Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/41971
Title: Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.
Authors: Robinson, Susan W.
Bourgognon, Julie-Myrtille
Spiers, Jereme G.
Breda, Carlo
Campesan, Susanna
Butcher, Adrian
Mallucci, Giovanna R
Dinsdale, David
Morone, Nobuhiro
Mistry, Raj
Smith, Tim M.
Guerra-Martin, Maria
Challiss, R. A. John
Giorgini, Flaviano
Steinert, Joern R.
First Published: 9-Apr-2018
Publisher: Public Library of Science
Citation: PLoS Biol, 2018, 16 (4), e2003611
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.
DOI Link: 10.1371/journal.pbio.2003611
ISSN: 1544-9173
eISSN: 1545-7885
Links: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2003611
http://hdl.handle.net/2381/41971
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. 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 author and source are credited.
Appears in Collections:Published Articles, Dept. of Genetics

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