CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Chew, Lindsey A.; Khanna, Rajesh

doi:10.1042/ns20170220

Cited by 42 publications

(30 citation statements)

References 169 publications

(180 reference statements)

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“…CRMP2 is expressed mainly in the nervous system as inferred from positive immunoblotting signals from brain and DRG homogenates while no expression was detected in intestine, lung, liver, kidney, heart, muscle or any other tissues from chicken. Our work has demonstrated CRMP2 to be a major hub for the trafficking of voltage-gated calcium and sodium channels in pain signaling [74,[97][98][99]. We identified a novel trafficking platform for Na V 1.7 driven by hierarchical interactions with post-translationally modified versions of the binding partner CRMP2 [73]; a finding confirmed by the Wood group [49].…”

Section: (N) Collapsin Response Mediator Protein 2 (Crmp2)supporting

confidence: 54%

“…Co-localization of calcium-calmodulin protein kinase II alpha (CaMKIIα) and MAP2 alongside coincident modulation of their expression within the trigeminal subnucleus caudalis in an inferior alveolar nerve transection model of neuropathic pain reinforce MAP2's role in the context of pain signaling [71]. Known functions of MAP2 in tubulin binding also provide a link to the collapsin response mediator family of cytosolic proteins, with more recently described roles in the regulation of voltage gated calcium and sodium channel trafficking [72][73][74]. The aforementioned shifts in expression within models of neuropathic pain ideally position MAP2 for coordinating a nociceptive response within dendrites.…”

Section: (F) Microtubule-associated Protein 2 (Map2)mentioning

confidence: 95%

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Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

Chew

Bellampalli

Dustrude

et al. 2019

Biochemical Pharmacology

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The peripherally expressed voltage-gated sodium Na V 1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na V 1.7 has been the focus of intense investigation but, to date, no Na V 1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na V 1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na V 1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na V 1.7 therapeutics is currently unknown. The demonstration that loss of Na V 1.7 function is associated with upregulation of endogenous opioids and potentiation of mu-and delta-opioid receptor activities, suggests that targeting only Na V 1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial and disputed. Thus, additional new targetsregulators, modulators-are needed. In this context, we mine the literature for the known interactome of Na V 1.7 with a focus on protein interactors that affect the channel's trafficking or

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Section: (N) Collapsin Response Mediator Protein 2 (Crmp2)supporting

confidence: 54%

Section: (F) Microtubule-associated Protein 2 (Map2)mentioning

confidence: 95%

Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

Chew

Bellampalli

Dustrude

et al. 2019

Biochemical Pharmacology

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“…While there is extensive literature on how phosphorylation of CRMP2 controls its canonical functions of neurite outgrowth/branching (see review by Khanna [17] and Ip [65]), how posttranslational modifications of CRMP2 control ion channel trafficking are only now beginning to be understood [66,22,23,20,11,34,10,25]. While our recent work has focused on Cdk5, a 'priming' kinase in the context of CRMP2 [34,67,48,36,22], the current work suggests that RhoK phosphorylation site may also be important in shaping calcium influx.…”

Section: Discussionmentioning

confidence: 89%

Phosphorylated CRMP2 Regulates Spinal Nociceptive Neurotransmission

Moutal

Dorame

et al. 2018

Mol Neurobiol

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The collapsin response mediator protein 2 (CRMP2) has emerged as a central node in assembling nociceptive signaling complexes involving voltage-gated ion channels. Concerted actions of posttranslational modifications, phosphorylation and SUMOylation, of CRMP2 contribute to regulation of pathological pain states. In the present study, we demonstrate a novel role for CRMP2 in spinal nociceptive transmission. We found that, of six possible post-translational modifications, three phosphorylation sites on CRMP2 were critical for regulating calcium influx in dorsal root ganglion sensory neurons. Of these, only CRMP2 phosphorylated at serine 522 by cyclin dependent kinase 5 (Cdk5) contributed to spinal neurotransmission in a bidirectional manner. Accordingly, expression of a non-phosphorylatable CRMP2 (S522A) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), whereas expression of a constitutively phosphorylated CRMP2 (S522D) increased the frequency of sEPSCs. The presynaptic nature of CRMP2's actions were further confirmed by pharmacological antagonism of Cdk5-mediated CRMP2 phosphorylation with S-N-benzy-2-acetamido3-methoxypropionamide ((S)-Lacosamide; (S)-LCM) which (i) decreased sEPSC frequency, (ii) increased paired pulse ratio, and (iii) reduced the presynaptic distribution of CaV2.2 and NaV1.7, two voltage-gated ion

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“…SUMOylation of CRMP2 specifically controls trafficking and surface expression of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel NaV1.7 [10; 19; 21]. Decreasing CRMP2 SUMOylation, using CRMP2 mutants with disrupted SUMO motifs, reduced NaV1.7 currents.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Ubc9 E2 SUMO-conjugating enzyme–CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain

François‐Moutal¹,

Dustrude²,

Wang³

et al. 2018

PAIN

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We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in the axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking of the voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate the biophysical nature of the interaction between CRMP2 and the SUMOylation machinery, and test the hypothesis that a rationally designed CRMP2 SUMOylation motif (CSM) peptide can interrupt E2 SUMO-conjugating enzyme Ubc9-dependent modification of CRMP2 leading to a similar suppression of NaV1.7 currents. Microscale thermophoresis and amplified luminescent proximity homogeneous alpha assay revealed a low micromolar binding affinity between CRMP2 and Ubc9. A heptamer peptide harboring CRMP2's SUMO motif, also bound with similar affinity to Ubc9, disrupted the CRMP2-Ubc9 interaction in a concentration-dependent manner. Importantly, incubation of a tat-conjugated cell-penetrating peptide (t-CSM) decreased sodium currents, predominantly NaV1.7, in a model neuronal cell line. Dialysis of t-CSM peptide reduced CRMP2 SUMOylation and blocked surface trafficking of NaV1.7 in rat sensory neurons. Fluorescence dye-based imaging in rat sensory neurons demonstrated inhibition of sodium influx in the presence of t-CSM peptide; by contrast, calcium influx was unaffected. Finally, t-CSM effectively reversed persistent mechanical and thermal hypersensitivity induced by a spinal nerve injury, a model of neuropathic pain. Structural modeling has now identified a pocket-harboring CRMP2's SUMOylation motif that, when targeted through computational screening of ligands/molecules, is expected to identify small molecules that will biochemically and functionally target CRMP2's SUMOylation to reduce NaV1.7 currents and reverse neuropathic pain.

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CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Cited by 42 publications

References 169 publications

Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics

Phosphorylated CRMP2 Regulates Spinal Nociceptive Neurotransmission

Inhibition of the Ubc9 E2 SUMO-conjugating enzyme–CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain

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