Dynasore - not just a dynamin inhibitor

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Abstract

Dynamin is a GTPase protein that is essential for membrane fission during clathrin-mediated endocytosis in eukaryotic cells. Dynasore is a GTPase inhibitor that rapidly and reversibly inhibits dynamin activity, which prevents endocytosis. However, comparison between cells treated with dynasore and RNA interference of genes encoding dynamin, reveals evidence that dynasore reduces labile cholesterol in the plasma membrane, and disrupts lipid raft organization, in a dynamin-independent manner. To explore the role of dynamin it is important to use multiple dynamin inhibitors, alongside the use of dynamin mutants and RNA interference targeting genes encoding dynamin. On the other hand, dynasore provides an interesting tool to explore the regulation of cholesterol in plasma membranes.

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Most cited references 38

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A receptor-mediated pathway for cholesterol homeostasis.

M. Brown, J Goldstein (1986)

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Use of dynasore, the small molecule inhibitor of dynamin, in the regulation of endocytosis.

Tom Kirchhausen, Eric Macia, Henry E Pelish (2008)

The large GTPase dynamin is essential for clathrin-dependent coated-vesicle formation. Dynasore is a cell-permeable small molecule that inhibits the GTPase activity of dynamin1, dynamin2 and Drp1, the mitochondrial dynamin. Dynasore was discovered in a screen of approximately 16,000 compounds for inhibitors of the dynamin2 GTPase. Dynasore is a noncompetitive inhibitor of dynamin GTPase activity and blocks dynamin-dependent endocytosis in cells, including neurons. It is fast acting (seconds) and its inhibitory effect in cells can be reversed by washout. Here we present a detailed synthesis protocol for dynasore, and describe a series of experiments used to analyze the inhibitory effects of dynasore on dynamin in vitro and to study the effects of dynasore on endocytosis in cells.

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Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding.

J E Hinshaw, S L Schmid (1995)

DYNAMIN, a 100K member of the GTPase superfamily, is the mammalian homologue of the Drosophila shibire gene product. Mutations in shibire cause a defect in endocytosis leading to accumulation of coated pits and deep invaginations at the plasma membrane of all tissues examined. Similarly, invaginated coated pits accumulate in mammalian cells overexpressing dominant-negative mutants of dynamin, establishing that dynamin is required for the formation of 'constricted' coated pits and for coated vesicle budding. Whether dynamin functions in the classic GTPase mode as a molecular switch to regulate events leading to coated vesicle budding or instead actively participates as a mechanochemical enzyme driving coated vesicle formation is unclear. Here we show that dynamin spontaneously self-assembles into rings and stacks of interconnected rings, comparable in dimension to the 'collars' observed at the necks of invaginated coated pits that accumulate at synaptic terminals in shibire flies. We propose that invaginated coated pits become constricted by the assembly of dynamin into rings around their necks. A concerted conformational change would then close the rings and pinch off the budding coated vesicles.

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Author and article information

Contributors

Giulio Preta: g.preta@Swansea.ac.uk

James G Cronin: j.cronin@swansea.ac.uk

I Martin Sheldon: i.m.sheldon@swansea.ac.uk

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 10 April 2015

Publication date PMC-release: 10 April 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 24

Affiliations

Institute of Life Science, College of Medicine, Swansea University, Swansea, SA2 8PP UK

Article

Publisher ID: 102

DOI: 10.1186/s12964-015-0102-1

PMC ID: 4396812

PubMed ID: 25889964

SO-VID: f180afce-e79b-4798-8ff7-b7a7083d70f8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 4 February 2015

Date accepted : 26 March 2015

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: dynasore,gtpase,dynamin,endocytosis,cholesterol,lipid rafts

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: dynasore, gtpase, dynamin, endocytosis, cholesterol, lipid rafts

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