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HSP-4 endoplasmic reticulum (ER) stress pathway is not activated in a C. elegans model of ethanol intoxication and withdrawal

  • Original Paper
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Invertebrate Neuroscience

Abstract

Acute and chronic exposure of Caenorhabditis elegans to concentrations of ethanol in the range 250–350 mM elicits distinct behaviours. Previous genetic analysis highlights specific neurobiological substrates for these effects. However, ethanol may also elicit cellular stress responses which may contribute to the repertoire of ethanol-induced behaviours. Here, we have studied the effect of ethanol on an important arm of the cellular stress pathways, which emanates from the endoplasmic reticulum (ER) in response to several conditions including heat shock and chemical or genetic perturbations that lead to protein misfolding. HSP-4 is a heat shock protein and homologue of mammalian BiP. It is a pivotal upstream component of the ER stress response. Therefore, we used a C. elegans heat shock protein mutant, hsp-4, and a strain carrying a transcriptional reporter, Phsp-4::gfp, to test the role of the ER following chronic ethanol conditioning. We found no evidence for an overt ER response during acute or prolonged exposure to concentrations of ethanol that lead to defined ethanol-induced behaviours. Furthermore, whilst hsp-4 was strongly induced by tunicamycin, pre-exposure of C. elegans to low doses of tunicamycin followed by ethanol was not sufficient to induce an additive ER stress response. Behavioural analysis of an hsp-4 mutant indicated no difference compared to wild type in susceptibility to ethanol intoxication and withdrawal. There is a clear precedent for a significance of ER stress pathways particularly in clinical conditions associated with toxic or pathological effects of high doses of alcohol consumption. The concentrations of ethanol used in this C. elegans study equate to the highest blood alcohol levels measured in patients with chronic alcohol dependency. Taken together, these observations imply that the classic ER stress pathway in C. elegans is relatively refractory to induction by ethanol.

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Acknowledgments

Ben Ient was supported by graduate scholarship funds from the MRC and the Gerald Kerkut Charitable Trust. Richard Mould was supported by the Biotechnology and Biological Sciences Research Council UK Grant no. BB/E022251/1. Some nematode strains used in this work were provided by the Caenorhabditis elegans Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR).

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Authors and Affiliations

  1. Centre for Biosciences, University of Southampton, Building 85, University Road, Southampton, SO17 1BJ, UK

    Ben Ient, Richard Edwards, Richard Mould, Lindy Holden-Dye & Vincent O’Connor

  2. Division of Molecular Neuroendocrinology, NIMR, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Matthew Hannah

  3. Virus Reference Department, Health Protection Agency, 61 Colindale Avenue, London, NW9 5EQ, UK

    Matthew Hannah

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  1. Ben Ient
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  2. Richard Edwards
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  3. Richard Mould
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  4. Matthew Hannah
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  5. Lindy Holden-Dye
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  6. Vincent O’Connor
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Correspondence to Lindy Holden-Dye.

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Ient, B., Edwards, R., Mould, R. et al. HSP-4 endoplasmic reticulum (ER) stress pathway is not activated in a C. elegans model of ethanol intoxication and withdrawal. Invert Neurosci 12, 93–102 (2012). https://doi.org/10.1007/s10158-012-0136-7

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  • DOI: https://doi.org/10.1007/s10158-012-0136-7

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