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Identification and targeting of a unique NaV1.7 domain driving chronic pain, 2023, Gomez et al.

Discussion in 'Other health news and research' started by SNT Gatchaman, Aug 4, 2023.

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  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Identification and targeting of a unique NaV1.7 domain driving chronic pain
    Gomez, Kimberly; Stratton, Harrison J.; Duran, Paz; Loya, Santiago; Tang, Cheng; Calderon-Rivera, Aida; François-Moutal, Liberty; Khanna, May; Madura, Cynthia L.; Luo, Shizhen; McKiver, Bryan; Choi, Edward; Ran, Dongzhi; Boinon, Lisa; Perez-Miller, Samantha; Damaj, M. Imad; Moutal, Aubin; Khanna, Rajesh

    Significance
    The voltage-gated sodium channel isoform 1.7 (NaV1.7) has been widely implicated in chronic pain. We have discovered a unique intracellular region of NaV1.7 that facilitates its regulation by intracellular auxiliary proteins and which can be targeted to ameliorate chronic pain. Targeting this sequence produces robust reversal of mechanical allodynia in preclinical models of nerve injury, as well as a model of chemotherapy-induced peripheral neuropathy. A plasmid coding for this sequence packaged inside a viral capsid reduced NaV1.7 current density and neuropathic pain. The translational utility of our approach is illustrated by the finding that our genetic therapy reduced NaV1.7 function in macaque DRG neurons, which shares complete sequence homology with human NaV1.7.

    Abstract
    Small molecules directly targeting the voltage-gated sodium channel (VGSC) NaV1.7 have not been clinically successful. We reported that preventing the addition of a small ubiquitin-like modifier onto the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 function and was antinociceptive in rodent models of neuropathic pain.

    Here, we discovered a CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other NaV isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight VGSC isoforms decreased NaV1.7 currents. A cell-penetrant decoy peptide corresponding to the NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 expression, reduced spinal CGRP release, and reversed nerve injury-induced mechanical allodynia. Importantly, the NaV1.7-CRS peptide did not produce motor impairment, nor did it alter physiological pain sensation, which is essential for survival. As a proof-of-concept for a NaV1.7 -targeted gene therapy, we packaged a plasmid encoding the NaV1.7-CRS in an AAV virus. Treatment with this virus reduced NaV1.7 function in both rodent and rhesus macaque sensory neurons. This gene therapy reversed and prevented mechanical allodynia in a model of nerve injury and reversed mechanical and cold allodynia in a model of chemotherapy-induced peripheral neuropathy.

    These findings support the conclusion that the CRS domain is a targetable region for the treatment of chronic neuropathic pain.

    Link | PDF (Proceedings of the National Academy of Sciences)
     
    SNT Gatchaman, Aug 4, 2023
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  2. Hutan

    Hutan Moderator Staff Member

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    They've reduced the chronic pain of rats without giving them a stern talking to about vicious cycles of fear of movement and deconditioning? :eek:
     
    Hutan, Aug 4, 2023
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  3. Hutan

    Hutan Moderator Staff Member

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    So, NaV1.7 is a type of voltage-gated sodium channel in neurons transmitting the sensation of pain. A protein (CRMP2), when phosphorylated and SUMOlyated, is important in keeping the channel in place on the membrane of the synapse. If you stop the phosphorylation or SUMOlyation, the channel is internalised, and the sensation of pain is not transmitted.

    This team found a binding site where the CRMP2 attaches to the channel to activate it. A decoy protein can bind to the channel, but doesn't activate it, stopping the channel from working and so, stopping the pain.

    They note that this works with neuropathic pain, but that it doesn't stop physiological pain, which they note is protective. It also doesn't seem to have other bad effects e.g. on motor coordination.

    (It's interesting how the authors seem to use 'chronic pain' as a synonym for 'neuropathic pain' - I don't think they are the same things.)

    Wikipedia tells me that CRMP2 is expressed in injured neurons (both CNS and peripheral neurons) where it is thought to be associated with nerve regeneration. That all makes sense to me - you damage a nerve, and the CRMP2 activates nerve regeneration and lets you know that you need to protect the tissue.

    Wikipedia says:
     
    Last edited: Aug 4, 2023
    Hutan, Aug 4, 2023
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  4. Hutan

    Hutan Moderator Staff Member

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    The authors undertook genetic therapy, although I don't think the targeting of that binding site need necessarily be done with genetic therapy:
    Limitation - in rats, but they think it will work in humans:
    So, potentially some good options for the control of neuropathic pain
     
    Hutan, Aug 4, 2023
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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    SNT Gatchaman, Aug 4, 2023
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  6. RedFox

    RedFox Senior Member (Voting Rights)

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    This is the type of research we should be doing on chronic pain, figuring out the biochemistry of why people experience it. Sometimes (as in fibromyalgic or idiopathic back pain) it occurs in the absence of an obvious injury, perhaps implicating the nervous system.
     
    RedFox, Aug 4, 2023
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  7. Hutan

    Hutan Moderator Staff Member

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    Of course, people keen on exercise are onto this molecule. I found a study where mice were given regular treadmill exercise, and were found to have reduced phosphorylation of CRMP2:
    Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice, 2022
    In the 2023 study, pain transmission was happening when CRMP2 was phosphorylated.
    So, a question is, is phosphorylation of CRMP2 at Thr514 (as was reduced in the exercise mice in the 2022 study) the same as what was happening in the rats with pain in the 2023 study?
    The authors of the 2023 study note that CDK5 was doing the phosphorylation, and I found this by googling:
    So, if the mice study is correct, possibly exercise could reduce the phosphorylation of CRMP2, and reduce the activation of the channel transmitting pain signals. Or, the Thr514 site may not have much to do with the functioning of the CRMP2 with respect to the sodium channel for pain transmission.

    Edit - I've put this discussion in a spoiler, because, when I looked a bit closer at the mouse study, it turns out that exercise had no effect whatsoever on the phosphorylation of CRMP2 in normal mice. It only had an impact on a specific sort of mouse that supposedly was a model for Alzheimers. So, I don't think the mouse study is evidence for exercise reducing neuropathic pain.
     
    Last edited: Aug 4, 2023
    Hutan, Aug 4, 2023
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