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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).
Local immune response as novel disease mechanism underlying abdominal pain in patients with irritable bowel syndrome
Published in Acta Clinica Belgica, 2022
J. Aguilera-Lizarraga, M. Florens, H. Hussein, G. Boeckxstaens
Visceral pain is initiated by the activation of spinal sensory afferents that innervate the gastrointestinal tract (colonic nociceptors). These afferents express a plethora of molecular nociceptors, i.e. pro-nociceptive ion channels and receptors, including acid-sensing ion channels (ASIC), protease activated receptors, G protein-coupled receptors, transient receptor potential (TRP) channels, ionotrophic receptors, purinergic receptors, and voltage-gated ion channels (CaV, NaV) [49]. These molecular sensors can detect noxious stimuli among which are reactive chemicals, damaging temperatures (either heat or cold), mechanical injury, and ATP and immune mediators (including histamine and cytokines). The latter are released from a wide range of immune cells such as mast cells, macrophages, and neutrophils wherewith the peripheral nerve terminals are located in close proximity. Upon detection of the noxious stimuli, molecular sensors are activated, upregulated and/or sensitized, and action potentials are generated at colonic nociceptive nerve terminals. Based on the location of their soma, colonic nociceptors can be subdivided into splanchnic nerves, whose cell bodies are located within the thoracolumbar dorsal root ganglia (DRG) (T10-L1), and pelvic afferents, with cell bodies within the lumbosacral DRG (L5-S2) [49]. When activated, visceral afferents signal to the dorsal horn of the spinal cord. Prolonged stimulations of primary afferent endings, in turn, can result in chronic facilitation of nociceptive transmission from the gut.
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.
Chronic orofacial pain animal models - progress and challenges
Published in Expert Opinion on Drug Discovery, 2018
Heitor G. Araújo-Filho, Erik W.M. Pereira, Adriana Rolim Campos, Lucindo J. Quintans-Júnior, Jullyana S.S. Quintans
Rossi, Jenkins [89] showed that behavioral changes after CCI-IoN were accompanied by an increase in TRPV1 positive cells and an increased intensity of TRPM8 staining. After the injury, inflammatory mediators activate intracellular signaling pathways in the nociceptor terminal, promoting an increase in the production, transport and insertion in the membrane of transducer channels and voltage-dependent ion channels, such as the transient receptor potential vanilloids 1 and 2 (TRPV1 and TRPV2); the transient receptor potential melastatin 8 (TRPM8); the acid sensitive ion channel (ASIC); and the tetrodotoxin resistant sodium channels, Nav 1.8 and 1.9, which increase sodium and calcium currents, contributing to the generation of ectopic potentials [90]. In a study with diabetic rats, a number of differences were observed following partial lesion of the peripheral nerve: the lesion triggered lower regulation of the VR1 receptors in the injured fibers, but greater regulation in receptors in intact A and C fibers in the dorsal horn of the spinal cord [91]. This persistence of VR1 receptors in nerves close to the lesion and intact dorsal root ganglia may be crucial for the development or maintenance of neuropathic pain [92].