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Eukaryotic Mechanosensitive Ion Channels
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Acid-sensing ion channels (ASICs) are activated by extracellular acidosis and belong to the degenerin/epithelial sodium channel protein family, a group of cation channels expressing in the nervous system and types of epithelial and immune cells [4]. As the major proton sensors of the cell, ASICs detect tissue acidosis occurring from tissue injury, inflammation, ischemia, stroke, and tumors as well as transmit pain signals to the brain in the peripheral sensory neurons [5]. Though ASICs have been recognized as a chemosensor, accumulating evidence shows that ASICs are gated by mechanical force in a tether model, in which the extracellular matrix or cytoplasmic cytoskeletons act like a gating-spring to tether and transmit the force to the channels. Accordingly, genetic knock-out of ASICs in mice suggests their roles in proprioceptors, mechanoreceptors, and nociceptors to monitor the homoeostatic status of muscle contraction, blood volume, and blood pressure as well as pain sensation [4]. Although the murine phenotypes show that ASICs are involved in many mechanotransduction systems, there is no evidence to reconstitute the ASIC-mediated MA current in a heterologous expression system. On the other hand, a recent work by Fronius et al. found that shear stress modulates the ASICs channel activity at low pH or in the presence of non-proton ligands in Xenopus oocytes, while it doesn’t gate ASCIs at neutral pH when the channels are closed. The finding supports the notion that ASICs can be modulated but not directly gated by mechanical force [6].
Oesophagus
Published in Paul Ong, Rachel Skittrall, Gastrointestinal Nursing, 2017
Mucosal damage arises from the diffusion of high concentrations of hydrogen ions from the lumen of the oesophagus into the mucosal tissue, down a concentration gradient. These changes are sensed by afferent sensory nerves containing acid sensing ion channels. These activate the nerve fibres and produce heartburn (Orlando, 2006). At the same time, acid is allowed to penetrate into the basal layer of the squamous cell epithelium of the oesophagus through gaps in the damaged epithelium. Acid entering the cells initiates the process of mucosal destruction, causing erosion and ulceration. Pro-inflammatory cytokines produced during this inflammatory process affect the neuromuscular control of the lower oesophageal sphincter causing weakness and decreased peristalsis (Orlando, 2006; Reider et al., 2010). This increases the probability of reflux and continued acid injury.
Stratum Corneum and Sensitive Skin
Published in Golara Honari, Rosa M. Andersen, Howard Maibach, Sensitive Skin Syndrome, 2017
Several research studies, however, are investigating the molecular basis for sensory hyperreactivity. Transient receptor potential, vanilloid family 1 (TRPV1) is a nonreceptive, thermosensitive ion channel which reacts to noxious stimuli, most notably noxious heat and low pH. TRPV1 is expressed on fibroblasts, mast cells, and endothelial cells; activation results in pain or pruritus with a burning component. TRPV1 is also dramatically upregulated by inflammatory mediators (14) as well as heat and capsaicin. It has been hypothesized that the development of sensitive skin may be related to the dysregulation of muscle contraction and relaxation process (15); actin-bound myosin cross bridges in sensitive skin had more compacted shape than those in nonsensitive skin, indicating more contracted cross-bridge state in sensitive skin tissues. This could also be linked to altered adenosine triphosphate metabolism and response of skin pH. These data demonstrated that subjects with sensitive skin showed impaired pH homeostasis after lactic acid stimulation and increase of detection ability for pH upon internal or external stimuli such as lactic acid (15). Enhanced acidity might induce pain via the stimulation of TRPV1, acid-sensing ion channel subunit 3, and CGRP in the human sensitive skin. SC microbiome has also been investigated in subjects affected by sensitive skin, and no differences versus normal controls have been reported (16).
An overview of carbonic anhydrases and membrane channels of synoviocytes in inflamed joints
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Acid-sensing ion channels (ASICs) mediate tissue acidosis by pH changes are known as voltage-insensitive, ligand-gated cation channels with protons53,54. The ASICs are associated with inflammatory pain, and especially ASIC1 and ASIC3 contribute to the musculoskeletal pain55. The ASIC3 is expressed in the sensory neurons that innervate the synovial joints by increasing the intracellular Ca2+ levels upon sensing a decrease of pH in the inflamed joint56,57. Synovial inflammation and inflammatory cytokine levels were increased that led to joint destruction in ASIC3–/– mice55. FLS were activated with the decrease in pH; the acidic environment increased the intracellular Ca2+ levels by ASIC357. Activation of FLS in acidic pH mediates the accumulation of inflammatory cytokines. In addition, activation of ASIC3 by acidic pH evokes Ca2+ signalling, which lead to the apoptosis of FLS by phosphorylation of the MAP kinase ERK in synovial inflammation; thus, it could be a blockade of synovial proliferation58. Activation of ASIC3 can be a therapeutic strategy for reducing inflammatory FLS level and subsequent disease progression in an inflamed joint.
Retinal pH and Acid Regulation During Metabolic Acidosis
Published in Current Eye Research, 2018
Alyssa Dreffs, Desmond Henderson, Andrey V. Dmitriev, David A. Antonetti, Robert A. Linsenmeier
Specifically, we have investigated mRNA for acid-regulating genes in the retinas of Long–Evans rats treated with NH4Cl to produce systemic metabolic acidosis. First, we confirmed that this systemic acidosis produced retinal acidosis as well. Previous studies had shown that several genes of interest are expressed in the retina. The genes investigated were carbonic anhydrase II (CA-II), believed to be intracellular14 in Müller cells15 and photoreceptors,16 carbonic anhydrase XIV (CA-XIV), believed to be extracellular,17 anion-exchange protein 3 (AEP-3) 18, and the sodium-hydrogen exchanger 1 (NHE-1).19,20 The two isoforms of CA are the only ones that have been reported in the retina. We also investigated acid-sensing ion channels (ASICs) 1 and 4. While not directly involved in acid regulation, ASICs are widely distributed in the retina,21,22 and may play a role in retinal responses to pH changes.21–25
Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents
Published in Current Eye Research, 2018
Dorota L. Stankowska, Brett H. Mueller, Hidehiro Oku, Tsunehiko Ikeda, Adnan Dibas
Neurodegeneration in the central nervous system (CNS) has been linked to the activation of various signaling cascades by influx and accumulation of intra-axonal Na+ and Ca2+ ions.3,4 Acid-sensing ion channels (ASICs) belong to a proton-gated subcategory of the degenerin–epithelial channel family of cation channels, which are responsible for Na+ and Ca2+ influxes. Members of ASICs family are expressed in many neurons of mammalian central and peripheral nervous systems.5–9 ASICs (ASIC1a homomeric channels and ASIC1a/2b heteromeric channels) are also permeable to divalent cations, such as calcium, suggesting that they could play a particularly important role in intracellular signaling as well as membrane excitability.5,10 Following acidification, cells expressing homotrimeric rat ASIC1a increased cytosolic calcium.11 ASIC1 is a postsynaptic proton receptor that controls the intracellular Ca2+ concentration in variety of neurons12 and regulates Na+ and Ca2+ influxes during stress, such as ischemia or tissue acidosis.13 In CNS, ASICs play a role in mechanosensation14,15 and pain perception induced by acidosis.16–18 ASICs in the brain, in particular ASIC1, are involved in synaptic plasticity, learning and memory.19