Target | Modification Site | Effect of SNO on Target Function | Presumed Consequence in Terms of Nociception | Reference |
---|---|---|---|---|
NMDA-R subunit NR2A | Cys399 | Reduction of calcium influx | Prevention of glutamate excitotoxicity and control of hyperexcitability | Lipton et al., 1993; Choi et al., 2000 |
NMDA-R subunit NR1 | Cys744 and Cys798 Subsequent facilitation of S-nitrosylation at further sites | Reduction of calcium influx, sensitization of other cysteines for NO-mediated modification | Prevention of glutamate excitotoxicity during ischemia and hypoxia | Takahashi et al., 2007 |
Serine racemase | Cys113 | Restriction of catalytic activity and production of d-serine, which acts as coactivator at NMDA-R | Modulation of NMDA-R dependent LTP | Mustafa et al., 2007 |
Glutamine synthase | N.D. | N.D. | Prevention of glutamate excitotoxicity by conversion to nontoxic glutamine | Görg et al., 2007 |
Excitatory glutamate transporter EAAT2 (GLT1) | N.D. | N.D. | Glutamate reuptake in astrocytes | Butterfield et al., 2006 |
Dexras1 | Cys11 | Increase of the proportion of GTP-bound Ras leading to increase of neuronal iron import | Regulation of iron supply for heme-dependent enzymes | Cheah et al., 2006 |
p21/Ras | Cys118 | Increase of the proportion of GTP-bound Ras leading to increased activation of PI3Kγ and PKB/Akt kinase | Prosurvival effect after nerve injury | Lander et al., 1995 |
NSF | Cysteines 11, 21, 334, 568, and 582 | Inhibition of SNARE complex disassembly, reduction of synaptic vesicle exocytosis, increase of membrane insertion of AMPA-R GluR2 | Decrease of nociceptive neuron sensitivity to noxious stimuli, decrease of LTP at nociceptive synapses | Matsushita et al., 2003; Huang et al., 2005 |
Syntaxin | Cys145 | Regulation of synaptic vesicle exocytosis | Prevention of excess glutamate or neuropeptide release | Palmer et al., 2008 |
Stargazin | Cys302 intracellular in the C-terminal tail | Increase of AMPA-R membrane insertion | Increase of nociceptive neuron sensitivity | Selvakumar et al., 2009 |
Caspase 3 | Cys163, catalytic site | Constitutively nitrosylated mitochondrial caspase 3, denitrosylation through Trx caused activation and apoptosis | Prevention of glutamate excitotoxicity and neuron death after axonal injury | Mannick et al., 1999; Mannick et al., 2001 |
TRPC5 | C553+C558 N-terminal cytoplasmic tail, pore forming region | Increase of channel gating for calcium entry | Increase of nociceptive neuron sensitivity | Yoshida et al., 2006 |
TRPC5 | Extracellularly accessible cysteines sensitive to reduced extracellular thioredoxin | Reduced extracellular rTRX evoked increase of channel gating for calcium entry | Increase of nociceptive neuron sensitivity | Xu et al., 2008b |
TRPA1 | N-terminal cytoplasmic side, pore-forming region, Cys415, 422, 622 | Covalent binding of endogenous and chemical reactive electrophilic compounds, increase of calcium influx | Increase of nociceptive neuron sensitivity, pain sensation evoked by chemical irritants | Macpherson et al., 2007 |
TRPV1 | N-terminal cytoplasmic side, pore-forming region | Covalent binding of endogenous and chemical reactive electrophilic compounds, increase of calcium influx | Increase of nociceptive neuron sensitivity, pain sensation evoked by chemical irritants | Salazar et al., 2008 |
VGCCs | N.D. | Increase of calcium influx | Increase of nociceptive neuron sensitivity | Jian et al., 2007 |
Membrane K-ATP, Kir6.2/Sur1 | N.D. | Increase of potassium influx | Hyperpolarization of primary sensory neurons, antinociceptive effects of NO, peripheral antinociceptive effects of morphine | Kawano et al., 2009a; Cunha et al., 2010 |
Ryanodine channel | RyR1 C3635 muscle | Increase of CICR | Modulation of EPSCs in lamina II nociceptive neurons in spinal cord slices | Sun et al., 2001; Aracena-Parks et al., 2006 |
Ryanodine channel | RyR2, RyR3 brain | Increase of CICR, neuropeptide release sensory neurons | Modulation of EPSCs in lamina II nociceptive neurons in spinal cord slices | Bull et al., 2003, 2008 |
sGC | Cysteines in vicinity to heme group C243 in alpha and C122 in beta subunit | Desensitization of sGC, decrease of cGMP production | Desensitization of sGC positive projecting neurons | Sayed et al., 2007 |
CNG2, rat | Cys460 within C-linker region | Increase of cation entry into cell | Enhancement of nociceptive neuron sensitivity | Broillet, 2000 |
HCN | N.D. | Setting of the excitation threshold in sensory neurons | Hyperexcitability and spontaneous discharge after nerve injury | Jaffrey et al., 2001 |
c-Jun N-terminal kinase (JNK1) | Cys116 | Inhibition of catalytic activity | Reduction of microglia activation after nerve injury | Park et al., 2000 |
SHP-1 phosphotyrosine phosphatase | Cys453, active site | Inhibition of phosphatase activity | Increase of NGF mediated hyperalgesia due to enhanced phosphorylation of TrkA | Barrett et al., 2005 |
MAP kinase phosphatase (MKP7) | N.D. | Inhibition of phosphatase activity, leading to JNK activation | Proinflammatory, activation of microglia and neuronal stress response | Pi et al., 2009 |
MMP-9 | Increase of catalytic activity | Enhancement of glia activation after nerve injury, increase of hyperalgesia | Gu et al., 2002; McCarthy et al., 2008 | |
cPLA2 | Cys152 | Increase of catalytic activity and release of arachidonic acid from membrane lipids | Facilitation of the production of proinflammatory lipid mediators such as prostaglandins | Xu et al., 2008a |
COX-2 | N.D. | Increase of catalytic activity and prostaglandin E2 production | Direct activation of nociceptive neurons and disinhibition, promoting glutamate NMDA-R-dependent excitotoxicity | Tian et al., 2008 |
Myeloid differentiation primary response gene (MyD88) | N.D. | Control of Toll-like receptor-mediated signaling | Anti-inflammatory effects | Into et al., 2008 |
IKKβ | Cys179 located between critical phosphorylation site at Ser177 and Ser181, conserved in IKKα | Inhibition of IKK-mediated IκBα phosphorylation resulting in inhibition of NF-κB activation | Anti-inflammatory effects | Reynaert et al., 2004 |
NF-κB p50 | Cys62 | Inhibition of DNA binding capacity | Anti-inflammatory effects | Marshall and Stamler, 2001 |
NF-κB p65 | N.D. | Inhibition of DNA binding capacity | Anti-inflammatory effects | Kelleher et al., 2007 |
HIF1-α | Cys533, oxygen-dependent degradation domain | Stabilization of HIF-1alpha and increase of its transcriptional activity | Increase of nociceptive neuron sensitivity, pro-inflammatory | Palmer et al., 2000; Li et al., 2007 |
Adenylyl cyclase (AC6) | N.D. | Inhibition of cAMP production | Antinociceptive effects (e.g. reduction of PACAP-signaling) | Ostrom et al., 2004 |
GRK2 | Cys340 | Prevention of agonist-stimulated receptor desensitization | Modulation of GPCR signaling | Whalen et al., 2007 |
Dynamin | Cys607 conserved in dynamin 1 and 2 | Facilitation of GPCR endocytosis and desensitization | Modulation of GPCR signaling, synaptic vesicle exo- and endocytosis, axonal transport, general membrane fission | Wang et al., 2006 |
Dynamin-related protein 1 (Drp1) | Cys644 | Promotion of mitochondrial fission, control of neuronal cell death | Enhancement of neuronal death after axonal injury | Cho et al., 2009; Westermann, 2009 |
β-Arrestin | Cys410 | Promotion of GPCR endocytosis and recycling | Function of cannabinoid and opioid receptors, implications for opioid and cannabinoid tolerance | Ozawa et al., 2008 |
GAPDH | Increase of GAPDH binding to and signaling of Siah | Increase of glutamate excitotoxicity | Molina y Vedia et al., 1992; Hara et al., 2005 | |
GOSPEL | Cys47 | Facilitation of GAPDH-GOSPEL binding, and neuroprotection by GOSPEL. | Decrease of glutamate excitotoxicity | Sen et al., 2009 |
PDI | Inhibition of catalytic activity, accumulation of polyubiquitinated proteins, and activation of the unfolded protein response | Increase of ER stress | Uehara et al., 2006 | |
Trx 1 | Cys69 and Cys73, upon oxidative stress active site Cys32 and Cys35 | Reduction of catalytic activity, transnitrosylation of caspase 3 | Modulation of apoptosis, modulation of constitutively nitrosylated proteins | Mitchell and Marletta, 2005; Hashemy and Holmgren, 2008 |
Peroxiredoxin (Prx2) | Cys51 and Cys172, catalytic site | Inhibition of catalytic activity, loss of antioxidant capacity | May increase neuronal damage after injury | Forrester et al., 2009 |
Glutaredoxin, (Grx1) | Cys-8 and either Cys-79 or Cys-83 | Partial inhibition of catalytic activity, loss of antioxidant capacity | May increase neuronal damage after injury | Hashemy et al., 2007 |
Glutathione transferase (GST) pi | Cys47 and Cys101 | NO-carrier function | Lo Bello et al., 2001; Townsend et al., 2006 |
EPSC, excitatory postsynaptic current; PACAP, pituitary adenylate cyclase-activating polypeptide; PI3K, phosphatidylinositol 3-kinase; -R, receptor.