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"This fifteen amino acid peptide has been shown to interfere with the interaction between CRMP2 and CaV2.2, resulting in disrupted surface colocalization of the two proteins and reduced calcium influx through CaV2.2 channels [29]."
31359322
sparser
"The study of CaV2.2 trafficking modulators xref led us to identify axon/dendrite specification collapsin response mediator protein 2 (CRMP2) as a CaV2.2-binding partner, xref which enhances CaV2.2 membrane trafficking and facilitates synaptic transmission. xref , xref CaV2.2 membrane trafficking was effectively disrupted by a 15-amino-acid region of CRMP2, named Ca 2+ channel-binding domain 3 (CBD3). xref Systemic injection of CBD3 peptide conjugated to the cell-penetrating motif of the HIV transduction domain protein tat (tat-CBD3) reduced hypersensitive behavior in chemically induced inflammatory and neuropathic pain models. xref , xref , xref , xref tat-CBD3 reduced CaV2.2-mediated currents by inhibiting CaV2.2–CRMP2 interaction, xref which resulted in reduced nociceptor excitability, diminished neuropeptide release from primary sensory neurons, and lowered excitatory synaptic transmission. xref "
25782368
sparser
"We previously showed that CRMP2 is a novel binding partner of CaV2.2. xref , xref A 15-amino acid peptide derived from CRMP2 (designated CBD3 for calcium channel binding domain) uncoupled the CaV2.2–CRMP2 interaction leading to a decrement in Ca 2+ current and neurotransmitter release and, consequently, suppressed persistent inflammatory and neuropathic hypersensitivity. xref , xref , xref Mutating single residues within the CBD3 peptide sequence or changing the cell-penetrating motif improved the efficacy of CBD3 in models of neuropathic pain. xref , xref Here, we tested the hypothesis that tethering the CBD3 peptide to the membrane with myristate would confine the myristoylated peptide’s action(s) to uncoupling membrane CaV2.2–CRMP2 interactions, block Ca 2+ influx in sensory neurons, and be effective in reducing pain-related behaviors in models of pain."
25782368
sparser
"Binding of GSK-3β-phosphorylated CRMP-2 to CaV2.2 was not significantly different from samples without exogenous kinases."
23022559
sparser
"The CRMP2–CaV2.2 interaction was dynamic as potassium chloride-induced depolarization led to an increase in the interaction."
23831344
sparser
"These findings suggested that the biochemical interaction between CRMP2 and CaV2.2 was required for proper channel trafficking and function."
23831344
sparser
"Our initial mapping of the CaV2.2:CRMP2 interaction had identified a surface-exposed region in CRMP2, which we designated calcium channel binding domain 3 (CBD3) [ xref ]."
23831344
sparser
"As CBD3 disrupts the interaction between CRMP2 and CaV2.2, this supports the conclusion that the interaction between CRMP2 and CaV2.2 is likely responsible for the observed increase in Ca 2+ currents."
23831344
sparser
"TAT-CBD3 peptide interfered with CRMP2-CaV2.2 interactions resulting in acute inhibition of CaV2.2 currents in sensory and hippocampal neurons; acute inhibition of frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in spinal cord slices as well as layer V pyramidal neurons suggesting reduction in probability of glutamate release from stimulated presynaptic terminals; and inhibition of evoked calcitonin gene-related peptide (CGRP) in sensory neurons in culture (acute and long-term inhibition observed) and in spinal cord slices."
23831344
sparser
"Similar to TAT-CBD, the R9-conjugated CBD3 peptide interfered with the CaV2.2–CRMP2 interaction."
23831344
sparser
"From these findings, we propose that TAT-CBD3 allows suppression of pain hypersensitivity without directly blocking CaV2.2, but rather by inhibiting the binding of a regulator of CaV2.2 function, CRMP-2."
21642979
sparser
"The functional consequence of the disrupted CaV2.2–CRMP2 interaction was a significantly higher extent (i.e. efficacy) of inhibition of calcium influx in sensory neurons."
23831344
reach
"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 (Fig. 1A; top blot, lane 2)."
27537210
sparser
"In 2009, we reported the existence of a biochemical complex between CRMP-2 and CaV2.2 in hippocampal/cortical neurons [11] ; the interaction was enhanced in an activity-dependent fashion implying dyna[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23022559
sparser
"We previously showed that tat-CBD3 inhibited the CaV2.2–CRMP2 interaction. xref Therefore, we next tested whether the myristoylated CBD3 peptide could interfere with the CaV2.2–CRMP2 interaction."
25782368
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"The CBD3 peptide bound to immobilized loop 1 and the distal part of the carboxyl terminus of CaV2.2 and in a concentration-dependent fashion, blocked the interaction between recombinantly purified CRMP2 and loop regions of CaV2.2, between full-length native CaV2.2 and recombinantly purified CRMP2, demonstrating usefulness as a tool for interrupting the interaction between this protein complex."
23831344
sparser
"We reported that collapsin response mediator protein 2 (CRMP2) interacts with CaV2.2 and enhances its functional activity [ xref ; xref ; xref ; xref ]."
27537210
sparser
"We previously reported that CBD3, a 15 amino acid fragment of CRMP2, disrupts the CRMP2–CaV2.2 interaction [ xref ] irrespective of the cell penetrating motif it is appended to: the HIV-1 transactivator of transcription domain (TAT) [ xref ], a myristate (Myr) tag [ xref ], or homopolyarginine (R9) [ xref ]."
27537210
sparser
"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 ( xref ; top blot, lane 2)."
25782368
sparser
"R9-CBD3-A6K disrupts the CRMP2–CaV2.2 interaction and inhibits surface trafficking of CaV2.2 in DRGs."
27537210
sparser
"We previously showed that all cell penetrant forms of CBD3 inhibited the CRMP2–CaV2.2 interaction [ xref ; xref ; xref ; xref ]."
27537210
sparser
"These results demonstrate that the R9-conjugated mutant peptide retains its ability to efficiently uncouple the CRMP2–CaV2.2 interaction."
27537210
sparser
"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 ( xref ; top blot, lane 2 )."
27537210
sparser
"Phosphorylation of CRMP-2 by Cdk5 also increases the interaction between CaV2.2 and CRMP-2."
23022559
sparser
"Although the control peptides did not alter this interaction, the tat-CBD3 peptide was able to inhibit CaV2.2–CRMP2 interaction by ~43% at 10 μM. Myr-tat-CBD3, in a concentration-dependent manner, attenuated this interaction with greater than ~81% inhibition at 10 μM ( xref ; top blot and xref )."
25782368
sparser
"These results demonstrate that the myristoyl group improves the ability of the peptide to break the CaV2.2–CRMP2 interaction."
25782368
sparser
"These results demonstrate that by uncoupling the CaV2.2– CRMP2 interaction, both tat-CBD3 and myr-tat-CBD3 reduce surface trafficking of CaV2.2 (eg, 0.60 PCC and 0.65 MOC for the myr-tat-CBD3-treated DRG as noted by the lack of colocalization in the insets)."
25782368
sparser
"Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo ."
31359322
reach
"Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822-829 (2011)]."
22662308
sparser
"Based on findings in the literature, we tested whether chronic cocaine self-administration and extinction would decrease CRMP2 abundance in the PFC and to what extent drug-paired cues (without drug delivery) would alter CRMP2-CaV2.2 expression in the PFC."
31359322
reach
"These findings suggest that the biochemical interaction between CRMP-2 and CaV2.2 is required for proper channel trafficking and function."
22662308
reach
"Disruption of the interaction between CaV2.2 and CRMP2 by a short peptide (CBD3) corresponding to a 15 amino acid region of CRMP-2 produces a number of changes including pain signal transmission [21]."
22662308
reach
"The interaction between CaV2.2 and CRMP2 can be disrupted by a short peptide (CBD3) corresponding to a 15 amino acid region of CRMP-2 (Figure 1A,C)."
22662308
reach
"The effect of the novel G14F CBD3 peptide on chronic pain is likely attributed to its ability to block the functional interaction of CRMP2 and CaV2.2."
22662308
sparser
"This fifteen amino acid peptide has been shown to interfere with the interaction between CRMP2 and CaV2.2, resulting in disrupted surface colocalization of the two proteins and reduced calcium influx through CaV2.2 channels [ xref ]."
31359322
sparser
"We used a GST-pull down approach to detect CRMP2 interaction with CaV2.2 and βIII-tubulin as a positive control ( xref )."
31359322
sparser
"We next used myr-TAT-CBD3 in vivo to examine if disrupting the interaction between CRMP2 and CaV2.2 reduced drug-seeking behavior."
31359322
sparser
"Furthermore, disruption of the CRMP2-CaV2.2 protein-protein interaction in the mPFC decreased cue-induced (but not cocaine-primed) reinstatement of cocaine seeking."
31359322
sparser
"The breadth of CRMP2 protein interactions are numerous and widespread, yet our results suggest that in the PFC, CRMP2 interactions with CaV2.2 are critical for cued-reinstatement of cocaine, an animal model of relapse."
31359322
sparser
"Based on the structure of the calcium channel binding domain (CBD) of CRMP2, CBD peptides have been developed to disrupt CRMP2 interaction with the I-III loop of CaV2.2."
31888223
sparser
"Because we observed increased CaV2.2 expression following cue-induced reinstatement, we tested if a functional CRMP2-CaV2.2 protein-protein interaction in the PFC was required for cued-reinstatement."
31359322
sparser
"Although CBD3 has been previously demonstrated to interfere with the CaV2.2–CRMP2 interaction, the dynamics of the disruption over time by this peptide have never been studied."
25782368
sparser
"Having established that both peptides can inhibit the CaV2.2– CRMP2 interaction in vitro, we next asked whether this translated into a disruption in cells."
25782368
sparser
"Thus, we used immunofluorescent microscopy to determine the time course of CBD3-mediated disruption of the CaV2.2–CRMP2 interaction."
25782368
sparser
"When applied locally to the PFC, this peptide reduced both CRMP2 binding to CaV2.2 and reinstatement in response to drug-cues, but not to cocaine-priming."
31359322
sparser
"This ( R )-enantiomer of lacosamide effectively blocks CRMP2-dependent microtubule formation, but is without action on CaV2.2 channel function or CRMP2 phosphorylation states, the regulatory event driving CRMP2-CaV2.2 association [ xref ]."
31359322
sparser
"Therefore, targeting the CaV2.2-CRMP2 protein-protein interaction may be most effective at eliminating relapse behavior once drug-seeking behavior is already learned."
31359322
sparser
"In addition to tubulin, CRMP2 also interacts with the N-type voltage gated calcium channel Cav2.2, targeting it to neuronal membranes ( xref )."
35791633
sparser
"These results suggest that regulation of CRMP-2’s interaction with CaV2.2 is specific to Ser-522 phosphorylation as mutation to the Thr-555 sites elicited no change in Ca 2+ -influx."
23022559
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"CRMP2 binds to CaV2.2 and increases the Ca level on the cell surface."
35479088
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"CRMP2 binds directly with CaV2.2 leading to increased Ca current density and increased neurotransmitter release in sensory neurons [18]."
31009417
sparser
"Our findings demonstrate that Cdk5-phosphorylation of CRMP-2 enhances the interaction between CRMP-2 and CaV2.2 while reducing axon growth [28] ."
23022559
sparser
"The present findings make a compelling case for the use of a myristoylated CRMP2 peptide, which uncouples the CaV2.2–CRMP2 interaction, for the treatment of inflammatory and incision-induced pain."
25782368
sparser
"As it was recently demonstrated that Cdk5 signals through the adaptor protein Ca 2+ /calmodulin-dependent serine protein kinase (CASK) to regulate trafficking of CaV2.2 [35] , we utilized Cdk5 phospho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
23022559
sparser
"The pharmacological action of peptides observed in our in vitro experiments is linked to uncoupling of the CaV2.2–CRMP2 interaction culminating in alleviation of inflammatory and neuropathic pain. xref , xref , xref , xref , xref Sustained, but incomplete, relief of neuropathic pain has been successfully demonstrated for a nonmyristoylated CRMP2 peptide. xref We postulate that the myristoylated version described herein may afford greater efficacy and clinical utility as a gene therapy strategy for chronic pain."
25782368
sparser
"As previously described, CaV2.2–CRMP2 disruption by tat-CBD3 decreased surface CaV2.2 in DRG. xref , xref Myr-tat-CBD3 peptide interfered with the CaV2.2–CRMP2 interaction more efficiently than tat-CBD3 as observed by a reduction in colocalization within minutes of incubation ( xref )."
25782368
sparser
"Concomitant expression of CaV2.2, CRMP2, and CGRP was detected in a subset of neurons from the ophthalmic branch of TGs that receive input from the dura mater. xref These results suggest a coordinated mechanism involving interactions between CRMP2 and CaV2.2 to facilitate the release of pro-nociceptive CGRP that consequently leads to cephalic pain."
27917413
sparser
"CRMP2 binds to CaV2.2 and increases the Ca 2+ level on the cell surface."
35479088
sparser
"We reported that Cdk5-mediated CRMP2 phosphorylation increases its binding to CaV2.2, which augments calcium influx xref ; thus, the increased interaction between CRMP2 and CaV2.2 may underlie the mechanism of antinociception in this particular model."
25782368
reach
"ST1-104, which disrupts the interaction between CaV2.2 and CRMP2 interaction, reduces persistent mechanical hypersensitivity induced by systemic administration of ddC [188]."
24403874
reach
"Challenging the catechism of therapeutics for chronic neuropathic pain: targeting CaV2.2 interactions with CRMP2 peptides."
23831344
reach
"These findings suggested that the biochemical interaction between CRMP2 and CaV2.2 was required for proper channel trafficking and function."
23831344
reach
"As CBD3 disrupts the interaction between CRMP2 and CaV2.2, this supports the conclusion that the interaction between CRMP2 and CaV2.2 is likely responsible for the observed increase in Ca currents."
23831344
reach
"Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo."
31359322
reach
"CRMP2 also regulates N-type voltage-gated Ca 2+ channels (Cav2.2) and transmitter release, and phosphorylation of CRMP2 by Cdk5 increases the interaction between CaV2.2 and CRMP2 and regulates CaV2.2 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29758318
sparser
"69 Sema3A activates Cdk5, which phosphorylates CRMP2 at Ser522.36,70 The in vitro phosphorylated CRMP2 at Ser522 was shown to enhance its interaction with Cav2.2.67 This enhanced interaction between CRMP2 and Cav2.2 was associated with an activation of Cav2.2."
27392015
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"This peptide was characterized extensively in previous studies [29] and found to inhibit specifically the interaction between CRMP2 and CaV2.2."
31359322
sparser
"Data here demonstrate a novel efficacious compound to inhibit pain without demonstrating any addiction or motor deficits ( xref , xref ) providing an instructive example of how designing peptides tailored to limit membrane CaV2.2–CRMP2 interactions can have a great utility in the treatment of post-surgical and inflammatory pain."
25782368
sparser
"Here, we investigated the effects of a functional association of CRMP-2 with Cav2.2 in sensory neurons."
19903690
sparser
"In a series of studies examining targets of synthetic CBD peptides, conjugated to the HIV1 TAT (t−) domain for cell penetrance, only t-CBD3, comprised of CRMP2 residues 484-498, succeeded in biochemically inhibiting the CRMP2-Cav2.2 interaction [ xref ]."
30364788
sparser
"Co-immunoprecipitation experiments showed that CRMP-2 associates with Cav2.2 from DRG lysates."
19903690
sparser
"Importantly, disrupting the CRMP2-Cav2.2 interaction did not alter core sympathetic nervous system functions such as pulsatile arterial pressure, mean arterial pressure, heart rate, and core body temperature [ xref ]."
30364788
sparser
"Binding affinity of Ct-Cav2.2/CRMP2 was ~75 fold greater than between L1-Cav2.2/CRMP2, and only disruption of the Ct-Cav2.2/CRMP2 interaction inhibited evoked CGRP release in rat DRGs [ xref ]."
30364788
reach
"Because CRMP2 directly binds and regulates the expression of presynaptic CaV2.2 [16], decreased CRMP2 expression levels after extinction of cocaine self-administration would be expected to alter CaV2.2 expression."
31359322
sparser
"In rat DRGs, only CBD3’s N-terminal fragment successfully inhibited depolarization-evoked calcium influx, reduced Ca 2+ currents, and disrupted the CRMP2-Cav2.2 interaction in situ [ xref ]."
30364788
sparser
"While activation of Cdk5 and increased CRMP2 expression in rat DRGs contribute to several pain phenotypes, ( S )-LCM biochemically disrupts the CRMP2-Cav2.2 interaction while inhibiting depolarization-evoked Ca 2+ influx and Ca 2+ currents [ xref , xref , xref – xref ]."
30364788
sparser
"Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al ., Nature Medicine 17:822–829 (2011)]."
22662308
sparser
"Systemic administration of ( S )-LCM to mice, at three daily doses of 20 mg/kg over four days, successfully uncoupled the CRMP2-Cav2.2 interaction in brain lysates, with no detectable effects on locomotion, feeding, or behavior [ xref ]."
30364788
sparser
"We previously reported that blunting CRMP2 phosphorylation or interfering with the CRMP2-CaV2.2 interaction could reverse mechanical allodynia following a paw incision [ xref ; xref ]."
32569093
sparser
"CRMP2 binds directly with CaV2.2 leading to increased Ca 2+ current density and increased neurotransmitter release in sensory neurons [ xref ]."
31009417
sparser
"We determined that CRMP-2 interacts with CaV2.2 and that overexpression of CRMP-2 leads to increased surface expression of CaV2.2 and enhanced Ca 2+ currents [ xref , xref , xref ]."
22662308
reach
"We next used myr-TAT-CBD3 in vivo to examine if disrupting the interaction between CRMP2 and CaV2.2 reduced drug-seeking behavior."
31359322
reach
"The breadth of CRMP2 protein interactions are numerous and widespread, yet our results suggest that in the PFC, CRMP2 interactions with CaV2.2 are critical for cued-reinstatement of cocaine, an animal model of relapse."
31359322
reach
"When applied locally to the PFC, this peptide reduced both CRMP2 binding to CaV2.2 and reinstatement in response to drug-cues, but not to cocaine-priming."
31359322
sparser
"In parallel, it was discovered that phosphorylation of CRMP2 by Cdk5 dynamically regulates and increases the association of CRMP2 with Cav2.2 [ xref ]."
30364788
sparser
"These findings suggest that the biochemical interaction between CRMP-2 and CaV2.2 is required for proper channel trafficking and function."
22662308
sparser
"Disruption of the interaction between CaV2.2 and CRMP2 by a short peptide (CBD3) corresponding to a 15 amino acid region of CRMP-2 produces a number of changes including pain signal transmission [ xref ]."
22662308
sparser
"Over the last few years, we have described an interaction between CaV2.2 and tetrameric collapsin response mediator protein 2 (CRMP-2) that positively regulates channel function by increasing cell surface trafficking [ xref , xref , xref ]."
22662308
sparser
"The interaction between CaV2.2 and CRMP2 can be disrupted by a short peptide (CBD3) corresponding to a 15 amino acid region of CRMP-2 ( xref )."
22662308
reach
"Our previous work identified the axonal growth and specification collapsin response mediator protein 2 (CRMP2) as a novel regulator of Cav2.2 activity: direct binding between Cav2.2 and CRMP2 leads to a CRMP2-mediated increase in Ca current density and increased transmitter release in sensory neurons."
28767512
sparser
"In 2012, Wilson and colleagues demonstrated the efficacy of 15-amino acid peptides derived from the C-terminus of CaV2.2 and CaV1.2 (Ct-dis) to disrupt CRMP2-CaV2.2 interaction and inhibit resulting NF1-pain [ xref ]."
31009417
reach
"Probing of the CRMP2-enriched fraction with a Cav2.2 antibody demonstrated a robust interaction between Cav2.2 and CRMP2 (Fig. 4C; top blot, lane 2)."
28767512
sparser
"Although the precise nature of NF1-linked pain syndromes remains unknown, patients clearly experience pain independent of their tumor burden, and these findings affirm the necessity of CRMP2 in NF1-related pain, while suggesting a physiological role for neurofibromin’s C-terminal domain-mediated inhibition of the CRMP2-Cav2.2 interaction [ xref ]."
30364788
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"Direct protein interactions between CRMP2 and Cav2.2 in DRG sensory neurons were evident with PLA (Fig. 4E)."
28767512
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"We previously reported CRMP2 binds to and regulates CaV2.2 and NaV1.7 by maintaining their membrane localization and function [48]."
36564853
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"Since CRMP2 facilitates synaptic vesicle loading in hippocampal neurones, inhibition of the CRMP2–Cav2.2 complex would predictably reduce the recruitment of synaptic vesicles to Cav2.2 localized in the membrane [24]."
30364788
reach
"Subsequent studies documented t-CBD3-mediated disruption of the CRMP2–Cav2.2 complex and efficacy in migraine, AIDS therapy-induced peripheral neuropathy, and tibial nerve injury-induced neuropathic pain [23,89,90] (Table 1)."
30364788
reach
"Here we report suppression of both inflammatory and neuropathic hypersensitivity by inhibiting the binding of the axonal collapsin response mediator protein 2 (CRMP-2) to CaV2.2, thus reducing channel function."
21642979
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"These results suggest that uncoupling the CRMP2–Cav2.2 complex is non-addictive, while still engaging the centralized affective component of pain and peripheral sensory mechanisms [95,96]."
30364788
reach
"These findings suggest that the biochemical interaction between CRMP-2 and CaV2.2 is required for proper channel trafficking and function."
21642979
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"Investigating CBD3’s pharmacological mechanism by synthesizing Cav2.2-derived peptides revealed that Cav2.2’s first intracellular loop (L1-Cav2.2, residues 388–402) and distal C-terminus (Ct-Cav2.2, residues 2014–2028) directly bind CRMP2 [97]."
30364788
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"Thus, our results indicate that using TAT-CBD3 which interferes with CaV2.2 and CRMP-2 interactions can reduce inflammatory and neuropathic pain behaviors."
21642979
reach
"We reasoned that by uncoupling the interaction between CaV2.2 and CRMP-2 within primary afferent sensory neurons, we would be able to mimic the inhibition of neurotransmitter release observed with siRNA knockdown of CRMP-2."
21642979
reach
"Phosphorylation of CRMP-2 by Cdk5 also increases the interaction between CaV2.2 and CRMP-2."
23022559
reach
"Our findings demonstrate that Cdk5-phosphorylation of CRMP-2 enhances the interaction between CRMP-2 and CaV2.2 while reducing axon growth [28] ."
23022559
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"Interestingly, in this animal model of pain, the peptide is administered systemically after the development of chronic hypersensitivity and is still able to effectively attenuate nociceptive behaviors, suggesting a continued role for the interaction of CRMP-2 and CaV2.2 on neurotransmitter release."
21642979
reach
"Interference of the protein-protein interaction between the target collapsin response mediator protein 2 (CRMP2) and CaV2.2 in sensory neurons by unique peptides effectively diminishes trafficking of the ion channel to the plasma membrane and serves to attenuate peripheral sensitization in rodent models of inflammation or neuropathic pain (Brittain et al. 2011b, Piekarz et al. 2012, Ripsch et al. 2012, Wilson et al. 2011, Wilson et al. 2012a)."
23106100
sparser
"Uncoupling the CRMP2-CaV2.2 Interaction Reduces Pain-Like Behavior in a Preclinical Joint-Pain Model."
39233208
sparser
"This value is in agreement with an IC 50 value of ~2.8 µM for inhibition of Ca 2+ influx for a membrane-tethered CRMP2 peptide that uncouples the CRMP2-CaV2.2 interaction that we recently reported [ xref ]."
26967696
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"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 (Figure 1; top blot, lanes 1, 2) whereas a glutathione beads only pull-down did not capture any CaV2.2 (Figure 1; top blot, lane 7)."
23106100
sparser
"Competition between syntaxin 1A and neurofibromin for a singular CRMP2 binding domain regulates CRMP2’s direct interaction with Cav2.2."
30364788
sparser
"CRMP2 bound to CaV2.2 leading to increased Ca 2+ current density and increased neurotransmitter release in sensory neurons [ xref ]."
31246731
reach
"The interaction between CaV2.2 and CRMP2 is enhanced by CRMP2 phosphorylation at Ser522 by Cdk5."
29758318
sparser
"CRMP2 also regulates N-type voltage-gated Ca 2+ channels (Cav2.2) and transmitter release, and phosphorylation of CRMP2 by Cdk5 increases the interaction between CaV2.2 and CRMP2 and regulates CaV2.2 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29758318
sparser
"In addition, more recent studies have reported that CRMP-2 can bind to the voltage-gated calcium channel Cav2.2, and this interaction may play a crucial role in neurotransmitter release from the presynaptic terminals of hippocampal neurons ( xref )."
29209207
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"The association between CRMP2 and CaV2.2 can be enhanced by Cdk5-mediated phosphorylation of CRMP2 at S522 ( Moutal et al., 2019a )."
32437854
reach
"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 (Fig. 2A; top blot, lane 2)."
25782368
sparser
"The interaction between CaV2.2 and CRMP2 is enhanced by CRMP2 phosphorylation at Ser522 by Cdk5."
29758318
reach
"We reported that Cdk5-mediated CRMP2 phosphorylation increases its binding to CaV2.2, which augments calcium influx ; thus, the increased interaction between CRMP2 and CaV2.2 may underlie the mechanism of antinociception in this particular model."
25782368
sparser
"Probing of the CRMP2-enriched fraction with a Cav2.2 antibody demonstrated a robust interaction between Cav2.2 and CRMP2 ( xref ; top blot, lane 2 )."
28767512
sparser
"Finally, to confirm the disruption of CRMP2 interaction with Cav2.2 in sensory neurons, we used a PLA."
28767512
sparser
"ST1-104, which disrupts the interaction between CaV2.2 and CRMP2 interaction, reduces persistent mechanical hypersensitivity induced by systemic administration of ddC [ xref ]."
24403874
sparser
"One plausible mechanism is that Sema3A signaling may involve the interaction between CRMP2 and Cav2.2, a voltage-gated calcium channel belonging to the Cav2 family."
27392015
reach
"Binding of the axonal CRMP2 to CaV2.2 reduces the channel function during the suppression of neuropathic pain."
32652266
sparser
"CRMP-2 binds directly to CaV2.2 in two regions: the channel domain I-II intracellular loop and the distal C terminus."
19755421
sparser
"The authors’ results demonstrated that a direct interaction between CRMP2 and CaV2.2 increases cell surface trafficking of CaV2.2 as well as calcium current density, which leads not only to an increased release of the neurotransmitter glutamate and synaptic vesicle recycling but also impacts axonal growth of hippocampal neurons."
23308041
sparser
"Second , despite being an indirect ‘blocker’ of Ca 2+ influx, ( S )-LCM provides improved efficacy compared to TROX-1, a small-molecule, state-dependent blocker of CaV2 channels [ xref ] as well as a membrane-tethered CRMP2 peptide that uncouples the CRMP2-CaV2.2 interaction that we recently reported [ xref ]."
26967696
reach
"CRMP2 bound to CaV2.2 leading to increased Ca current density and increased neurotransmitter release in sensory neurons [16]."
31246731
reach
"These results suggest a coordinated mechanism involving interactions between CRMP2 and CaV2.2 to facilitate the release of pro-nociceptive CGRP that consequently leads to cephalic pain."
27917413
reach
"In this model, phosphorylated CRMP2 may play a role in localizing CaV2.2 to presynaptic terminals where the channel can participate in nociceptive transmission.In a series of studies, we identified the axonal CRMP2 as a novel regulator of CaV2.2 activity; direct binding between CaV2.2 and CRMP2 leads to CRMP2-mediated increase in Ca current density and increased transmitter release in sensory neurons."
27917413
sparser
"CRMP2’s interactions with CaV2.2 neurons have been found to enhance CaV2.2 channel surface expression ( xref , xref ) and Ca 2+ current in DRG [ xref ; xref ]."
32773603
sparser
"Consequently, when CRMP2 and CaV2.2 interaction is disrupted, neuropeptide release from sensory neurons, dependent on Ca 2+ currents, is inhibited, and in turn, excitatory synaptic transmission in the spinal dorsal horn is inhibited [ xref ]."
32773603
sparser
"Cdk5/p25 phosphorylation of CRMP2 increases CRMP2’s binding to CaV2.2, ultimately resulting in a persistence of CaV2.2 membrane localization which results in enhancement of currents via CaV2.2 [ xref ]."
32773603
reach
"Since CRMP2 interactions with NMDARs and CaV2.2 channels modulate calcium influx into neurons, lower CRMP2 levels in descending motor neurons could lead to reduced Ca influx, reduced protease activation, and maintenance of AIS and fiber integrity.In this study, we also examined the importance of CRMP2 phosphorylation on the development of EAE."
31795726
sparser
"Here we report suppression of both inflammatory and neuropathic hypersensitivity by inhibiting the binding of the axonal collapsin response mediator protein 2 (CRMP-2) to CaV2.2, thus reducing channel function."
21642979
sparser
"We determined that CRMP-2 interacts with CaV2.2 and that overexpression of CRMP-2 leads to increased surface expression of CaV2.2 and enhanced Ca 2+ currents xref , xref ."
21642979
sparser
"We previously identified ST1-104, a short peptide from the collapsin response mediator protein 2 (CRMP2), which disrupted the CaV2.2–CRMP2 interaction and suppressed a model of HIV-related neuropathy induced by antiretroviral therapy but not traumatic neuropathy."
23106100
sparser
"In addition to tubulin, CRMP2 also interacts with CaV2.2, the presynaptic N-type voltage gated calcium channel (VGCC) ( xref ; xref ; xref , xref ), which regulates neuronal excitability and has roles in neuropathic pain ( xref ; xref ; xref ; Chew and Khanna, 2018; xref ; xref )."
31795726
sparser
"Here, we report ST2-104 –a peptide wherein the cell-penetrating TAT motif has been supplanted with a homopolyarginine motif, which dose-dependently inhibits the CaV2.2–CRMP2 interaction and inhibits depolarization-evoked Ca 2+ influx in sensory neurons."
23106100
sparser
"Interference of the protein-protein interaction between the target collapsin response mediator protein 2 (CRMP2) and CaV2.2 in sensory neurons by unique peptides effectively diminishes trafficking of the ion channel to the plasma membrane and serves to attenuate peripheral sensitization in rodent models of inflammation or neuropathic pain ( xref , xref , xref , xref , xref )."
23106100
sparser
"We show that ST2-104 interferes with the CaV2.2–CRMP2 interaction and inhibits Ca 2+ influx from sensory neurons."
23106100
sparser
"Pull-down studies demonstrated that myr-tat-CBD3 peptide interfered with the CRMP2–CaV2.2 interaction."
25782368
sparser
"We tested the hypothesis that replacement of the TAT motif with the presumably superior cell penetrating prowess of the homopolyarginine motif ( xref ) would prevent CRMP2–CaV2.2 interaction, block Ca 2+ influx in sensory neurons, and be effective in reducing pain-related behavior in various models of peripheral neuropathy."
23106100
sparser
"These findings suggest that the biochemical interaction between CRMP-2 and CaV2.2 is required for proper channel trafficking and function."
21642979
sparser
"We report that myristoylated tat-CBD3 is membrane tethered, restricts the CaV2.2–CRMP2 interaction, blocks CaV2.2 trafficking, and strongly inhibits Ca 2+ influx from primary sensory neurons."
25782368
sparser
"We first tested if the nona-arginine (R9) motif conjugated to the CBD3 peptide of CRMP2, designated ST2-104 peptide, could interfere with the CaV2.2–CRMP2 interaction."
23106100
sparser
"We tested the hypothesis ( xref ) that uncoupling the CRMP-2–CaV2.2 interaction would lead to a physiologically relevant decrease in Ca 2+ current and neurotransmitter release and, in turn, suppress persistent inflammatory and neuropathic hypersensitivity."
21642979
sparser
"To develop a reagent to disrupt the interaction of CRMP-2 with the CaV2.2 complex in vivo , we synthesized a series of overlapping 15-amino-acid peptides covering the entire length of CRMP-2, including three CaV binding domains (CBDs1–3) we had previously identified in vitro as crucial for the CRMP-2–CaV2.2 interaction xref ."
21642979
sparser
"Probing of the CRMP2-enriched fraction with a CaV2.2 antibody demonstrated a robust interaction between CaV2.2 and CRMP2 ( xref ; top blot, lanes 1, 2 ) whereas a glutathione beads only pull-down did not capture any CaV2.2 ( xref ; top blot, lane 7 )."
23106100
sparser
"Similar to TAT-conjugated CBD3 (designated ST1-104), the R9-conjugated CBD3 (designated ST2-104) peptide interfered with the CaV2.2–CRMP2 interaction."
23106100
sparser
"The functional consequence of the disrupted CaV2.2– CRMP2 interaction was a significantly higher extent (i.e. efficacy) of inhibition of calcium influx in sensory neurons."
23106100
sparser
"Reasoning that the reported superior cell penetrating ability of the nona-arginine CPP ( xref ) may allow for greater uptake of the peptide which may result in superior biochemical and functional uncoupling of the CaV2.2–CRMP2 interaction and suppression of transmitter release from nociceptive neurons culminating in efficacy in chronic pain models, we tested the R9 grafted CBD3 (i.e. ST2-104) peptide in the TNI model of traumatic neuropathy."
23106100
sparser
"These findings are entirely consistent with our previous results demonstrating longer periods of pain-related behavior reversal in the TNI versus the ddC model following systemic injection of a TAT-conjugated peptide from calcium channels that breaks the CaV2.2–CRMP2 interaction ( xref ) as well as with the CRMP2-derived ST1-104 peptide ( xref )."
23106100
sparser
"A screening protocol of >50 novel molecules unexpectedly identified the small molecule ( S )-lacosamide (( S )-LCM) xref as a novel inhibitor of CRMP2 interactions with CaV2.2."
27917413
sparser
"Immunoprecipitations from spinal cord lysates demonstrated that CBD3 peptide inhibited the interaction between CRMP-2 and CaV2.2 ( xref ; top, middle ) but did not affect the interaction between tubulin and CRMP-2 xref ( xref , bottom )."
21642979
sparser
"Thus, in vitro , CBD3 disrupts the CRMP-2-CaV2.2 interaction and affects CaV2.2 trafficking and Ca 2+ current density."
21642979
reach
"Direct interaction of the two proteins was confirmed using a short fifteen amino acid peptide from CRMP2, which when conjugated to the cell penetrant peptide from the TAT protein of HIV (designated TAT-CBD3), abrogated the interaction between CRMP2 and CaV2.2."
30915713
sparser
"Binding of the axonal CRMP2 to CaV2.2 reduces the channel function during the suppression of neuropathic pain."
32652266
sparser
"Thus, our results indicate that using TAT-CBD3 which interferes with CaV2.2 and CRMP-2 interactions can reduce inflammatory and neuropathic pain behaviors."
21642979
sparser
"We reasoned that by uncoupling the interaction between CaV2.2 and CRMP-2 within primary afferent sensory neurons, we would be able to mimic the inhibition of neurotransmitter release observed with siRNA knockdown of CRMP-2."
21642979
sparser
"Direct interaction of the two proteins was confirmed using a short fifteen amino acid peptide from CRMP2, which when conjugated to the cell penetrant peptide from the TAT protein of HIV (designated TAT-CBD3), abrogated the interaction between CRMP2 and CaV2.2."
30915713
sparser
"In physiological conditions, CRMP2’s interaction with CaV2.2 is finely tuned by post-translational modifications."
30915713
sparser
"N-myristate-tat-CBD3 peptide inhibits the CaV2.2–CRMP2 interaction."
25782368
sparser
"Interestingly, in this animal model of pain, the peptide is administered systemically after the development of chronic hypersensitivity and is still able to effectively attenuate nociceptive behaviors, suggesting a continued role for the interaction of CRMP-2 and CaV2.2 on neurotransmitter release."
21642979