Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors

Lin, Shing-Hong; Cheng, Yuan-Ren; Banks, Robert W.; Min, Ming‐Yuan; Bewick, Guy S.; Chen, Chih‐Cheng

doi:10.1038/ncomms11460

Cited by 105 publications

(152 citation statements)

References 61 publications

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“…Over the years, additional ion channels were implicated in mechanosensory transduction, including MEC/DEG/ASICS and TRPs in lower organisms, as well as in mammals (Chalfie, 2009;Christensen and Corey, 2007;Lin et al, 2016;Walker et al, 2000;Yan et al, 2013). However, so far no clear evidence was provided demonstrating their intrinsic mechanosensitivity.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Douguet

Honoré

2019

Cell

147

128

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The conversion of force into an electrical cellular signal is mediated by the opening of different types of mechanosensitive ion channels (MSCs), including TREK/TRAAK K 2P channels, Piezo1/2, TMEM63/OSCA and TMC1/2. Mechanoelectrical transduction plays a key role in hearing, balance, touch, proprioception and is also implicated in the autonomic regulation of blood pressure and breathing. Thus, dysfunction of MSCs is associated with a variety of inherited and acquired disease states. Significant progress has recently been made in identifying these channels, solving their structure and understanding the gating of both hyperpolarizing and depolarizing MSCs. Besides prototypical activation by membrane tension, additional gating mechanisms involving channel curvature and/or tethered elements are at play.

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Section: Discussionmentioning

confidence: 99%

Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Douguet

Honoré

2019

Cell

147

128

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“…The contribution of ASIC3 to nociceptive mechanotransduction under the physiological condition is a matter of debate (Cheng et al, ; Deval & Lingueglia, ; Lingueglia, ), whereas ASIC3 is reported to be involved in proprioceptive mechanotransduction (Lin et al, ). In the present study, a selective blocker of ASIC3 administered to the naïve muscle via intramuscular injection did not alter the mechanical withdrawal threshold, indicating that ASIC3 played no role in the normal mechanical pain sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Thin‐fibre receptors expressing acid‐sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise

Matsubara

Hayashi

Wakatsuki

et al. 2019

European Journal of Pain

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Background Delayed onset muscle soreness (DOMS) is characterized by mechanical hyperalgesia after lengthening contractions (LC). It is relatively common and causes disturbance for many people who require continuous exercise, yet its molecular and peripheral neural mechanisms are poorly understood. Methods We examined whether muscular myelinated Aδ‐fibres, in addition to unmyelinated C‐fibres, are involved in LC‐induced mechanical hypersensitivity, and whether acid‐sensing ion channel (ASIC)‐3 expressed in thin‐fibre afferents contributes to this type of pain using a rat model of DOMS. The peripheral contribution of ASIC3 was investigated using single‐fibre electrophysiological recordings in extensor digitorum longus muscle‐peroneal nerve preparations in vitro. Results Behavioural tests demonstrated a significant decrease of the muscular mechanical withdrawal threshold following LC to ankle extensor muscles, and it was improved by intramuscular injection of APETx2 (2.2 μM), a selective blocker of ASIC3. The lower concentration of APETx2 (0.22 µM) and its vehicle had no effect on the threshold. Intramuscular injection of APETx2 (2.2 μM) in naïve rats without LC did not affect the withdrawal threshold. In the ankle extensor muscles that underwent LC one day before the electrophysiological recordings, the mechanical response of Aδ‐ and C‐fibres was significantly facilitated (i.e. decreased response threshold and increased magnitude of the response). The facilitated mechanical response of the Aδ‐ and C‐fibres was significantly suppressed by selective blockade of ASIC3 with APETx2, but not by its vehicle. Conclusions These results clearly indicate that ASIC3 contributes to the augmented mechanical response of muscle thin‐fibre receptors in delayed onset muscular mechanical hypersensitivity after LC. Significance Here, we show that not only C‐ but also Aδ‐fibre nociceptors in the muscle are involved in mechanical hypersensitivity after lengthening contractions, and that acid‐sensing ion channel (ASIC)‐3 expressed in the thin‐fibre nociceptors is responsible for the mechanical hypersensitivity. ASIC3 might be a novel pharmacological target for pain after exercise.

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“…The beam walking test was conducted using a previously described method (Lin et al, ), with slight modifications. Briefly, mice were placed at a fixed point on a 0.5 cm wide ruler attached to a goal box (non‐transparent, 20 × 10 × 20 cm 3 ).…”

Section: Methodsmentioning

confidence: 99%

The deletion of dicer in mature myelinating glial cells causes progressive axonal degeneration but not overt demyelination in adult mice

Wang

et al. 2018

Glia

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Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro-RNAs (miRNAs). Despite the importance of Dicer in initiating myelination, the role of Dicer in mature MGCs is still unclear. Here, Dicer was specifically deleted in mature MGCs in 2-month old mice (PLP-CreERT; Dicer fl/fl) by tamoxifen administration. Progressive motor dysfunction was observed in the Dicer conditional knockout mice, which displayed hind limb ataxia at 3 months post recombination that deteriorated into paralysis within 5 months. Massive axonal degeneration/atrophy in peripheral nerves was responsible for this phenomenon, but overt demyelination was not observed in either the CNS or PNS. In contrast to the PNS, signs of axonal degeneration were not observed in the CNS of these animals. We induced a Dicer deletion in oligodendroglia at postnatal day 5 in NG2-CreERT; Dicer fl/fl mice to evaluate whether Dicer expression in OLs is essential for axonal survival. Dicer deletion in oligodendroglia did not cause motor dysfunction at the age of 7 months. Neither axonal atrophy nor demyelination was observed in the CNS. Based on our results, Dicer expression in SCs is required to maintain axon integrity in adult PNS, and Dicer is dispensable for maintaining myelin sheaths in MGCs.

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Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors

Cited by 105 publications

References 61 publications

Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels

Thin‐fibre receptors expressing acid‐sensing ion channel 3 contribute to muscular mechanical hypersensitivity after exercise

The deletion of dicer in mature myelinating glial cells causes progressive axonal degeneration but not overt demyelination in adult mice

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