Robinson, S. W. et al. (2018) Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability. PLoS Biology, 16(4), e2003611. (doi: 10.1371/journal.pbio.2003611) (PMID:29630591) (PMCID:PMC5890968)
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Abstract
Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.
Item Type: | Articles |
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Additional Information: | Medical Research Council. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Henry Smith Charity https://www. henrysmithcharity.org.uk/ (grant number 20150312). JMB was funded. BBSRC/EPSRC (grant number L01386X). |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bourgognon, Dr Julie-Myrtille |
Creator Roles: | |
Authors: | Robinson, S. W., Bourgognon, J.-M., Spiers, J. G., Breda, C., Campesan, S., Butcher, A., Mallucci, G. R., Dinsdale, D., Morone, N., Mistry, R., Smith, T. M., Guerra-Martin, M., Challiss, R. A. J., Giorgini, F., and Steinert, J. R. |
College/School: | College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing |
Journal Name: | PLoS Biology |
Publisher: | Public Library of Science |
ISSN: | 1544-9173 |
ISSN (Online): | 1545-7885 |
Published Online: | 09 April 2018 |
Copyright Holders: | Copyright © 2018 Robinson et al. |
First Published: | First published in PLoS Biology 16(4): e2003611 |
Publisher Policy: | Reproduced under a Creative Commons License |
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