S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors

Selvakumar, B; Huganir, Richard L.; Snyder, Solomon H.

doi:10.1073/pnas.0908949106

Cited by 71 publications

(77 citation statements)

References 36 publications

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“…Rapid endocytosis of AMPARs regulates their synaptic surface expression and therefore is critical in modulation of LTD, a form of synaptic plasticity (14). The NMDAR-stimulated calcium influx critical for LTP (2), and involved in AMPAR endocytosis (26), also triggers S-nitrosylation of proteins as the result of activation of nNOS (7,11,13). Our findings establish that AMPAR phosphorylation, conductance, and endocytosis are physiologically regulated by GluA1 S-nitrosylation at C875, and may be a mechanism by which NO regulates synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of the NO/cGMP cascade reduces GluA1 surface expression (22). Stargazin, an AMPAR auxiliary protein that binds to a large fraction of different types of AMPAR subunits (24) and facilitates the phosphorylation-mediated increase in heteromeric GluA1/GluA2 receptor conductance (5), also enhances GluA1 surface expression when nitrosylated (13). Postsynaptic density protein-95 (PSD-95), a scaffolding protein that regulates AMPAR clustering in the postsynaptic density, is reciprocally regulated by S-nitrosylation and palmitoylation (25).…”

Section: Discussionmentioning

confidence: 99%

“…Transmembrane AMPAR regulatory proteins are prominent auxiliary proteins for AMPARs, with stargazin being the best characterized (12). NMDAR transmission triggers S-nitrosylation of stargazin, which increases surface expression of GluA1 (13).…”

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confidence: 99%

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S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis

Selvakumar

Jenkins

Hussain

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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NMDA receptor activation can elicit synaptic plasticity by augmenting conductance of the AMPA receptor GluA1 subsequent to phosphorylation at S831 by Ca 2+ -dependent kinases. NMDA receptor activation also regulates synaptic plasticity by causing endocytosis of AMPA receptor GluA1. We demonstrate a unique signaling cascade for these processes mediated by NMDA receptor-dependent NO formation and GluA1 S-nitrosylation. Thus, S-nitrosylation of GluA1 at C875 enhances S831 phosphorylation, facilitates the associated AMPA receptor conductance increase, and results in endocytosis by increasing receptor binding to the AP2 protein of the endocytotic machinery.A MPA receptors (AMPARs) are tetramers in their physiologic form, with GluA1 being one of the more important regulatory subunits (1). Synaptic plasticity frequently is mediated by activation of NMDA receptors (NMDARs), which can modulate surface expression and single-channel conductance of AMPARs during the early phase of long-term potentiation (LTP) (1, 2). Phosphorylation of S831 of GluA1 mediates such plasticity, as phosphorylation of this site increases during LTP (3, 4), and mutant mice overexpressing a phosphomimetic S831D mutation display enhanced AMPAR conductance and LTP (5, 6).Mechanisms whereby NMDAR transmission augments AMPAR conductance have been unclear. NMDAR activation leads to calcium entry, which stimulates catalytic activity of neuronal nitric oxide synthase (nNOS) (7,8). NO (nitric oxide) signals by activating guanylate cyclase, and by S-nitrosylating cysteines of many target proteins (9, 10). NO regulates AMPARs by targeting AMPARinteracting proteins that determine receptor surface expression. Thus, physiologic S-nitrosylation of NSF (N-ethylmaleimide sensitive factor) elicits enhanced surface expression of GluA2 (11). Transmembrane AMPAR regulatory proteins are prominent auxiliary proteins for AMPARs, with stargazin being the best characterized (12). NMDAR transmission triggers S-nitrosylation of stargazin, which increases surface expression of GluA1 (13).The surface expression of AMPARs that determines synaptic plasticity is regulated by endocytosis because inhibitors of endocytosis block AMPAR removal from the plasma membrane, resulting in increased surface expression of AMPARs and long term depression (LTD) (14). Although NO has been implicated in regulation of protein endocytosis (15), its role in regulating AMPAR endocytosis is unknown.In the present study, we show that GluA1 is physiologically S-nitrosylated under basal conditions, with increased nitrosylation upon NMDAR stimulation. Moreover, the NMDAR-dependent phosphorylation of GluA1-S831 is regulated by endogenous NO, which acts by S-nitrosylating GluA1-C875. These events regulate single-channel conductance of GluA1, as the increase of such conductance by phosphorylation is markedly slowed in GluA1-C875S mutants. Endocytosis of AMPAR also is regulated by nitrosylation of GluA1-C875, because the C875S mutant of GluA1 reduces AMPAR endocytosis in neuronal cells and decreases binding ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis

Selvakumar

Jenkins

Hussain

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Canonical NO signaling is through binding to soluble guanylate cyclase (sGC), whereby sGC activation increases cGMP formation to stimulate protein kinase G and affect ERK phosphorylation and CREB-mediated changes in gene expression (Gabach et al, 2013). Although sGC is the only known receptor for NO, the reactive nitrogen chemical properties of NO allow it to S-nitrosylate a great number of proteins, and this post-translational modification is involved in modifying the activity state and/or binding properties of many enzymes and proteins (Jaffrey et al, 2001;Gu et al, 2002;Selvakumar et al, 2009).…”

Section: B Interneuronsmentioning

confidence: 99%

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

et al. 2016

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“…However, enzymes like S-nitrosoglutathione reductase (GSNOR) have been shown to mediate the denitrosylation (72). Many ion channels (or their regulators) (46), including the RyR channel (4), voltage-gated sodium channel (97), the voltage-gated (6), the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (103,104), the TRP channel (140), and the K ATP channel (21,58,64,67,120), are found to be regulated by S-nitrosylation or NO.…”

Section: Ion Channel S-nitrosylation and Its Relationship With S-glutmentioning

confidence: 99%

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

Yang

Jin²,

Jiang³

2014

Antioxidants & Redox Signaling

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Significance: Ion channels control membrane potential, cellular excitability, and Ca ++ signaling, all of which play essential roles in cellular functions. The regulation of ion channels enables cells to respond to changing environments, and post-translational modification (PTM) is one major regulation mechanism. Recent Advances: Many PTMs (e.g., S-glutathionylation, S-nitrosylation, S-palmitoylation, S-sulfhydration, etc.) targeting the thiol group of cysteine residues have emerged to be essential for ion channels regulation under physiological and pathological conditions. Critical Issues: Under oxidative stress, S-glutathionylation could be a critical PTM that regulates many molecules. In this review, we discuss S-glutathionylation-mediated structural and functional changes of ion channels. Criteria for testing S-glutathionylation, methods and reagents used in ion channel S-glutathionylation studies, and thiol modification crosstalk, are also covered. Mechanotransduction, and S-glutathionylation of the mechanosensitive K ATP channel, are discussed. Future Directions: Further investigation of the ion channel S-glutathionylation, especially the physiological significance of S-glutathionylation and thiol modification crosstalk, could lead to a better understanding of the thiol modifications in general and the ramifications of such modifications on cellular functions and related diseases. Antioxid. Redox Signal. 20, 937-951.

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S-nitrosylation of stargazin regulates surface expression of AMPA-glutamate neurotransmitter receptors

Cited by 71 publications

References 36 publications

S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis

S-nitrosylation of AMPA receptor GluA1 regulates phosphorylation, single-channel conductance, and endocytosis

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

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