Abstract
Nitric oxide (NO) is a multifunctional neurotransmitter that plays a major role in neuronal and synaptic functions. S-nitrosylation (SNO), the NO-mediated protein posttransitional modification (PTM), is known to regulate physiological and pathological processes in the brain. However, the physiological role in different neuroanatomical brain regions has not been well investigated. To understand the role of SNO in the brain of juvenile WT mice, we used SNOTRAP technology. We mapped the SNO-proteome in three different neuroanatomical regions: cortex, striatum, and hippocampus. By conducting systems biology analysis, we found that the three brain regions share similar biological processes (BP) including biogenesis and developmental processes. Exclusive and different BP and molecular functions were found for each of the regions. Unraveling the BP and signaling mechanisms of SNO in the cortex, striatum, and hippocampus may help to understand the functional differences between the three regions under physiological conditions.
This is a preview of subscription content, access via your institution.






Data Availability
The data were deposited in ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the dataset identifier < PXD006907 > and < PXD010106 > .
References
Amal H, Barak B, Bhat V, Gong G, Joughin BA, Wang X, Wishnok JS, Feng G, Tannenbaum SR (2018) Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function. Mol Psychiatry 25(8):1835–1848
Amal H, Gong G, Gjoneska E, Lewis SM, Wishnok JS, Tsai LH, Tannenbaum SR (2019) S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy. Transl Psychiatry 9(1):44
Amal H, Gong G, Yang H, Joughin BA, Wang X, Knutson CG, Kartawy M, Khaliulin I, Wishnok JS, Tannenbaum SR (2020b) Low doses of arsenic in a mouse model of human exposure and in neuronal culture lead to S-nitrosylation of synaptic proteins and apoptosis via nitric oxide. Int J Mol Sci 21(11)
Annus T, Wilson LR, Hong YT, Acosta-Cabronero J, Fryer TD, Cardenas-Blanco A, Smith R, Boros I, Coles JP, Aigbirhio FI, Menon DK, Zaman SH, Nestor PJ, Holland AJ (2016) The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement 12(5):538–545
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29
Atallah HE, Frank MJ, O’Reilly RC (2004) Hippocampus, cortex, and basal ganglia: insights from computational models of complementary learning systems. Neurobiol Learn Mem 82(3):253–267
Benjamini Y, Hochberg Y, (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 289–300
Bin Saifullah MA, Nagai T, Kuroda K, Wulaer B, Nabeshima T, Kaibuchi K, Yamada K (2018) Cell type-specific activation of mitogen-activated protein kinase in D1 receptor-expressing neurons of the nucleus accumbens potentiates stimulus-reward learning in mice. Sci Rep 8(1):14413
Bredt DS, Snyder SH (1994) NITRIC OXIDE: a physiologic messenger molecule. Annu Rev Biochem 63(1):175–195
Brown TI, Ross RS, Keller JB, Hasselmo ME, Stern CE (2010) Which way was I going? Contextual retrieval supports the disambiguation of well learned overlapping navigational routes. J Neurosci 30(21):7414–7422
Chung KKK, Dawson VL, Dawson TM (2005) S-Nitrosylation in Parkinson’s disease and related neurodegenerative disorders. Methods in Enzymology, Academic Press 396:139–150
Cohen AD, McDade E, Christian B, Price J, Mathis C, Klunk W, Handen BL (2018) Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer’s disease from late-onset amyloid deposition. Alzheimers Dement 14(6):743–750
Dagher A, Owen AM, Boecker H, Brooks DJ (2001) The role of the striatum and hippocampus in planning: A PET activation study in Parkinson’s disease. Brain 124(5):1020–1032
Delcasso S, Huh N, Byeon JS, Lee J, Jung MW, Lee I (2014) Functional relationships between the hippocampus and dorsomedial striatum in learning a visual scene-based memory task in rats. J Neurosci 34(47):15534
Farhy-Tselnicker I, Allen NJ (2018) Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev 13(1):7
Ferbinteanu J (2016) Contributions of hippocampus and striatum to memory-guided behavior depend on past experience. J Neurosci 36(24):6459
Fouquet C, Babayan BM, Watilliaux A, Bontempi B, Tobin C, Rondi-Reig L (2013) Complementary roles of the hippocampus and the dorsomedial striatum during spatial and sequence-based navigation behavior. PLoS One 8(6):e67232
Fritz M, Klawonn AM, Nilsson A, Singh AK, Zajdel J, Wilhelms DB, Lazarus M, Löfberg A, Jaarola M, Kugelberg U, Billiar TR, Hackam DJ, Sodhi CP, Breyer MD, Jakobsson J, Schwaninger M, Schütz G, Parkitna JR, Saper CB, Blomqvist A, Engblom D (2016) Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. J Clin Invest 126(2):695–705
Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KTS (2015) The role of the nitric oxide pathway in brain injury and its treatment — from bench to bedside. Exp Neurol 263:235–243
Ghiglieri V, Sgobio C, Costa C, Picconi B, Calabresi P (2011) Striatum-hippocampus balance: from physiological behavior to interneuronal pathology. Prog Neurobiol 94(2):102–114
Goodroe SC, Starnes J, Brown TI (2018) The complex nature of hippocampal-striatal interactions in spatial navigation. Front Hum Neurosci 12(250)
Hanseeuw BJ, Lopera F, Sperling RA, Norton DJ, Guzman-Velez E, Baena A, Pardilla-Delgado E, Schultz AP, Gatchel J, Jin D, Chen K, Reiman EM, Johnson KA, Quiroz YT (2019) Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease. Alzheimers Res Ther 11(1):17
Haun F, Nakamura T, Shiu AD, Cho D-H, Tsunemi T, Holland EA, La Spada AR, Lipton SA (2013) S-Nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington’s disease. Antioxid Redox Signal 19(11):1173–1184
Herweg NA, Apitz T, Leicht G, Mulert C, Fuentemilla L, Bunzeck N (2016) Theta-alpha oscillations bind the hippocampus, prefrontal cortex, and striatum during recollection: evidence from simultaneous EEG–fMRI. J Neurosci 36(12):3579
Kartawy M, Khaliulin I, Amal H (2020) Systems biology reveals reprogramming of the S-nitroso-proteome in the cortical and striatal regions of mice during aging process. Sci Rep 10(1):13913
Kelly A, Laroche S, Davis S (2003) Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase in hippocampal circuitry is required for consolidation and reconsolidation of recognition memory. J Neurosci 23(12):5354–5360
Khaliulin I, Kartawy M, Amal H (2020) Sex differences in biological processes and nitrergic signaling in mouse brain. Biomedicines 8(5)
Kokane SS, Perrotti LI (2020) Sex differences and the role of estradiol in mesolimbic reward circuits and vulnerability to cocaine and opiate addiction. Front Behav Neurosci 14:74
Lau B, Glimcher PW (2008) Value representations in the primate striatum during matching behavior. Neuron 58(3):451–463
Lin MT, Wu JJ, Chern YF (1984) Administration of prostaglandin E2 into the striatum induces hyperthermia in rats. Exp Neurol 85(2):391–399
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8(6):427–437
Nakamura T, Lipton SA (2011) Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death Differ 18(9):1478–1486
Nakamura T, Prikhodko OA, Pirie E, Nagar S, Akhtar MW, Oh C-K, McKercher SR, Ambasudhan R, Okamoto S-I, Lipton SA (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99–108
Nakamura T, Tu S, Akhtar MW, Sunico CR, Okamoto S-I, Lipton SA (2013) Aberrant protein s-nitrosylation in neurodegenerative diseases. Neuron 78(4):596–614
Piechota M, Korostynski M, Golda S, Ficek J, Jantas D, Barbara Z, Przewlocki R (2017) Transcriptional signatures of steroid hormones in the striatal neurons and astrocytes. BMC Neurosci 18(1):37
Plassmann H, Doherty JP, Rangel A (2010) Appetitive and aversive goal values are encoded in the medial orbitofrontal cortex at the time of decision making. J Neurosci 30(32):10799
Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA (2011) S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide. Proc Natl Acad Sci USA 108(34):14330–14335
Raju K, Doulias PT, Evans P, Krizman EN, Jackson JG, Horyn O, Daikhin Y, Nissim I, Yudkoff M, Nissim I, Sharp KA, Robinson MB, Ischiropoulos H (2015) Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation. Sci Signal 8(384):68
Rappsilber J, Mann M, Ishihama Y (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2(8):1896–1906
Represa A, Deloulme JC, Sensenbrenner M, Ben-Ari Y, Baudier J (1990) Neurogranin: immunocytochemical localization of a brain-specific protein kinase C substrate. J Neurosci 10(12):3782–3792
Ross RS, Sherrill KR, Stern CE (2011) The hippocampus is functionally connected to the striatum and orbitofrontal cortex during context dependent decision making. Brain Res 1423:53–66
Seneviratne U, Nott A, Bhat VB, Ravindra KC, Wishnok JS, Tsai L-H, Tannenbaum SR (2016) S-nitrosation of proteins relevant to Alzheimer’s disease during early stages of neurodegeneration. Proc Natl Acad Sci 113(15):4152–4157
Seth D, Hess DT, Hausladen A, Wang L, Wang Y-J, Stamler JS (2018) A multiplex enzymatic machinery for cellular protein S-nitrosylation. Mol Cell 69(3):451-464.e456
Shi X, McGinty JF (2006) Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum. Neuroscience 138(4):1289–1298
Shi Z-Q, Sunico CR, McKercher SR, Cui J, Feng G-S, Nakamura T, Lipton SA (2013) S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke. Proc Natl Acad Sci 110(8):3137
Snyder SH, Bredt DS (1992) Biological roles of nitric oxide. Sci Am 266(5):68–71, 74–67
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP (2015) STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(D1):D447–D452
Takahashi H, Xia P, Cui J, Talantova M, Bodhinathan K, Li W, Saleem S, Holland EA, Tong G, Piña-Crespo J, Zhang D, Nakanishi N, Larrick JW, McKercher SR, Nakamura T, Wang Y, Lipton SA (2016) Corrigendum: Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease. Sci Rep 6:20750
Tripathi MK, Kartawy M, Amal H (2020) The role of nitric oxide in brain disorders: autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders. Redox Biol 34:101567
Uehara T, Nakamura T, Yao D, Shi Z-Q, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441(7092):513–517
Zhao Q-F, Yu J-T, Tan L (2015) S-Nitrosylation in Alzheimer’s disease. Mol Neurobiol 51(1):268–280
Acknowledgements
We acknowledge the Satell Family Foundation for their generous support.
Author information
Authors and Affiliations
Contributions
W.H.: system biology (SB) analysis and writing the manuscript, F.VL.: SB analysis, M.K.: SB analysis and contribution to the discussion, S.M.: SB analysis, H.S.: SB analysis, I.K.: contributing to the discussion, H.A.: supervision the project and writing the manuscript.
Corresponding author
Ethics declarations
Ethics Approval and Consent to Participate
The authors accept all ethical responsibilities.
Consent for Publication
All authors have read the manuscript and approved its submission to the journal.
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hamoudi, W., von Lendenfeld, F., Kartawy, M. et al. Regional Differences in S-Nitrosylation in the Cortex, Striatum, and Hippocampus of Juvenile Male Mice. J Mol Neurosci 71, 2383–2392 (2021). https://doi.org/10.1007/s12031-021-01792-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-021-01792-z
Keywords
- Nitric oxide
- S-nitrosylation
- Cortex
- Striatum
- Hippocampus
- System biology
- Posttranslational modification
- Proteomics
- Brain