Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel–CRMP-2 signaling complex

Wilson, Sarah M.; Brittain, Joel M.; Piekarz, Andrew D.; Ballard, Carrie J.; Ripsch, Matthew S.; Cummins, Theodore R.; Hurley, Joyce H.; Khanna, May; Hammes, Nathan; Samuels, Brian C; White, Fletcher A.; Khanna, Rajesh

doi:10.4161/chan.5.5.17363

Cited by 42 publications

(67 citation statements)

References 33 publications

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“…Our laboratory has championed CRMP-2 as an important determinant of synaptic transmission [11][12][13]17,18]. Our findings demonstrate that Cdk5-phosphorylation of CRMP-2 enhances the interaction between CRMP-2 and CaV2.2 while reducing axon growth [28].…”

Section: Discussionmentioning

confidence: 50%

“…A cell penetrant version of the CBD3 peptide acutely inhibited synaptic transmission in hippocampal slices further suggesting a dynamic regulation of CaV2.2 by CRMP-2 [17]. Importantly, systemic administration of the cell permeable CBD3 peptide exhibited remarkable efficacy in attenuating tactile hyperalgesia in several models of neuropathic pain with no off-target effects [17][18][19], consistent with previous reports wherein genetic or pharmacological ablation of CaV2.2 led to similar reductions in tactile hyperalgesia [20,21]. Collectively, these findings have established CRMP-2 as an important regulator of CaV2.2 function.…”

Section: Introductionmentioning

confidence: 99%

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Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

et al. 2012

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Edited by Maurice Montal Keywords:CaV2.2 CRMP-2 Interaction Cdk5 RhoK Phosphorylation a b s t r a c tThe axon/dendrite specification collapsin response mediator protein-2 (CRMP-2) bidirectionally regulates N-type voltage-gated Ca 2+ channels (CaV2.2). But how cyclin dependent kinase 5 (Cdk5)-mediated phosphorylation of CRMP-2 affects its interaction/regulation with CaV2.2 is unknown. CRMP-2-mediated enhancement of currents via CaV2.2 was not observed with a Cdk5 phospho-null CRMP-2-S522A mutant or in cells expressing an inactive Cdk5. Concomitant knockdown of endogenous CRMP2 and overexpression of CRMP2-S522A mutant refractory to knockdown phenocopied the reduction in Ca 2+ influx while the Rho kinase CRMP2-T555A mutant was ineffective. Cdk5-phosphorylated CRMP-2 had increased association with CaV2.2. These results identify an important role for Cdk5 in CRMP2-mediated CaV2.2 regulation. Structured summary of protein interactions:Gsk3b phosphorylates Crmp2by phosphatase assay (View interaction) Crmp2 physically interacts with Cav2.2 by anti tag coimmunoprecipitation (View interaction)

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

et al. 2012

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“…We recently demonstrated that the interaction between CaV2.2 and collapsin response mediator protein 2 (CRMP2) (10), a positive regulator of channel surface expression, could be disrupted by a 15-aa peptide derived from the C terminus of CRMP2 (TAT CBD3). Interfering with this interaction efficiently reduced pain behaviors associated with a variety of rodent models of chronic neuropathic/inflammatory pain (11)(12)(13). Despite achieving similar levels of analgesic relief, TAT CBD3 treatment did not result in the adverse side effects observed with direct channel inhibition.…”

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confidence: 94%

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

Wilson

Schmutzler

Brittain

et al. 2012

Journal of Biological Chemistry

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Background: N-type Ca 2ϩ channels (CaV2.2) are clinically validated targets for chronic pain. Results: Two peptides from CaV2.2 and CaV1.2 perturb binding to a regulatory protein, CRMP2, inhibit calcium influx, and attenuate mechanical hyperalgesia in a rodent model of drug-induced chronic pain. Conclusion: Ca 2ϩ channel peptides block drug-and nerve injury-induced chronic pain. Significance: Ca 2ϩ channel peptide therapeutics can be useful in mitigating chronic pain.

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“…In this sense, the development and administration of TAT-CBD3, a polypeptide that interferes with intracellular transportation of voltage-dependent calcium channel (Cav2.2), reduces hyperalgesia and allodynia responses, after a chronic nerve constriction injury. 118 …”

Section: Therapeutic Approaches In Neuropathic Pain Based On the Neurmentioning

confidence: 99%

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

et al. 2016

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Study design: This is a narrative review of the literature. Objectives: This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. Setting: This study was conducted in Girona, Catalonia, Spain. Methods: A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. Results and conclusion: Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltagegated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system.

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Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel–CRMP-2 signaling complex

Cited by 42 publications

References 33 publications

Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

Cdk5‐mediated phosphorylation of CRMP‐2 enhances its interaction with CaV2.2

Inhibition of Transmitter Release and Attenuation of Anti-retroviral-associated and Tibial Nerve Injury-related Painful Peripheral Neuropathy by Novel Synthetic Ca2+ Channel Peptides

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

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