Parkin Inhibits Static Mechanical Pain by Suppressing Membrane Trafficking of Mechano-transducing Ion Channel TACAN

Lei, Yi; Xie, Man-Xiu; Cao, Xianying; Zhang, Xi; Xiao, Yi-Bin; Tian, Xiaoyu; Zhu, Yuan-Xin; Zhang, Xiaolong

doi:10.1007/s12264-022-00843-8

Cited by 6 publications

(14 citation statements)

References 15 publications

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“…Lei et al found that low expression of Parkin facilitates the transfer of TACAN from the cytoplasm to the cell membrane. 35,36 We already know that the high expression of TACAN is related to pain, and we found that the expression of TACAN was increased in the model of IC/BPS, so we speculate that TACAN might be a potential target for the treatment of hyperalgesia in IC/BPS.…”

Section: Discussionmentioning

confidence: 83%

The expression and distribution of TACAN in human and rat bladders

Lu,

Liu,

Chen

et al. 2023

LUTS

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ObjectivesA lot of ion channels participate in the regulation of bladder function. TACAN, a new mechanosensitive ion channel, was first discovered in 2020. TACAN has been found to be expressed in many tissues, such as the dorsal root ganglia (DRG) and adipose tissue. However, it is unclear whether or not TACAN is expressed in the bladder. In this work, we decided to study the expression and distribution of TACAN in human and rat bladders. Meanwhile, the expression of TACAN in the rat model of interstitial cystitis/bladder pain syndrome (IC/BPS) was studied.MethodsHuman bladder tissues were obtained from female patients. Cyclophosphamide (CYP) was used to build the rat model of IC/BPS. Real‐time polymerase chain reaction, agarose gel electrophoresis, and western blotting were used to assess the expression of TACAN in human and rat bladders. Immunohistochemistry and immunofluorescence were used to observe the distribution of TACAN in human and rat bladders. Hematoxylin‐eosin stain, withdrawal threshold, and micturition interval were used to evaluate animal models.ResultsThe results of agarose gel electrophoresis and western blotting suggested that TACAN was expressed in human and rat bladders. Immunohistochemical results suggested that TACAN showed positive immunoreaction in the urothelial and detrusor layers. The immunofluorescence results indicated that TACAN was co‐stained with UPKIII, α‐SMA, and PGP9.5. The IC/BPS model was successfully established with CYP. The mRNA and protein expression of TACAN was upregulated in the CYP‐induced rat model of IC/BPS.ConclusionsTACAN was found in human and rat bladders. TACAN was mainly distributed in the urothelial and detrusor layers and bladder nerves. The expression of TACAN was upregulated in the CYP‐induced rat model of IC/BPS. This new discovery will provide a theoretical basis for future research on the function of TACAN in the bladder and a potential therapeutic target for IC/BPS.

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Section: Discussionmentioning

confidence: 83%

The expression and distribution of TACAN in human and rat bladders

Lu,

Liu,

Chen

et al. 2023

LUTS

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“…The trafficking of ion channels toward the cell membrane is an essential step in regulating neuronal functions, such as the response to mechanical or thermal stimulation [ 23 , 24 , 65 ]. Study shows that motor protein kinesins play crucial roles in the trafficking of neuronal cargos such as ion channels and receptors [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking

Xie,

Lai,

Xiao

et al. 2024

Military Med Res

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Background Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear. Methods Male and female C57BL/6 mice (8–12 weeks) and male cynomolgus monkeys (7–10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms. Results The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates. Conclusions Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.

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“…39,40 Various plasma membrane and intracellular potassium channels could be pharmacologically targeted to treat pain diseases, [41][42][43][44] such as Piezo2, Nav1.8 and TACAN. 45,46 Kv1.1 channel controls the excitability of neuronal cells. The voltage-gated potassium channel Kv1.1 belongs to the Shaker subfamily and regulates mouse hippocampal excitatory neurons to dampen excitability in CNS and PNS.…”

Section: Discussionmentioning

confidence: 99%

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

Liu

Wang

et al. 2022

Mol Pain

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Background: Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. Methods: The miRNA-155-5p levels and cellular distribution were determined by RNA sequencing, fluorescent in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Immunoblotting, qPCR, dual-luciferase reporter gene assays, immunofluorescence, recombinant overexpression adeno-associated virus, small interfering RNA, intraspinal administration, and behavioral tests were utilized for exploring the downstream signaling pathway. Results: The miR-155-5p high expression in spinal neurons contributes to BCP maintenance. The miR-155-5p blockage via the intrathecal injection of miR-155-5p antagomir alleviated the pain behavior; in contrast, upregulating miR-155-5p by agomir induced pain hypersensitivity. The miR-155-5p bounds directly to TCF4 mRNA’s 3′ UTR. BCP significantly reduced protein expression of TCF4 versus the Sham group. The miR-155-5p inhibition relieved the spinal TCF4 protein’s down-expression level, while miR-155-5p upregulation by miR-155-5p agomir intrathecal injection decreased TCF4 protein expression in naïve rats. Additionally, TCF4 overexpression in BCP rats could increase Kv1.1. Moreover, TCF4 knockdown inhibited Kv1.1 expression in BCP rats. Indeed, TCF4 and Kv1.1 were co-expressed in BCP spinal cord neurons. Conclusion: The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155 could be a promising target in treating BCP.

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Parkin Inhibits Static Mechanical Pain by Suppressing Membrane Trafficking of Mechano-transducing Ion Channel TACAN

Cited by 6 publications

References 15 publications

The expression and distribution of TACAN in human and rat bladders

The expression and distribution of TACAN in human and rat bladders

Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking

miR-155-5p in the spinal cord regulates hypersensitivity in a rat model of bone cancer pain

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