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Ion Channel Conformational Coupling in Ischemic Neuronal Death
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
ASIC1a belongs to the H+-gated subgroup of the degenerin/epithelial Na+ channel (DEG/ENaC) family of non-selective cation channels (Wang and Xu, 2011; Wemmie et al., 2013). In mammals, ASIC1a is widely expressed in both central nervous system and peripheral nervous system. In neurons, ASIC1a is distributed across dendritic membranes of neurons, including postsynaptic membranes, where it is involved in regulating membrane excitability and neurotransmission (Kreple et al., 2014). In addition, ASIC1a is also found to exist in mitochondrial membrane of mouse cortical neurons and shown to regulate mitochondrial permeability transition (Wang et al., 2013). Since pH alteration is a common phenomenon in many physiological and pathological processes, ASIC1a broadly contributes to a variety of pathophysiological conditions such as nociception, seizure, and brain ischemic damage (Wang and Xu, 2011; Wemmie et al., 2013). Ischemic stroke usually leads to a persistent acidosis in the brain (Pignataro et al., 2007). The pH value of the ischemic brain rapidly drops from 7.4 to around 6.0 after the onset of ischemic stroke, and this lasts for hours. Treatment with sodium bicarbonate not only restores brain pH to the neutral value but also significantly reduces the extent of ischemic brain injury, suggesting that persistent acidosis is a leading cause of ischemic neuronal death (Pignataro et al., 2007). As the major proton sensor in the brain, pharmacological inhibition of ASIC1a by psalmotoxin (PcTX1) or amiloride showed a similar degree of neuroprotection as the sodium bicarbonate treatment (Xiong et al., 2004). On the contrary, enhancement of ASIC1a currents by phosphorylation of Ser478 and Ser479 at the carboxyl terminus (Gao et al., 2005), or sensitization of ASIC1a by extracellular spermine (Duan et al., 2011), exacerbated acidosis-induced ischemic neuronal death. Furthermore, mice without the Asic1a gene demonstrate significant resistance to ischemic injury in middle cerebral artery occlusion (MCAO) model (Xiong et al., 2004). All these findings strongly suggest that ASIC1a mediates acidosis-induced neuronal death in ischemic brain.
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.
Emerging drugs for primary progressive multiple sclerosis
Published in Expert Opinion on Emerging Drugs, 2018
Ram Narendra Narayan, Thomas Forsthuber, Olaf Stüve
Although there is growing evidence for a role of excess intracellular cations, particularly calcium ions, in neuronal and glial cell injury in MS, as well as in noninflammatory neurological conditions, the molecular mechanisms involved are not fully elucidated. When the acid-sensing ion channel 1 (ASIC1) gets activated (as in the acidotic milieu found in inflammatory lesions), there is influx of sodium and calcium ions, leading to axonal injury in EAE. ASIC1 is upregulated in axons and oligodendrocytes within lesions from mice with acute EAE and from patients with active MS. Blocking ASIC1 with amiloride protected both myelin and neurons from damage in the acute model, when given early in the course of the disease, and ameliorated disability in mice with chronic-relapsing EAE [65,66]. In a translational study, the neuroprotective effect of amiloride was tested in a cohort of 14 patients with PPMS using MRI markers of neurodegeneration as outcome measures of neuroprotection. A significant reduction was noted in the normalized annual rate of whole-brain volume (brain atrophy) during the treatment phase, as compared with the pretreatment phase [67]. These studies suggest that amiloride may exert neuroprotective effects in patients with PPMS. There are no ongoing trials in PPMS designed yet.
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