The University of Southampton
University of Southampton Institutional Repository

UNC-18 modulates ethanol sensitivity in caenorhabditis elegans

UNC-18 modulates ethanol sensitivity in caenorhabditis elegans
UNC-18 modulates ethanol sensitivity in caenorhabditis elegans
Acute ethanol exposure affects the nervous system as a stimulant at low concentrations and as a depressant at higher concentrations, eventually resulting in motor dysfunction and uncoordination. A recent genetic study of two mouse strains with varying ethanol preference indicated a correlation with a polymorphism (D216N) in the synaptic protein Munc18-1. Munc18-1 functions in exocytosis via a number of discrete interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1. We report that the mutation affects binding to syntaxin but not through either a closed conformation mode of interaction or through binding to the syntaxin N terminus. The D216N mutant instead has a specific impairment in binding the assembled SNARE complex. Furthermore, the mutation broadens the duration of single exocytotic events. Expression of the orthologous mutation (D214N) in the Caenorhabditis elegans UNC-18 null background generated transgenic rescues with phenotypically similar locomotion to worms rescued with the wild-type protein. Strikingly, D214N worms were strongly resistant to both stimulatory and sedative effects of acute ethanol. Analysis of an alternative Munc18-1 mutation (I133V) supported the link between reduced SNARE complex binding and ethanol resistance. We conclude that ethanol acts, at least partially, at the level of vesicle fusion and that its acute effects are ameliorated by point mutations in UNC-18.
1059-1524
43-55
Graham, Margaret E.
b4e2593f-e1a3-44dc-a8ed-b42995bfe7a3
Edwards, Mark R.
2fc48b57-bee4-45b9-88cf-0046616239c4
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e
Morgan, Alan
2286495f-49cc-4ef2-a53b-29ab76090208
Burgoyne, Robert D.
2a4208e5-2341-483d-a8cb-2e806eef7de5
Barclay, Jeff W.
629262d1-10cf-4418-b338-7af9b5f5192d
Graham, Margaret E.
b4e2593f-e1a3-44dc-a8ed-b42995bfe7a3
Edwards, Mark R.
2fc48b57-bee4-45b9-88cf-0046616239c4
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e
Morgan, Alan
2286495f-49cc-4ef2-a53b-29ab76090208
Burgoyne, Robert D.
2a4208e5-2341-483d-a8cb-2e806eef7de5
Barclay, Jeff W.
629262d1-10cf-4418-b338-7af9b5f5192d

Graham, Margaret E., Edwards, Mark R., Holden-Dye, Lindy, Morgan, Alan, Burgoyne, Robert D. and Barclay, Jeff W. (2009) UNC-18 modulates ethanol sensitivity in caenorhabditis elegans. Molecular Biology of the Cell, 20 (1), 43-55. (doi:10.1091/mbc.E08-07-0689).

Record type: Article

Abstract

Acute ethanol exposure affects the nervous system as a stimulant at low concentrations and as a depressant at higher concentrations, eventually resulting in motor dysfunction and uncoordination. A recent genetic study of two mouse strains with varying ethanol preference indicated a correlation with a polymorphism (D216N) in the synaptic protein Munc18-1. Munc18-1 functions in exocytosis via a number of discrete interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1. We report that the mutation affects binding to syntaxin but not through either a closed conformation mode of interaction or through binding to the syntaxin N terminus. The D216N mutant instead has a specific impairment in binding the assembled SNARE complex. Furthermore, the mutation broadens the duration of single exocytotic events. Expression of the orthologous mutation (D214N) in the Caenorhabditis elegans UNC-18 null background generated transgenic rescues with phenotypically similar locomotion to worms rescued with the wild-type protein. Strikingly, D214N worms were strongly resistant to both stimulatory and sedative effects of acute ethanol. Analysis of an alternative Munc18-1 mutation (I133V) supported the link between reduced SNARE complex binding and ethanol resistance. We conclude that ethanol acts, at least partially, at the level of vesicle fusion and that its acute effects are ameliorated by point mutations in UNC-18.

This record has no associated files available for download.

More information

Published date: 1 January 2009

Identifiers

Local EPrints ID: 142813
URI: http://eprints.soton.ac.uk/id/eprint/142813
ISSN: 1059-1524
PURE UUID: f1138ad0-0931-44eb-8f20-8356ec1c7331
ORCID for Lindy Holden-Dye: ORCID iD orcid.org/0000-0002-9704-1217

Catalogue record

Date deposited: 01 Apr 2010 15:07
Last modified: 14 Mar 2024 02:32

Export record

Altmetrics

Contributors

Author: Margaret E. Graham
Author: Mark R. Edwards
Author: Alan Morgan
Author: Robert D. Burgoyne
Author: Jeff W. Barclay

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×