Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain

Cachemaille, Matthieu; Cj, Laedermann; Pertin, Marie; Abriel, Hugues; Gosselin, Romain–Daniel; Décosterd, Isabelle

doi:10.1016/j.neuroscience.2012.09.044

Cited by 33 publications

(33 citation statements)

References 66 publications

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“…The functional relevance of NEDD4-2 in sensory neurons, as well as its possible involvement in pain sensitivity, have yet to be investigated. NEDD4-2 was recently shown to be decreased in rat DRG in the spared nerve injury (SNI) model of traumatic nerve injuryinduced neuropathic pain (25). The present study postulated that reduced levels of NEDD4-2 jeopardize the correct addressing or anchoring of Na v s in DRG nociceptive neurons.…”

Section: Introductionmentioning

confidence: 69%

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

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

119

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: Introductionmentioning

confidence: 69%

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

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

119

160

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“…Interestingly, NEDD4L expression is downregulated after nerve injury and results in the accumulation of Na v 1.7 and Na v 1.8 in DRG, where enhanced sodium influx causes neuron excitability and hypersensitivity to pain. 111,112 In conclusion, both NEDD4 and NEDD4L play an important role in regulating the stability of membrane proteins, which mainly regulate the transportation of molecules between cell-cell and ions from extracellular space to the cytosol. Deficiency in NEDD4 or NEDD4L contributes to the accumulation of ion channels in the membrane, and the enhanced ion flow causes neuronal diseases.…”

Section: Regulation Of Membrane Voltage-gated Sodium Channels (Na Vmentioning

confidence: 99%

“…NEDD4L has been identified as a regulator of both Na v 1.7 and Na v 1.8 and negatively regulates the levels of both sodium channels in dorsal root ganglia (DRG). Interestingly, NEDD4L expression is downregulated after nerve injury and results in the accumulation of Na v 1.7 and Na v 1.8 in DRG, where enhanced sodium influx causes neuron excitability and hypersensitivity to pain …”

Section: Role Of Ww Domain‐containing E3 Ligases In Neurological/rarementioning

confidence: 99%

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

2020

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The ubiquitin‐proteasome system (UPS) governs the protein degradation process and balances proteostasis and cellular homeostasis. It is a well‐controlled mechanism, in which removal of the damaged or excessive proteins is essential in driving signal pathways for cell survival or death. Accumulation of damaged proteins and failure in removal may contribute to disease initiation such as in cancers and neurodegenerative diseases. In this notion, specific protein‐protein interaction is essential for the recognition of targeted proteins in UPS. WW domain plays an indispensable role in the protein‐protein interactions during signaling. Among the 51 WW domain‐containing proteins in the human proteomics, near one‐quarter of them are involved in the UPS, suggesting that WW domains are crucial modules for driving the protein‐protein binding and subsequent ubiquitination and degradation. In this review, we detail a broad spectrum of WW domains in protein‐protein recognition, signal transduction, and relevance to diseases. New perspectives in dissecting the molecular interactions are provided.

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“…Cachemaille et al reported that Nedd4-2 expression was downregulated upon induction of neuropathic pain by the spared nerve injury model, and the authors postulated that this might contribute to the dysregulation of Na v 1.7 and Na v 1.8 associated with peripheral nerve injury. 55 Recently, a seminal work performed by the same group demonstrated that Nedd4-2 indeed regulates the surface expression of Na v 1.7 and Na v 1.8 in adult dorsal root ganglion (DRG) neurons in response to neuropathic pain. 54 Moreover, the levels of Na v 1.7 and Na v 1.8 were enhanced in a knockout of Nedd4-2 in nociceptive neurons.…”

Section: Regulation Of Vgics By Nedd4-2 Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…In addition to the altered functionality of Na v due to mutations, regulation of its localization and expression are highly relevant for the development of peripheral neuropathic pain. In a spared nerve injury model, Nedd4-2 expression was decreased in DRG neurons, 54,55 leading to increased Na v 1.7…”

Section: Voltage-gated Ion Channels and Diseasementioning

confidence: 99%

Nedd4-2 regulation of voltage-gated ion channels: an update on structure–function relationships and the pathophysiological consequences of dysfunction

Arévalo

2015

JRLCR

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Neuronal excitability is mediated mainly by voltage-gated ion channels (VGICs), which include voltage-gated Na + , K + , and Cl − channels located along the axon and at neuronal synapses. Voltage-gated channels play pivotal roles in the proper functioning of the nervous system because they set the resting membrane potential, initiate and propagate action potentials, and regulate neurotransmitter release. The abnormal activity or misregulation of VGICs caused by mutations has been directly linked to neurological and cardiac diseases. Among other posttranslational modifications, the ubiquitination of VGICs is a key to the regulation of the number of channels in the cell surface, and hence, neuronal excitability. Nedd4-2 is an E3 ubiquitin ligase that ubiquitinates several proteins, including different VGICs. Accordingly, understanding the molecular mechanisms underlying channel regulation will provide insights to design drugs to treat illnesses. The focus of the present review is to provide an update about the regulation of VGICs upon ubiquitination by Nedd4-2 and the relevance of such regulation in the pathophysiological consequences of dysfunction.

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Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain

Cited by 33 publications

References 66 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

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

Nedd4-2 regulation of voltage-gated ion channels: an update on structure–function relationships and the pathophysiological consequences of dysfunction

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Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: Modulation in the spared nerve injury model of neuropathic pain

Cited by 33 publications

References 66 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

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

Nedd4-2 regulation of voltage-gated ion channels: an update on structure&ndash;function relationships and the pathophysiological consequences of dysfunction

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Nedd4-2 regulation of voltage-gated ion channels: an update on structure–function relationships and the pathophysiological consequences of dysfunction