzuki, Matthew M. Ukalovic, Kresimir Silverman, Michael A. Schroer, Trina A. Levitan, Edwin S. Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title | Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title_full | Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title_fullStr | Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title_full_unstemmed | Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title_short | Mycalolide B dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
title_sort | mycalolide b dissociates dynactin and abolishes retrograde axonal transport of dense-core vesicles |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501363/ https://www.ncbi.nlm.nih.gov/pubmed/26023088 http://dx.doi.org/10.1091/mbc.E14-11-1564 |
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