Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

Abstract

BackgroundAcid-sensing ion channels (ASICs) are a group of amiloride-sensitive ligand-gated ion channels belonging to the family of degenerin/epithelial sodium channels. ASICs are predominantly expressed in both the peripheral and central nervous system and have been characterized as potent proton sensors to detect extracellular acidification in the periphery and brain.Main bodyHere we review the recent studies focusing on the physiological roles of ASICs in the nervous system. As the major acid-sensing membrane proteins in the nervous system, ASICs detect tissue acidosis occurring at tissue injury, inflammation, ischemia, stroke, and tumors as well as fatiguing muscle to activate pain-sensing nerves in the periphery and transmit pain signals to the brain. Arachidonic acid and lysophosphocholine have been identified as endogenous non-proton ligands activating ASICs in a neutral pH environment. On the other hand, ASICs are found involved in the tether model mechanotransduction, in which the extracellular matrix and cytoplasmic cytoskeletons act like a gating-spring to tether the mechanically activated ion channels and thus transmit the stimulus force to the channels. Accordingly, accumulating evidence has shown ASICs play important roles in mechanotransduction of proprioceptors, mechanoreceptors and nociceptors to monitor the homoeostatic status of muscle contraction, blood volume, and blood pressure as well as pain stimuli.ConclusionTogether, ASICs are dual-function proteins for both chemosensation and mechanosensation involved in monitoring physiological homoeostasis and pathological signals.

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

“…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.…”

“…ASIC3 is a sensor capable of detecting extracellular pH and metabolites in the muscle (Cheng et al, 2018;Deval et al, 2010;Deval & Lingueglia, 2015;Light et al, 2008;Molliver et al, 2005). In rats, the expression of ASIC3 is more abundant in small sensory neurons innervating the muscle than those innervating the skin (Fujii et al, 2008;Molliver et al, 2005).…”

“…ASIC3, together with ASIC1a and ASIC2a heteromers, is one of the principal channels in mouse skeletal muscle afferents, and is responsible for sensing extracellular acidosis and metabolites released during ischaemia and exercise (Gautam & Benson, 2013). Although the contribution of ASIC3 to normal mechanotransduction in the muscle is unclear (Cheng, Jiang, & Chen, 2018), ASIC3 has been demonstrated to be involved in mechanical hypersensitivity in several muscle pain models (Chen et al, 2014;Gregory, Brito, Fusaro, & Sluka, 2016;Hori et al, 2010;Sluka et al, 2003Sluka et al, , 2007Taguchi et al, 2015). The expression of ASIC3 was increased by nerve growth factor (NGF) in cultured DRG neurons (Mamet, Baron, Lazdunski, & Voilley, 2002).…”

Impairment of proprioceptive movement and mechanical nociception in Drosophila melanogaster larvae lacking Ppk30, a Drosophila member of the Degenerin/Epithelial Sodium Channel family

“…Alternatively, the experimental conditions tested to date may not have been appropriate for producing mechanosensitive currents from cells expressing Ppk channels. Similarly, ASICs in mammals, which respond to acid and have been implicated in mechanosensation in vivo, have not been shown to directly produce currents in cells by mechanical force. In this regard, Ppk1 and Ppk30 are similar to mammalian ASICs.…”

The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

“…This alteration in metabolism produces lactic acid and H + , which are the by-products responsible for the decreased pH and increased acidity (Li et al, 2016). Acidsensing ion channels are cation channels belonging to the family of degenerin/epithelial sodium channels that are gated by H + (Cheng, Jiang, & Chen, 2018;Waldmann, Champigny, Bassilana, Heurteaux, & Lazdunski, 1997). These channels have dual functions of chemo-sensing and mechano-sensing (Cheng et al, 2018).…”