Activity of T-type calcium channels is independent of CRMP2 in sensory neurons

Cai, Sanjun; Shan, Zhiming; Zhang, Zhongjun; Moutal, Aubin; Khanna, Rajesh

doi:10.1080/19336950.2019.1608129

Cited by 8 publications

(8 citation statements)

References 29 publications

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“…Importantly, in the present study, CBD3063 did not exert an effect on any other voltage-gated calcium channel, which argues for selectivity of our peptidomimetic compound for Ca v 2.2. This is in line with our previous observations that the activity of low-voltage-activated Ca 2+ channels is independent of CRMP2 (Cai, Shan, Zhang, Moutal & Khanna, 2019). We have shown that Cdk5-mediated CRMP2 phosphorylation at residue S522 increases its binding to Ca v 2.2, which leads to an increase in calcium influx (Brittain, Wang, Eruvwetere & Khanna, 2012).…”

Section: Discussionsupporting

confidence: 92%

A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain

Gómez

Santiago

Duran

et al. 2022

Preprint

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Background and Purpose Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated pain targets. Clinical block of Cav2.2 (e.g., with Prialt) or indirect modulation (e.g., with gabapentinoids) mitigates chronic pain but is constrained by side effects. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release and pain. Homology-guided mutagenesis of CBD3 revealed an antinociceptive core at A1RSR4. Here, the A1R2 CBD3 dipeptide was identified as critical for Cav2.2 molecular recognition and served as a scaffold for identification of small molecule peptidomimetic allosteric regulators of Cav2.2. Experimental Approach We developed and applied a novel molecular dynamics approach to identify the Cav2.2 recognition motif of the core CBD3 peptide as the A1R2 dipeptide and used its presenting motif to design pharmacophore models to screen 27 million compounds in the open access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization‐evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Nine compounds were tested using electrophysiology and one compound (CBD3063) was evaluated biochemically, electrophysiologically, and behaviorally effects in a model of experimental pain: Key Results CBD3063 reduced membrane Cav2.2 expression and currents, inhibited neuronal excitability, uncoupled the Cav2.2-CRMP2 interaction, and reversed mechanical allodynia in rats with spared nerve injury. Conclusions and Implications These results identify CBD3063, as a selective, first-in-class, CRMP2-based peptidomimetic, which allosterically regulates Cav2.2 to achieve analgesia.

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Section: Discussionsupporting

confidence: 92%

A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain

Gómez

Santiago

Duran

et al. 2022

Preprint

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“…All electrophysiological recordings were performed using established procedures. Primary cultures of DRG neurons from adult female SD rats (pathogen-free; 140–160 g; Envigo) were made. ,,,,,,− Naringenin treatment was applied overnight at 100 μM using 0.1% DMSO as a vehicle control. While relatively high, a concentration of 100 μM naringenin has been previously reported to be needed to detect biological effects including neuroprotection against LPS-induced dopamine neurotoxicity, inhibition of osteoclast formation, induction of anion transport across the rat colonic mucosa, caspase-3 activity in neutrophils, or suppression of prostate tumor cell proliferation .…”

Section: Methodsmentioning

confidence: 99%

The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels

Zhou

Cai

Moutal

et al. 2019

ACS Chem. Neurosci.

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Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channelboth of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca 2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca 2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na + channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin.

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“…Inhibitors of VDCC are thus used to treat neuropathic pain, such as Prialt ® [5,36], a synthetic version of µ-conotoxin MVIIA which blocks CaV2.2, or most commonly gabapentinoids like gabapentin or pregabalin [37] which inhibit α2-δ partner protein. CRMP2 (collapsin response mediator protein 2), another partner protein of VDCC (for a review see [38]), has been shown to interact specifically with CaV2.2 and no other VDCC [39] to promote its trafficking and to increase calcium current density [38]. 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.…”

Section: Targeting Voltage-dependent Calcium Channel Interactionsmentioning

confidence: 99%

Partners in Crime: Towards New Ways of Targeting Calcium Channels

Noyer

Lemonnier

Mariot

et al. 2019

IJMS

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The characterization of calcium channel interactome in the last decades opened a new way of perceiving ion channel function and regulation. Partner proteins of ion channels can now be considered as major components of the calcium homeostatic mechanisms, while the reinforcement or disruption of their interaction with the channel units now represents an attractive target in research and therapeutics. In this review we will focus on the targeting of calcium channel partner proteins in order to act on the channel activity, and on its consequences for cell and organism physiology. Given the recent advances in the partner proteins’ identification, characterization, as well as in the resolution of their interaction domain structures, we will develop the latest findings on the interacting proteins of the following channels: voltage-dependent calcium channels, transient receptor potential and ORAI channels, and inositol 1,4,5-trisphosphate receptor.

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Activity of T-type calcium channels is independent of CRMP2 in sensory neurons

Cited by 8 publications

References 29 publications

A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain

A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain

The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels

Partners in Crime: Towards New Ways of Targeting Calcium Channels

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