A Role of the Ubiquitin–Proteasome System in Neuropathic Pain

Moss, Andrew; Blackburn-Munro, Gordon; Garry, Emer M.; Blakemore, James; Dickinson, Tracey; Rosie, Roberta; Mitchell, Rory; Fleetwood-Walker, Susan M.

doi:10.1523/jneurosci.22-04-01363.2002

Cited by 54 publications

(47 citation statements)

References 47 publications

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“…Given that the abnormal functioning of sodium channels is a key event in the etiology of neuropathic pain, these results support a new paradigm in the treatment of this pathology. Ubiquitylation-dependent mechanisms have already been implicated in neuropathic pain in a study reporting that the intrathecal delivery of proteasome inhibitors attenuated hyperalgesia in rats (46). Another posttranslational modification of sodium channels induced by the accumulation of the glycolytic metabolite methylglyoxal was recently found to play an important role in diabetic neuropathy (47).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

116

160

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Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Na v s) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na v s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Na v s, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na v 1.7-specific inhibitor, ProTxII, allowed the isolation of Na v 1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na v 1.7 and Na v 1.8 currents. The redistribution of Na v 1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L -/-). SNS-Nedd4L -/-mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na v 1.7 and Na v 1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na v s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

116

160

View full text Add to dashboard Cite

show abstract

“…PTEN and Nedd4) could offer a new strategy for treating certain neurological disorders (1-5, 22, 58) and improving clinical opioid therapy in chronic and cancer pain treatment (59). These possibilities are supported by a recent study showing that inhibition of proteasomal activity attenuated neuropathic pain behaviors in rats (60), which is also regulated by the glutamatergic system including glutamate transporters (22).…”

Section: Discussionmentioning

confidence: 99%

Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation

Yang

Wang

Sung

et al. 2008

Journal of Biological Chemistry

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Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance. However, how the glutamate transporter turnover is regulated remains poorly understood. Here we show that chronic morphine exposure induced posttranscriptional downregulation of the glutamate transporter EAAC1 in C6 glioma cells with a concurrent decrease in glutamate uptake and increase in proteasome activity, which were blocked by the selective proteasome inhibitor MG-132 or lactacystin but not the lysosomal inhibitor chloroquin. At the cellular level, chronic morphine induced the PTEN (phosphatase and tensin homolog deleted on chromosome Ten)-mediated up-regulation of the ubiquitin E3 ligase Nedd4 via cAMP/protein kinase A signaling, leading to EAAC1 ubiquitination and proteasomal degradation. Either Nedd4 or PTEN knockdown with small interfering RNA prevented the morphine-induced EAAC1 degradation and decreased glutamate uptake. These data indicate that cAMP/protein kinase A signaling serves as an intracellular regulator upstream to the activation of the PTEN/ Nedd4-mediated ubiquitin-proteasome system activity that is critical for glutamate transporter turnover. Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn. Thus, inhibition of the ubiquitin-proteasome-mediated glutamate transporter degradation may be an important mechanism for preventing glutamate overexcitation and may offer a new strategy for treating certain neurological disorders and improving opioid therapy in chronic pain management.Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance (1-5). However, how the glutamate transporter degradation is regulated remains unclear (6 -8). The ubiquitin-proteasome system (UPS) 2 is a major non-lysosomal proteolytic pathway that degrades cellular proteins including those with important roles in the regulation of cell growth and function (9 -11). In addition, activation of UPS has been shown to regulate the PSD-95 degradation and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor surface expression (12), suggesting a possible relationship between UPS and glutamatergic activities. Ubiquitination is a process involving three enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase) (13,14). Interactions between an E3 ligase and its target molecule are considered a key step in determining the selectivity of UPS for a target molecule and its subsequent proteasomal degradation, a process that is subject to intracellular modulation by various upstream regulators (14). PTEN (phosphatase and tensin homolog deleted on chromosome Ten) is a tumor suppressor and lipid phosphatase, which has been shown to regulate cell surviva...

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“…*p Յ 0.05; **p Յ 0.01 (two-sample t test). some inhibitors attenuate learning and memory (Hegde et al, 1997;Chain et al, 1999;Lopez-Salon et al, 2002) and suppress functional plasticity (Moss et al, 2003), whereas compromised proteasome function has been linked with aging (Keller et al, 2000) and with memory impairment in humans . This suggests a facilitatory role for the proteasome in plasticity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Neuronal Proteasome by Zif268 (Egr1)

2006

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Most forms of neuronal plasticity are associated with induction of the transcription factor Zif268 (Egr1/Krox24/NGF-IA). In a genomewide scan, we obtained evidence for potential modulation of proteasome subunit and regulatory genes by Zif268 in neurons, a finding of significance considering emerging evidence that the proteasome modulates synaptic function. Bioinformatic analysis indicated that the candidate proteasome Zif268 target genes had a rich concentration of putative Zif268 binding sites immediately upstream of the transcriptional start sites. Regulation of the mRNAs encoding the psmb9 (Lmp2) and psme2 (PA28␤) proteasome subunits, along with the proteasome-regulatory kinase serum/glucocorticoid-regulated kinase (SGK) and the proteasome-associated antigen peptide transporter subunit 1 (Tap1), was confirmed after transfection of a neuronal cell line with Zif268. Conversely, these mRNAs were upregulated in cerebral cortex tissue from Zif268 knock-out mice relative to controls, confirming that Zif268 suppresses their expression in the CNS. Transfected Zif268 reduced the activity of psmb9, SGK, and Tap1 promoter-reporter constructs. Altered psmb9, SGK, and Tap1 mRNA levels were also observed in an in vivo model of neuronal plasticity involving Zif268 induction: the effect of haloperidol administration on striatal gene expression. Consistent with these effects on proteasome gene expression, increased Zif268 expression suppressed proteasome activity, whereas Zif268 knock-out mice exhibited elevated cortical proteasome activity. Our findings reveal that Zif268 regulates the expression of proteasome and related genes in neuronal cells and provide new evidence that altered expression of proteasome activity after Zif268 induction may be a key component of long-lasting CNS plasticity.

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A Role of the Ubiquitin–Proteasome System in Neuropathic Pain

Cited by 54 publications

References 47 publications

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation

Regulation of the Neuronal Proteasome by Zif268 (Egr1)

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