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  • Post translational ubiquitination has been shown

    2022-08-05

    Post-translational ubiquitination has been shown to regulate a wide range of cellular responses, such as the synaptic trafficking and turnover of neurotransmitter receptors (Rape, 2018). Ubiquitination is also engaged in the modification of protein-protein interaction and intracellular signaling transduction (Rape, 2018). Previous studies have indicated that GlyRs-α1 subunit can be ubiquitinated when ectopically expressed in Xenopus oocytes (Buttner et al., 2001). Here we found that HUWE1 was the E3 ligase that located at inhibitory synapses and specifically interacted with GlyRs-α1. This molecular complex formation was activity-dependent and required the activation of NMDAR. By binding to GlyRs-α1, HUWE1 catalyzed the ubiquitination of GlyRs-α1, induced GlyRs-α1 L-Stepholidine synthesis and impaired glycinergic transmission. Knockdown of HUWE1 expression potentiated glycinergic currents in the injured animals and more importantly, alleviated inflammatory pain. Therefore, interference with HUWE1 expression might represent a specific way to resume GlyRs-α1-mediated synaptic inhibition.
    Summary Taken together, the current study revealed a selective interaction of HUWE1 with GlyRs-α1 subunit in spinal dorsal horn, which contributed to glycinergic disinhibition during inflammatory pain. GlyRs-α1 subunit contains 10 potential ubiquitination sites (lysine residues) within the large intracellular loop between the transmembrane domain 3 and 4 (Buttner et al., 2001). The identification of the lysine residue ubiquitinated by HUWE1 awaits further investigation.
    Acknowledgement This work was supported by the National Natural Science Foundation of China (№. 31771160). We declare that we have no conflict of interest.
    Introduction Gelsemium is a small genus of plant from the family Loganiaceae, consisting five species including popular Gelsemium sempervirens Ait. and Gelsemium elegans Benth., which are respectively indigenous to North America and China/East Asia. At least 120 alkaloids with indole, oxindole and bisindole nuclei have been identified from Gelsemium, and the predominant indole-nuclei alkaloids are gelsemine, koumine, gelsedine, gelsemicine and gelsenicine. Gelsemine is the principal active alkaloid from Gelsemium sempervirens Ait., whereas koumine and gelsemine are the most and second-most dominant alkaloids from Gelsemium elegans Benth. [1], [2], [3], [4]. The Gelsemium extracts and active alkaloids have been traditionally used to treat pain, neuralgia, anxiety, insomnia, asthma, respiratory ailments and cancers [1], [5], [6]. Analgesia and pain management are primary indications of both Gelsemium sempervirens Ait. and Gelsemium elegans Benth. [7]. When given systemically or intrathecally, the extracts and major active alkaloids of Gelsemium were shown to be antinociceptive in a variety of animal pain models, including inflammatory pain induced by acetic acid, formalin, collagen and complete Freund’s adjuvant, postoperative pain, diabetes pain, neuropathic pain induced by peripheral nerve injury, and bone cancer pain [8], [9], [10], [11], [12], [13], [14]. The molecular mechanisms underlying Gelsemium and its alkaloids-induced antinociception remain unclear. Spinal microglia and astrocytes in peripheral nerve injury undergo a series of morphological and chemical modification that are associated with establishment of neuropathic pain [15]. It was reported that in vitro treatment with koumine inhibited attenuated lipopolysaccharide-stimulated inflammation in RAW264.7 macrophages [13] and M1 microglial polarization in BV2 microglial cells [16]. In addition, subcutaneous and intrathecal injection of koumine blocked chronic constriction injury of the sciatic nerve-induced neuropathic pain and postoperative pain, which were attenuated by the specific inhibitor of the 18 kDa translocator protein (TSPO) that was expressed in activated microglia and astrocytes. Injection of koumine inhibited activation of microglia and astrocytes and expression of neuroinflammatory cytokines in the spinal cords after peripheral nerve injury or inflammation, suggesting that koumine antinociception was through inhibition of spinal neuroinflammation and activation of TSPO [14], [16].