Journal articles: 'ASIC'

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Dusenkova, Svetlana, Fei Ru, Lenka Surdenikova, Christina Nassenstein, Jozef Hatok, Robert Dusenka, Peter Banovcin, Jan Kliment, Milos Tatar, and Marian Kollarik. "The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 9 (November 1, 2014): G922—G930. http://dx.doi.org/10.1152/ajpgi.00129.2014.

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Acid-sensing ion channels (ASICs) have been implicated in esophageal acid sensing and mechanotransduction. However, insufficient knowledge of ASIC subunit expression profile in esophageal afferent nerves hampers the understanding of their role. This knowledge is essential because ASIC subunits form heteromultimeric channels with distinct functional properties. We hypothesized that the esophageal putative nociceptive C-fiber nerves (transient receptor potential vanilloid 1, TRPV1-positive) express multiple ASIC subunits and that the ASIC expression profile differs between the nodose TRPV1-positive subtype developmentally derived from placodes and the jugular TRPV1-positive subtype derived from neural crest. We performed single cell RT-PCR on the vagal afferent neurons retrogradely labeled from the esophagus. In the guinea pig, nearly all (90%–95%) nodose and jugular esophageal TRPV1-positive neurons expressed ASICs, most often in a combination (65–75%). ASIC1, ASIC2, and ASIC3 were expressed in 65–75%, 55–70%, and 70%, respectively, of both nodose and jugular TRPV1-positive neurons. The ASIC1 splice variants ASIC1a and ASIC1b and the ASIC2 splice variant ASIC2b were similarly expressed in both nodose and jugular TRPV1-positive neurons. However, ASIC2a was found exclusively in the nodose neurons. In contrast to guinea pig, ASIC3 was almost absent from the mouse vagal esophageal TRPV1-positive neurons. However, ASIC3 was similarly expressed in the nonnociceptive TRPV1-negative (tension mechanoreceptors) neurons in both species. We conclude that the majority of esophageal vagal nociceptive neurons express multiple ASIC subunits. The placode-derived nodose neurons selectively express ASIC2a, known to substantially reduce acid sensitivity of ASIC heteromultimers. ASIC3 is expressed in the guinea pig but not in the mouse vagal esophageal TRPV1-positive neurons, indicating species differences in ASIC expression.

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Martínez-Barbero, Graciela, Yolanda García-Mesa, Ramón Cobo, Patricia Cuendias, Benjamín Martín-Biedma, Olivia García-Suárez, Jorge Feito, Teresa Cobo, and José A. Vega. "Acid-Sensing Ion Channels’ Immunoreactivity in Nerve Profiles and Glomus Cells of the Human Carotid Body." International Journal of Molecular Sciences 24, no. 24 (December 5, 2023): 17161. http://dx.doi.org/10.3390/ijms242417161.

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The carotid body is a major peripheral chemoreceptor that senses changes in arterial blood oxygen, carbon dioxide, and pH, which is important for the regulation of breathing and cardiovascular function. The mechanisms by which the carotid body senses O2 and CO2 are well known; conversely, the mechanisms by which it senses pH variations are almost unknown. Here, we used immunohistochemistry to investigate how the human carotid body contributes to the detection of acidosis, analyzing whether it expresses acid-sensing ion channels (ASICs) and determining whether these channels are in the chemosensory glomic cells or in the afferent nerves. In ASIC1, ASIC2, and ASIC3, and to a much lesser extent ASIC4, immunoreactivity was detected in subpopulations of type I glomus cells, as well as in the nerves of the carotid body. In addition, immunoreactivity was found for all ASIC subunits in the neurons of the petrosal and superior cervical sympathetic ganglia, where afferent and efferent neurons are located, respectively, innervating the carotid body. This study reports for the first time the occurrence of ASIC proteins in the human carotid body, demonstrating that they are present in glomus chemosensory cells (ASIC1 < ASIC2 > ASIC3 > ASIC4) and nerves, presumably in both the afferent and efferent neurons supplying the organ. These results suggest that the detection of acidosis by the carotid body can be mediated via the ASIC ion channels present in the type I glomus cells or directly via sensory nerve fibers.

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Storozhuk, Maksim, Andrii Cherninskyi, Oleksandr Maximyuk, Dmytro Isaev, and Oleg Krishtal. "Acid-Sensing Ion Channels: Focus on Physiological and Some Pathological Roles in the Brain." Current Neuropharmacology 19, no. 9 (September 14, 2021): 1570–89. http://dx.doi.org/10.2174/1570159x19666210125151824.

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Acid-sensing ion channels (ASICs) are Na+-permeable ion channels activated by protons and predominantly expressed in the nervous system. ASICs act as pH sensors leading to neuronal excitation. At least eight different ASIC subunits (including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4, ASIC5) are encoded by five genes (ASIC1-ASIC5). Functional ASICs assembled in the plasma membrane are homo- or heteromeric trimers. ASIC1a-containing trimers are of particular interest as, in addition to sodium ions, they also conduct calcium ions and thus can trigger or regulate multiple cellular processes. ASICs are widely but differentially expressed in the central and peripheral nervous systems. In the mammalian brain, a majority of neurons express at least one ASIC subunit. Several recent reviews have summarized findings of the role of ASICs in the peripheral nervous system, particularly in nociception and proprioception, and the structure-function relationship of ASICs. However, there is little coverage on recent findings regarding the role of ASICs in the brain. Here we review and discuss evidence regarding the roles of ASICs: (i) as postsynaptic receptors activated by protons coreleased with glutamate at glutamatergic synapses; (ii) as modulators of synaptic transmission at glutamatergic synapses and GABAergic synapses; (iii) in synaptic plasticity, memory and learning; (iv) in some pathologies such as epilepsy, mood disorders and Alzheimer's disease.

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Jernigan, Nikki L., Michael L. Paffett, Benjimen R. Walker, and Thomas C. Resta. "ASIC1 contributes to pulmonary vascular smooth muscle store-operated Ca2+ entry." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 2 (August 2009): L271—L285. http://dx.doi.org/10.1152/ajplung.00020.2009.

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Acid-sensing ion channels (ASIC) are voltage-insensitive, cationic channels that have recently been identified in vascular smooth muscle (VSM). It is possible that ASIC contribute to vascular reactivity via Na+ and Ca2+ conductance; however, their function in VSM is largely unknown. In pulmonary VSM, store-operated Ca2+ entry (SOCE) plays a significant role in vasoregulatory mechanisms such as hypoxic pulmonary vasoconstriction and receptor-mediated arterial constriction. Therefore, we hypothesized that ASIC contribute to SOCE in pulmonary VSM. We examined SOCE resulting from depletion of intracellular Ca2+ stores with cyclopiazonic acid in isolated small pulmonary arteries and primary cultured pulmonary arterial smooth muscle cells by measuring 1) changes in VSM [Ca2+]i using fura-2 indicator dye, 2) Mn2+ quenching of fura-2 fluorescence, and 3) store-operated Ca2+ and Na+ currents using conventional whole cell patch-clamp configuration in voltage-clamp mode. The role of ASIC was assessed by the use of the ASIC inhibitors, amiloride, benzamil, and psalmotoxin 1, or siRNA directed towards ASIC1, ASIC2, or ASIC3 isoforms. We found that store-operated VSM [Ca2+]i responses, Mn2+ influx, and inward cationic currents were attenuated by either pharmacological ASIC inhibition or treatment with ASIC1 siRNA. These data establish a unique role for ASIC1 in mediating SOCE in pulmonary VSM and provide new insight into mechanisms of VSM Ca2+ entry and pulmonary vasoregulation.

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Hu, Zhuang-Li, Chao Huang, Hui Fu, You Jin, Wen-Ning Wu, Qiu-Ju Xiong, Na Xie, Li-Hong Long, Jian-Guo Chen, and Fang Wang. "Disruption of PICK1 attenuates the function of ASICs and PKC regulation of ASICs." American Journal of Physiology-Cell Physiology 299, no. 6 (December 2010): C1355—C1362. http://dx.doi.org/10.1152/ajpcell.00569.2009.

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Acid-sensing ion channels (ASICs) extensively exist in both central and peripheral neuronal systems and contribute to many physiological and pathological processes. The protein that interacts with C kinase 1 (PICK1) was cloned as one of the proteins interacting with protein kinase C (PKC) and colocalized with ASIC1 and ASIC2. Here, we used PICK1 knockout (PICK1-KO) C57/BL6 mice together with the whole cell patch clamp, calcium imaging, RT-PCR, Western blot, and immunocytochemistry techniques to explore the possible change in ASICs and the regulatory effects of PKC on ASICs. The results showed that PICK1 played a key role in regulation of ASIC functions. In PICK1-KO mouse cortical neurons, both the amplitude of ASIC currents and elevation of [Ca2+]i mediated by acid were decreased, which were attributable to the decreased expression of ASIC1a and ASIC2a proteins in the plasma membrane. PKC, a partner protein of PICK1, regulated ASIC functions via PICK1. The agonist and antagonist of PKC only altered ASIC currents and acid-induced increase in [Ca2+]i in wild-type, but not in KO mice. In conclusion, our data provided the direct evidence from PICK1-KO mice that a novel target protein, PICK1, would regulate ASIC function and membrane expression in the brain. In addition, PICK1 played the bridge role between PKC and ASICs.

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Dymowska, Agnieszka K., Aaron G. Schultz, Salvatore D. Blair, Danuta Chamot, and Greg G. Goss. "Acid-sensing ion channels are involved in epithelial Na+ uptake in the rainbow trout Oncorhynchus mykiss." American Journal of Physiology-Cell Physiology 307, no. 3 (August 1, 2014): C255—C265. http://dx.doi.org/10.1152/ajpcell.00398.2013.

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A role for acid-sensing ion channels (ASICs) to serve as epithelial channels for Na+ uptake by the gill of freshwater rainbow trout was investigated. We found that the ASIC inhibitors 4′,6-diamidino-2-phenylindole and diminazene decreased Na+ uptake in adult rainbow trout in a dose-dependent manner, with IC50 values of 0.12 and 0.96 μM, respectively. Furthermore, we cloned the trout ASIC1 and ASIC4 homologs and demonstrated that they are expressed differentially in the tissues of the rainbow trout, including gills and isolated mitochondrion-rich cells. Immunohistochemical analysis using custom-made anti-zASIC4.2 antibody and the Na+-K+-ATPase (α5-subunit) antibody demonstrated that the trout ASIC localizes to Na+/K+-ATPase-rich cells in the gill. Moreover, three-dimensional rendering of confocal micrographs demonstrated that ASIC is found in the apical region of mitochondrion-rich cells. We present a revised model whereby ASIC4 is proposed as one mechanism for Na+ uptake from dilute freshwater in the gill of rainbow trout.

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Xie, Jinghui, Margaret P. Price, John A. Wemmie, Candice C. Askwith, and Michael J. Welsh. "ASIC3 and ASIC1 Mediate FMRFamide-Related Peptide Enhancement of H+-Gated Currents in Cultured Dorsal Root Ganglion Neurons." Journal of Neurophysiology 89, no. 5 (May 1, 2003): 2459–65. http://dx.doi.org/10.1152/jn.00707.2002.

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The acid-sensing ion channels (ASICs) form cation channels that are transiently activated by extracellular protons. They are expressed in dorsal root ganglia (DRG) neurons and in the periphery where they play a function in nociception and mechanosensation. Previous studies showed that FMRFamide and related peptides potentiate H+-gated currents. To better understand this potentiation, we examined the effect of FMRFamide-related peptides on DRG neurons from wild-type mice and animals missing individual ASIC subunits. We found that FMRFamide and FRRFamide potentiated H+-gated currents of wild-type DRG in a dose-dependent manner. They increased current amplitude and slowed desensitization following a proton stimulus. Deletion of ASIC3 attenuated the response to FMRFamide-related peptides, whereas the loss of ASIC1 increased the response. The loss of ASIC2 had no effect on FMRFamide-dependent enhancement of H+-gated currents. These data suggest that FMRFamide-related peptides modulate DRG H+-gated currents through an effect on both ASIC1 and ASIC3 and that ASIC3 plays the major role. The recent discovery of RFamide-related peptides (RFRP) in mammals suggested that they might also modulate H+-gated current. We found that RFRP-1 slowed desensitization of H+-gated DRG currents, whereas RFRP-2 increased the peak amplitude. COS-7 cells heterologously expressing ASIC1 or ASIC3 showed similar effects. These results suggest that FMRFamide-related peptides, including the newly identified RFRPs, modulate H+-gated DRG currents through ASIC1 and ASIC3. The presence of several ASIC subunits, the diversity of FMRFamide-related peptides, and the distinct effects on H+-gated currents suggest the possibility of substantial complexity in modulation of current in DRG sensory neurons.

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Corrow, Kimberly, Beatrice M. Girard, and Margaret A. Vizzard. "Expression and response of acid-sensing ion channels in urinary bladder to cyclophosphamide-induced cystitis." American Journal of Physiology-Renal Physiology 298, no. 5 (May 2010): F1130—F1139. http://dx.doi.org/10.1152/ajprenal.00618.2009.

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The expression of acid-sensing ion channel (ASIC) isoforms, ASIC1, ASIC2a, and ASIC3, was examined in the urinary bladder after cyclophosphamide (CYP)-induced cystitis of varying duration (4 h, 48 h, and chronic). Immunohistochemical, Western blot, and quantitative PCR approaches were used to evaluate channel expression and effects of CYP-induced cystitis in whole urinary bladder and split-bladder preparations from control (no inflammation) and CYP-treated rats. Quantitative PCR demonstrated significant ( P ≤ 0.01) increases in ASIC2a and ASIC3 transcripts with CYP-induced cystitis (48 h and chronic) in the urothelium but no changes (e.g., ASIC3) or modest changes (e.g., ASIC2a) in detrusor smooth muscle. ASIC1 mRNA expression in the urothelium or detrusor was not affected by CYP-induced cystitis. Immunohistochemistry for ASIC2a and ASIC3 protein expression revealed significant ( P ≤ 0.01) increases in ASIC immunoreactivity in the urothelium and suburothelial plexus with CYP-induced cystitis at all time points examined. Western blotting for ASIC2a and ASIC3 protein expression was complementary and revealed significant ( P ≤ 0.01) increases in ASIC immunoreactivity. For the first time, these studies demonstrate that CYP-induced cystitis alters ASIC2a and ASIC3 expression in the urinary bladder; ASIC1 transcript expression is not altered by CYP-induced cystitis. Future studies are necessary to determine ASIC isoform contributions to micturition reflexes in control and inflamed urinary bladder.

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Lee, Ching-Yu, Tsung-Jen Huang, Meng-Huang Wu, Yen-Yao Li, and Kuan-Der Lee. "High Expression of Acid-Sensing Ion Channel 2 (ASIC2) in Bone Cells in Osteoporotic Vertebral Fractures." BioMed Research International 2019 (August 19, 2019): 1–10. http://dx.doi.org/10.1155/2019/4714279.

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Little is known about the function of acid-sensing ion channels (ASICs) in bone cells or osteoporotic vertebral fractures (OVF). This study delineated ASICs expression in adult human bone marrow-mesenchymal stem cells- (BM-MSC-) derived osteoblasts and in OVF bone cells. Adult BM-MSC-derived osteoblasts were isolated and cultured in different pH values. Osteogenic markers as alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OC) mRNA were assessed. Western blots method was applied to analyze ASICs protein expression in different pH values. Amiloride was added into the osteogenic media to analyze the Na+/K+ ATPase change. We harvested the vertebral cancellous bone through a bone biopsy needle in 26 OVF patients when performing percutaneous vertebroplasty. Six vertebral bone specimens obtained from 4 patients with high-energy vertebral fractures were used as the control. The reverse transcription polymerase chain reaction was performed to analyze the quantitative mRNA expression of ASICs. Osteogenic markers as ALP, OPN, and OC mRNA were higher expressed in increasing pH values throughout osteoblastogenesis. ASIC proteins were higher expressed in lower pH media, especially ASIC3, and ASIC4. The highest protein expression at days 7, 14, and 21 was ASIC2, ASIC4, and ASIC3, respectively. Expression of Na+/K+ ATPase was significantly decreased in cultured osteoblasts by addition of amiloride into the pH 6.9 osteogenic media. ASIC2 mRNA was most highly expressed with a 65.93-fold increase in the biopsied vertebral bone cells in OVF compared with the control. In conclusion, we found osteoblastogenesis was reduced in an acidic environment, and ASIC2, ASIC3, and ASIC4 were most highly expressed in turn during osteoblastogenesis within acidic media. ASIC2 was the most abundantly expressed gene in human bone cells in OVF compared with the control. ASIC2 could be crucial in the pathogenesis of osteoporosis and could serve as a therapeutic target for antiosteoporotic therapies.

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Kusama, Nobuyoshi, Mamta Gautam, Anne Marie S. Harding, Peter M. Snyder, and Christopher J. Benson. "Acid-sensing ion channels (ASICs) are differentially modulated by anions dependent on their subunit composition." American Journal of Physiology-Cell Physiology 304, no. 1 (January 1, 2013): C89—C101. http://dx.doi.org/10.1152/ajpcell.00216.2012.

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Acid-sensing ion channels (ASICs) are sodium channels gated by extracellular protons. ASIC1a channels possess intersubunit Cl−-binding sites in the extracellular domain, which are highly conserved between ASIC subunits. We previously found that anions modulate ASIC1a gating via these sites. Here we investigated the effect of anion substitution on native ASICs in rat sensory neurons and heterologously expressed ASIC2a and ASIC3 channels by whole cell patch clamp. Similar to ASIC1a, anions modulated the kinetics of desensitization of other ASIC channels. However, unlike ASIC1a, anions also modulated the pH dependence of activation. Moreover, the order of efficacy of different anions to modulate ASIC2a and -3 was very different from that of ASIC1a. More surprising, mutations of conserved residues that form an intersubunit Cl−-binding site in ASIC1a only partially abrogated the effects of anion modulation of ASIC2a and had no effect on anion modulation of ASIC3. The effects of anions on native ASICs in rat dorsal root ganglion neurons mimicked those in heterologously expressed ASIC1a/3 heteromeric channels. Our data show that anions modulate a variety of ASIC properties and are dependent on the subunit composition, and the mechanism of modulation for ASIC2a and -3 is distinct from that of ASIC1a. We speculate that modulation of ASIC gating by Cl− is a novel mechanism to sense shifts in extracellular fluid composition.

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Brockway, L. M., Z. H. Zhou, J. K. Bubien, B. Jovov, D. J. Benos, and K. T. Keyser. "Rabbit retinal neurons and glia express a variety of ENaC/DEG subunits." American Journal of Physiology-Cell Physiology 283, no. 1 (July 1, 2002): C126—C134. http://dx.doi.org/10.1152/ajpcell.00457.2001.

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Some members of the epithelial Na+ channel/degenerin (ENaC/DEG) family of ion channels have been detected in mammalian brain. Therefore, we examined the RNA and protein expression of these channels in another part of the central nervous system, the rabbit retina. We next sought to demonstrate physiological evidence for an amiloride-sensitive current in Müller glia, which, on the basis of a previous study, are thought to express α-ENaC (Golestaneh N, de Kozak Y, Klein C, and Mirshahi M. Glia 33: 160–168, 2001). RT-PCR of retinal RNA revealed the presence of α-, β-, γ-, and δ-ENaC as well as acid-sensing ion channel (ASIC)1, ASIC2, ASIC3, and ASIC4. Immunohistochemical localization with antibodies against α-ENaC and β-ENaC showed labeling in Müller cells and neurons, respectively. The presence of α-ENaC, β-ENaC, and ASIC1 was detected by Western blotting. Cultured Müller cells were whole cell patch clamped. These cells exhibited an inward Na+ current that was blocked by amiloride. These data demonstrate for the first time both the expression of a variety of ENaC and ASIC subunits in the rabbit retina as well as distinct cellular expression patterns of specific subunits in neurons and glia.

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Platonov, Maksym, Oleksandr Maximyuk, Alexey Rayevsky, Vasyl Hurmach, Olena Iegorova, Vasyl Naumchyk, Elijah Bulgakov, et al. "4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors." International Journal of Molecular Sciences 25, no. 7 (March 22, 2024): 3584. http://dx.doi.org/10.3390/ijms25073584.

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Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1–ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.

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Cegielski, Victoria, Rohan Chakrabarty, Shinghua Ding, Michael J. Wacker, Paula Monaghan-Nichols, and Xiang-Ping Chu. "Acid-Sensing Ion Channels in Glial Cells." Membranes 12, no. 2 (January 20, 2022): 119. http://dx.doi.org/10.3390/membranes12020119.

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Acid-sensing ion channels (ASICs) are proton-gated cation channels and key mediators of responses to neuronal injury. ASICs exhibit unique patterns of distribution in the brain, with high expression in neurons and low expression in glial cells. While there has been a lot of focus on ASIC in neurons, less is known about the roles of ASICs in glial cells. ASIC1a is expressed in astrocytes and might contribute to synaptic transmission and long-term potentiation. In oligodendrocytes, constitutive activation of ASIC1a participates in demyelinating diseases. ASIC1a, ASIC2a, and ASIC3, found in microglial cells, could mediate the inflammatory response. Under pathological conditions, ASIC dysregulation in glial cells can contribute to disease states. For example, activation of astrocytic ASIC1a may worsen neurodegeneration and glioma staging, activation of microglial ASIC1a and ASIC2a may perpetuate ischemia and inflammation, while oligodendrocytic ASIC1a might be involved in multiple sclerosis. This review concentrates on the unique ASIC components in each of the glial cells and integrates these glial-specific ASICs with their physiological and pathological conditions. Such knowledge provides promising evidence for targeting of ASICs in individual glial cells as a therapeutic strategy for a diverse range of conditions.

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Ruan, Nina, Jacob Tribble, Andrew M. Peterson, Qian Jiang, John Q. Wang, and Xiang-Ping Chu. "Acid-Sensing Ion Channels and Mechanosensation." International Journal of Molecular Sciences 22, no. 9 (May 1, 2021): 4810. http://dx.doi.org/10.3390/ijms22094810.

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Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer’s disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

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Sun, Hua-Wei, Xiang-Ping Chu, Roger P. Simon, Zhi-Gang Xiong, and Tian-Dong Leng. "Inhibition of Acid-Sensing Ion Channels by KB-R7943, a Reverse Na+/Ca2+ Exchanger Inhibitor." Biomolecules 13, no. 3 (March 10, 2023): 507. http://dx.doi.org/10.3390/biom13030507.

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KB-R7943, an isothiourea derivative, is widely used as a pharmacological inhibitor of reverse sodium–calcium exchanger (NCX). It has been shown to have neuroprotective and analgesic effects in animal models; however, the detailed molecular mechanisms remain elusive. In the current study, we investigated whether KB-R7943 modulates acid-sensing ion channels (ASICs), a group of proton-gated cation channels implicated in the pathophysiology of various neurological disorders, using the whole-cell patch clamp techniques. Our data show that KB-R7943 irreversibly inhibits homomeric ASIC1a channels heterologously expressed in Chinese Hamster Ovary (CHO) cells in a use- and concentration-dependent manner. It also reversibly inhibits homomeric ASIC2a and ASIC3 channels in CHO cells. Both the transient and sustained current components of ASIC3 are inhibited. Furthermore, KB-R7943 inhibits ASICs in primary cultured peripheral and central neurons. It inhibits the ASIC-like currents in mouse dorsal root ganglion (DRG) neurons and the ASIC1a-like currents in mouse cortical neurons. The inhibition of the ASIC1a-like current is use-dependent and unrelated to its effect on NCX since neither of the other two well-characterized NCX inhibitors, including SEA0400 and SN-6, shows an effect on ASIC. Our data also suggest that the isothiourea group, which is lacking in other structurally related analogs that do not affect ASIC1a-like current, may serve as a critical functional group. In summary, we characterize KB-R7943 as a new ASIC inhibitor. It provides a novel pharmacological tool for the investigation of the functions of ASICs and could serve as a lead compound for developing small-molecule drugs for treating ASIC-related disorders.

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Evlanenkov, Konstantin K., Maxim V. Nikolaev, Natalia N. Potapieva, Konstantin V. Bolshakov, and Denis B. Tikhonov. "Probing the Proton-Gated ASIC Channels Using Tetraalkylammonium Ions." Biomolecules 13, no. 11 (November 8, 2023): 1631. http://dx.doi.org/10.3390/biom13111631.

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The action of tetraalkylammonium ions, from tetrametylammonium (TMA) to tetrapentylammonium (TPtA), on the recombinant and native acid-sensing ion channels (ASICs) was studied using the patch-clamp approach. The responses of ASIC1a, ASIC2a, and native heteromeric ASICs were inhibited by TPtA. The peak currents through ASIC3 were unaffected, whereas the steady-state currents were significantly potentiated. This effect was characterized by an EC50 value of 1.22 ± 0.12 mM and a maximal effect of 3.2 ± 0.5. The effects of TPtA were voltage-independent but significantly decreased under conditions of strong acidification, which caused saturation of ASIC responses. Molecular modeling predicted TPtA binding in the acidic pocket of closed ASICs. Bound TPtA can prevent acidic pocket collapse through a process involving ASIC activation and desensitization. Tetraethylammonium (TEA) inhibited ASIC1a and native ASICs. The effect was independent of the activating pH but decreased with depolarization, suggesting a pore-blocking mechanism.

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Johnson, Martha B., KunLin Jin, Manabu Minami, Dexi Chen, and Roger P. Simon. "Global Ischemia Induces Expression of Acid-Sensing Ion Channel 2a in Rat Brain." Journal of Cerebral Blood Flow & Metabolism 21, no. 6 (June 2001): 734–40. http://dx.doi.org/10.1097/00004647-200106000-00011.

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Acid-sensing ion channels (ASICs) are ligand-gated cation channels that respond to acidic stimuli. They are expressed throughout the mammalian nervous system. In the peripheral nervous system, ASICs act as nociceptors, responding to the tissue acidosis that accompanies ischemic and inflammatory conditions. The function of ASICs in the central nervous system is not known. In this article, the authors present evidence that transient global ischemia induces ASIC 2a protein expression in neurons that survive ischemia. Western blot analysis with an anti-ASIC 2a antibody revealed up-regulation of an 80 kD protein in ischemic rat brain. Immunohistochemical analysis showed that ASIC 2a protein expression increased in neurons of the hippocampus and cortex. Klenow fragment-mediated labeling of DNA strand breaks determined that ASIC 2a induction did not occur in cells with detectable DNA damage. The current results suggest a possible role for ASICs in mediating a cellular response to ischemia.

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Cho, Jun-Hyeong, and Candice C. Askwith. "Presynaptic Release Probability Is Increased in Hippocampal Neurons From ASIC1 Knockout Mice." Journal of Neurophysiology 99, no. 2 (February 2008): 426–41. http://dx.doi.org/10.1152/jn.00940.2007.

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Acid-sensing ion channels (ASICs) are H+-gated channels that produce transient cation currents in response to extracellular acid. ASICs are expressed in neurons throughout the brain, and ASIC1 knockout mice show behavioral impairments in learning and memory. The role of ASICs in synaptic transmission, however, is not thoroughly understood. We analyzed the involvement of ASICs in synaptic transmission using microisland cultures of hippocampal neurons from wild-type and ASIC knockout mice. There was no significant difference in single action potential (AP)–evoked excitatory postsynaptic currents (EPSCs) between wild-type and ASIC knockout neurons. However, paired-pulse ratios (PPRs) were reduced and spontaneous miniature EPSCs (mEPSCs) occurred at a higher frequency in ASIC1 knockout neurons compared with wild-type neurons. The progressive block of NMDA receptors by an open channel blocker, MK-801, was also faster in ASIC1 knockout neurons. The amplitude and decay time constant of mEPSCs, as well as the size and refilling of the readily releasable pool, were similar in ASIC1 knockout and wild-type neurons. Finally, the release probability, which was estimated directly as the ratio of AP-evoked to hypertonic sucrose-induced charge transfer, was increased in ASIC1 knockout neurons. Transfection of ASIC1a into ASIC1 knockout neurons increased the PPRs, suggesting that alterations in release probability were not the result of developmental compensation within the ASIC1 knockout mice. Together, these findings demonstrate that neurons from ASIC1 knockout mice have an increased probability of neurotransmitter release and indicate that ASIC1a can affect presynaptic mechanisms of synaptic transmission.

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Sherwood, Thomas W., Erin N. Frey, and Candice C. Askwith. "Structure and activity of the acid-sensing ion channels." American Journal of Physiology-Cell Physiology 303, no. 7 (October 1, 2012): C699—C710. http://dx.doi.org/10.1152/ajpcell.00188.2012.

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The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviors including fear, anxiety, pain, depression, learning, and memory. ASICs have also been implicated in neuronal degeneration accompanying ischemia and multiple sclerosis. As a whole, ASICs represent novel therapeutic targets for several clinically important disorders. An understanding of the correlation between ASIC structure and function will help to elucidate their mechanism of action and identify potential therapeutics that specifically target these ion channels. Despite the seemingly simple nature of proton binding, multiple studies have shown that proton-dependent gating of ASICs is quite complex, leading to activation and desensitization through distinct structural components. This review will focus on the structural aspects of ASIC gating in response to both protons and the newly discovered activators GMQ and MitTx. ASIC modulatory compounds and their action on proton-dependent gating will also be discussed. This review is dedicated to the memory of Dale Benos, who made a substantial contribution to our understanding of ASIC activity.

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Vukicevic, Marija, and Stephan Kellenberger. "Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons." American Journal of Physiology-Cell Physiology 287, no. 3 (September 2004): C682—C690. http://dx.doi.org/10.1152/ajpcell.00127.2004.

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Extracellular acidification has been shown to generate action potentials (APs) in several types of neurons. In this study, we investigated the role of acid-sensing ion channels (ASICs) in acid-induced AP generation in brain neurons. ASICs are neuronal Na+ channels that belong to the epithelial Na+ channel/degenerin family and are transiently activated by a rapid drop in extracellular pH. We compared the pharmacological and biophysical properties of acid-induced AP generation with those of ASIC currents in cultured hippocampal neurons. Our results show that acid-induced AP generation in these neurons is essentially due to ASIC activation. We demonstrate for the first time that the probability of inducing APs correlates with current entry through ASICs. We also show that ASIC activation in combination with other excitatory stimuli can either facilitate AP generation or inhibit AP bursts, depending on the conditions. ASIC-mediated generation and modulation of APs can be induced by extracellular pH changes from 7.4 to slightly <7. Such local extracellular pH values may be reached by pH fluctuations due to normal neuronal activity. Furthermore, in the plasma membrane, ASICs are localized in close proximity to voltage-gated Na+ and K+ channels, providing the conditions necessary for the transduction of local pH changes into electrical signals.

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Liu, X., L. He, B. Dinger, and S. J. Fidone. "Chronic hypoxia-induced acid-sensitive ion channel expression in chemoafferent neurons contributes to chemoreceptor hypersensitivity." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 6 (December 2011): L985—L992. http://dx.doi.org/10.1152/ajplung.00132.2011.

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Previously we demonstrated that chronic hypoxia (CH) induces an inflammatory condition characterized by immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. It is well established that chronic inflammatory pain induces the expression of acid-sensitive ion channels (ASIC) in primary sensory neurons, where they contribute to hyperalgesia and allodynia. The present study examines the effect of CH on ASIC expression in petrosal ganglion (PG), which contains chemoafferent neurons that innervate oxygen-sensitive type I cells in the carotid body. Five isoforms of ASIC transcript were increased ∼1.5–2.5-fold in PG following exposure of rats to 1, 3, or 7 days of hypobaric hypoxia (380 Torr). ASIC transcript was not increased in the sympathetic superior cervical ganglion (SCG). In the PG, CH also increased the expression of channel-interacting PDZ domain protein, a scaffolding protein known to enhance the surface expression and the low pH-induced current density mediated by ASIC3. Western immunoblot analysis showed that CH elevated ASIC3 protein in PG, but not in SCG or the (sensory) nodose ganglion. ASIC3 transcript was likewise elevated in PG neurons cultured in the presence of inflammatory cytokines. Increased ASIC expression was blocked in CH rats concurrently treated with the nonsteroidal anti-inflammatory drug ibuprofen (4 mg·kg−1·day−1). Electrophysiological recording of carotid sinus nerve (CSN) activity in vitro showed that the specific ASIC antagonist A-317567 (100 μM) did not significantly alter hypoxia-evoked activity in normal preparations but blocked ∼50% of the hypoxic response following CH. Likewise, a high concentration of ibuprofen, which is known to block ASIC1a, reduced hypoxia-evoked CSN activity by ∼50% in CH preparations. Our findings indicate that CH induces inflammation-dependent phenotypic adjustments in chemoafferent neurons. Following CH, ASIC are important participants in chemotransmission between type I cells and chemoafferent nerve terminals, and these proton-gated channels appear to enhance chemoreceptor sensitivity.

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Sun, Amber W., Michelle H. Wu, Madhumathi Vijayalingam, Michael J. Wacker, and Xiang-Ping Chu. "The Role of Zinc in Modulating Acid-Sensing Ion Channel Function." Biomolecules 13, no. 2 (January 24, 2023): 229. http://dx.doi.org/10.3390/biom13020229.

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Acid-sensing ion channels (ASICs) are proton-gated, voltage-independent sodium channels widely expressed throughout the central and peripheral nervous systems. They are involved in synaptic plasticity, learning/memory, fear conditioning and pain. Zinc, an important trace metal in the body, contributes to numerous physiological functions, with neurotransmission being of note. Zinc has been implicated in the modulation of ASICs by binding to specific sites on these channels and exerting either stimulatory or inhibitory effects depending on the ASIC subtype. ASICs have been linked to several neurological and psychological disorders, such as Alzheimer’s disease, Parkinson’s disease, ischemic stroke, epilepsy and cocaine addiction. Different ASIC isoforms contribute to the persistence of each of these neurological and psychological disorders. It is critical to understand how various zinc concentrations can modulate specific ASIC subtypes and how zinc regulation of ASICs can contribute to neurological and psychological diseases. This review elucidates zinc’s structural interactions with ASICs and discusses the potential therapeutic implications zinc may have on neurological and psychological diseases through targeting ASICs.

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Gladkikh, Irina N., Anna A. Klimovich, Rimma S. Kalina, Yulia V. Kozhevnikova, Timur A. Khasanov, Dmitry I. Osmakov, Sergey G. Koshelev, et al. "Anxiolytic, Analgesic and Anti-Inflammatory Effects of Peptides Hmg 1b-2 and Hmg 1b-4 from the Sea Anemone Heteractis magnifica." Toxins 15, no. 5 (May 15, 2023): 341. http://dx.doi.org/10.3390/toxins15050341.

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Acid-sensing ion channels (ASICs) have been known as sensors of a local pH change within both physiological and pathological conditions. ASIC-targeting peptide toxins could be potent molecular tools for ASIC-manipulating in vitro, and for pathology treatment in animal test studies. Two sea anemone toxins, native Hmg 1b-2 and recombinant Hmg 1b-4, both related to APETx-like peptides, inhibited the transient current component of human ASIC3-Δ20 expressed in Xenopus laevis oocytes, but only Hmg 1b-2 inhibited the rat ASIC3 transient current. The Hmg 1b-4 action on rASIC3 as a potentiator was confirmed once again. Both peptides are non-toxic molecules for rodents. In open field and elevated plus maze tests, Hmg 1b-2 had more of an excitatory effect and Hmg 1b-4 had more of an anxiolytic effect on mouse behavior. The analgesic activity of peptides was similar and comparable to diclofenac activity in an acid-induced muscle pain model. In models of acute local inflammation induced by λ-carrageenan or complete Freund’s adjuvant, Hmg 1b-4 had more pronounced and statistically significant anti-inflammatory effects than Hmg 1b-2. It exceeded the effect of diclofenac and, at a dose of 0.1 mg/kg, reduced the volume of the paw almost to the initial volume. Our data highlight the importance of a comprehensive study of novel ASIC-targeting ligands, and in particular, peptide toxins, and present the slightly different biological activity of the two similar toxins.

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Jiang, N., K. K. Rau, R. D. Johnson, and B. Y. Cooper. "Proton Sensitivity Ca2+ Permeability and Molecular Basis of Acid-Sensing Ion Channels Expressed in Glabrous and Hairy Skin Afferents." Journal of Neurophysiology 95, no. 4 (April 2006): 2466–78. http://dx.doi.org/10.1152/jn.00861.2005.

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We contrasted the physiology and peripheral targets of subclassified nociceptive and nonnociceptive afferents that express acid-sensing ion channel (ASIC)–like currents. The threshold for current activation was similar in eight distinct cell subclasses regardless of functional modality (pH 6.8). When potency was determined from concentration–response curves, nonnociceptors exhibited currents with significantly greater potency than that of all but one class of nociceptors (pH50 = 6.54 and 6.75 vs. 6.20–6.34). In nonnociceptive cells, acid transduction was also confined to a very narrow range (0.1–0.3 vs. 0.8–1.4 pH units for nociceptors). Simultaneous whole cell recording and ratiometric imaging of three peptidergic nociceptive classes were consistent with the expression of Ca2+-permeable ASICs. Sensitivity to psalmotoxin and flurbiprofen indicated the presence of Ca2+-permeable ASIC1a. Immunocytochemistry on these subclassified populations revealed a differential distribution of five ASIC proteins consistent with Ca2+ permeability and differential kinetics of proton-gated currents (type 5: ASIC1a, 1b, 2a, 2b, 3; type 8a: ASIC1a, 1b, 3; type 8b: ASIC1a, 1b, 2a, 2b, 3). Using DiI tracing, we found that nociceptive classes had discrete peripheral targets. ASIC-expressing types 8a and 9 projected to hairy skin, but only types 8a and 13 projected to glabrous skin. Non-ASIC–expressing types 2 and 4 were present only in hairy skin. We conclude that ASIC-expressing nociceptors differ from ASIC-expressing nonnociceptors mainly by range of proton reactivity. ASIC- as well as non-ASIC–expressing nociceptors have highly distinct cutaneous targets, and only one class was consistent with the existence of a generic C polymodal nociceptor (type 8a).

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Orita, T., M. Uenomachi, K. Shimazoe, and H. Ikeda. "Time and Energy Resolving Time-over-Threshold ASIC for MPPC module in TOF-PET system (ToT-ASIC2)." Journal of Instrumentation 18, no. 09 (September 1, 2023): P09033. http://dx.doi.org/10.1088/1748-0221/18/09/p09033.

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Abstract ToT-ASIC2 is a new custom front-end application specific integrated circuit (ASIC) to readout silicon photomultiplier (SiPM) and multi-pixel photon counter (MPPC) for time-of-flight positron emission tomography (ToF-PET). ToT-ASIC2 is a 64-channel ASIC fabricated using a commercial 0.25 μm CMOS process. Each channel has an input-current buffer that sends signals to the SLOW and FAST paths, which are used for incident radiation energy and timing information, respectively. Time-over-Threshold (ToT) signals from these paths are combined into one ToT signal to be output outside the ASIC. The power consumption is approximately 2.9 mW per channel. This study developed a detection system comprising an MPPC with coupled GAGG pixelated scintillators, a front-end board with ToT-ASIC2 and ToT-DAQ. Consequently, energy and timing measurement experiments were performed using this system to confirm the ToT-ASIC2 energy- and timing-resolving capability. Prototype positron emission tomography experiments with 22Na indicated an energy resolution of 6.7% for 511 keV with the coincidence timing resolution being 215 ps.

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26

Magaki, Ikuo, Moein Khazraee, Luis Vega Gutierrez, and Michael Bedford Taylor. "ASIC clouds." ACM SIGARCH Computer Architecture News 44, no. 3 (October 12, 2016): 178–90. http://dx.doi.org/10.1145/3007787.3001156.

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Nicholson, Craig. "ASIC mind." Nature Reviews Neuroscience 9, no. 1 (January 2008): 6. http://dx.doi.org/10.1038/nrn2302.

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Flynn, M. J., and R. I. Winner. "ASIC microprocessors." ACM SIGMICRO Newsletter 20, no. 3 (August 1989): 237–43. http://dx.doi.org/10.1145/75395.75425.

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Taylor, Michael Bedford, Luis Vega, Moein Khazraee, Ikuo Magaki, Scott Davidson, and Dustin Richmond. "ASIC clouds." Communications of the ACM 63, no. 7 (June 18, 2020): 103–9. http://dx.doi.org/10.1145/3399734.

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Zhang, Ping, and Cecilia M. Canessa. "Single Channel Properties of Rat Acid–sensitive Ion Channel-1α, -2a, and -3 Expressed in Xenopus Oocytes." Journal of General Physiology 120, no. 4 (September 16, 2002): 553–66. http://dx.doi.org/10.1085/jgp.20028574.

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The mammalian nervous system expresses proton-gated ion channels known as acid-sensing ion channels (ASICs). Depending on their location and specialization some neurons express more than one type of ASIC where they may form homo- or heteromeric channels. Macroscopic characteristics of the ASIC currents have been described, but little is known at the single channel level. Here, we have examined the properties of unitary currents of homomeric rat ASIC1α, ASIC2a, and ASIC3 expressed in Xenopus oocytes with the patch clamp technique. We describe and characterize properties unique to each of these channels that can be used to distinguish the various types of ASIC channels expressed in mammalian neurons. The amplitudes of the unitary currents in symmetrical Na+ are similar for the three types of channels (23–18 pS) and are not voltage dependent. However, ASIC1α exhibits three subconductance states, ASIC2a exhibits only one, and ASIC3 none. The kinetics of the three types of channels are different: ASIC1α and ASIC2a shift between modes of activity, each mode has different open probability and kinetics. In contrast, the kinetics of ASIC3 are uniform throughout the burst of activity. ASIC1α, ASIC2a, and ASIC3 are activated by external protons with apparent pH50 of 5.9, 5.0, and 5.4, respectively. Desensitization in the continual presence of protons is fast and complete in ASIC1α and ASIC3 (2.0 and 4.5 s−1, respectively) but slow and only partial in ASIC2a (0.045 s−1). The response to external Ca2+ also differs: μM concentrations of extracellular Ca2+ are necessary for proton gating of ASIC3 (EC50 = 0.28 μM), whereas ASIC1α and ASIC2a do not require Ca2+. In addition, Ca2+ inhibits ASIC1α (KD = 9.2 ± 2 mM) by several mechanisms: decrease in the amplitude of unitary currents, shortening of the burst of activity, and decrease in the number of activated channels. Contrary to previous reports, our results indicate that the Ca2+ permeability of ASIC1α is very small.

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Verkest, Clément, Miguel Salinas, Sylvie Diochot, Emmanuel Deval, Eric Lingueglia, and Anne Baron. "Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects." Toxins 14, no. 10 (October 17, 2022): 709. http://dx.doi.org/10.3390/toxins14100709.

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Acid-sensing ion channels (ASICs) are voltage-independent H+-gated cation channels largely expressed in the nervous system of rodents and humans. At least six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) associate into homotrimers or heterotrimers to form functional channels with highly pH-dependent gating properties. This review provides an update on the pharmacological profiles of animal peptide toxins targeting ASICs, including PcTx1 from tarantula and related spider toxins, APETx2 and APETx-like peptides from sea anemone, and mambalgin from snake, as well as the dimeric protein snake toxin MitTx that have all been instrumental to understanding the structure and the pH-dependent gating of rodent and human cloned ASICs and to study the physiological and pathological roles of native ASICs in vitro and in vivo. ASICs are expressed all along the pain pathways and the pharmacological data clearly support a role for these channels in pain. ASIC-targeting peptide toxins interfere with ASIC gating by complex and pH-dependent mechanisms sometimes leading to opposite effects. However, these dual pH-dependent effects of ASIC-inhibiting toxins (PcTx1, mambalgin and APETx2) are fully compatible with, and even support, their analgesic effects in vivo, both in the central and the peripheral nervous system, as well as potential effects in humans.

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Ievglevskyi, O., D. Isaev, O. Netsyk, A. Romanov, M. Fedoriuk, O. Maximyuk, E. Isaeva, N. Akaike, and O. Krishtal. "Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1700 (August 5, 2016): 20150431. http://dx.doi.org/10.1098/rstb.2015.0431.

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Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca 2+ -permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg 2+ model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo . Our results reveal a significant novel role for ASICs. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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Patterson, EB, PG Holmes, and D. Morley. "Microprocessor/ASIC to total ASIC design for cycloconverter drives." Microprocessors and Microsystems 14, no. 4 (May 1990): 219–26. http://dx.doi.org/10.1016/0141-9331(90)90081-6.

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Grifoni, Samira C., Susan E. McKey, and Heather A. Drummond. "Hsc70 regulates cell surface ASIC2 expression and vascular smooth muscle cell migration." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 5 (May 2008): H2022—H2030. http://dx.doi.org/10.1152/ajpheart.01271.2007.

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Recent studies suggest members of the degenerin (DEG)/epithelial Na+channel (ENaC)/acid-sensing ion channel (ASIC) protein family play an important role in vascular smooth muscle cell (VSMC) migration. In a previous investigation, we found suppression of a certain DEG/ENaC/ASIC member, ASIC2, increased VSMC chemotactic migration, raising the possibility that ASIC2 may play an inhibitory role. Because ASIC2 protein was retained in the cytoplasm, we reasoned increasing surface expression of ASIC2 might unmask the inhibitory role of ASIC2 in VSMC migration so we could test the hypothesis that ASIC2 inhibits VSMC migration. Therefore, we used the chemical chaperone glycerol to enhance ASIC2 expression. Glycerol 1) increased cytoplasm ASIC2 expression, 2) permitted detection of ASIC2 at the cell surface, and 3) inhibited platelet-derived growth factor (PDGF)-bb mediated VSMC migration. Furthermore, ASIC2 silencing completely abolished the inhibitory effect of glycerol on migration, suggesting upregulation of ASIC2 is responsible for glycerol-induced inhibition of VSMC migration. Because other investigators have shown that glycerol regulates ENaC/ASIC via interactions with a certain heat shock protein, heat shock protein 70 (Hsc70), we wanted to determine the importance of Hsc70 on ASIC2 expression in VSMCs. We found that Hsc70 silencing increases ASIC2 cell surface expression and inhibits VSMC migration, which is abolished by cosilencing ASIC2. These data demonstrate that Hsc70 inhibits ASIC2 expression, and, when the inhibitory effect of Hsc70 is removed, ASIC2 expression increases, resulting in reduced VSMC migration. Because VSMC migration contributes to vasculogenesis and remodeling following vascular injury, our findings raise the possibility that ASIC2-Hsc70 interactions may play a role in these processes.

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Martin, Douglas, Samuel Beilin, Brett Hamilton, Darin York, Philip Baker, and Wai-Yat Leung. "Application of Advanced Back-Side Optical Techniques in ASICs." Microscopy Today 21, no. 3 (May 2013): 30–35. http://dx.doi.org/10.1017/s1551929513000540.

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Failure analysis is important in determining root cause for appropriate corrective action. In order to perform failure analysis of microelectronic application-specific integrated circuits (ASICs) delidding the device is often required. However, determining root cause from the front side is not always possible due to shadowing effects caused by the ASIC metal interconnects. Therefore, back-side polishing is used to reveal an unobstructed view of the ASIC silicon transistors. This paper details how back-side polishing in conjunction with laser-scanned imaging (LSI), laser voltage imaging (LVI), laser voltage probing (LVP), photon emission microscopy (PEM), and laser-assisted device alterations (LADA) were used to uncover the root cause of failure of two ASICs.

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FIJALKOWSKI, BOGDAN T., and JAN W. KROSNICKI. "CONCEPTS OF ELECTRONICALLY-CONTROLLED ELECTROMECHANICAL/MECHANOELECTRICAL STEER-, AUTODRIVE- AND AUTOABSORBABLE WHEELS FOR ENVIRONMENTALLY-FRIENDLY TRI-MODE SUPERCARS." Journal of Circuits, Systems and Computers 04, no. 04 (December 1994): 501–16. http://dx.doi.org/10.1142/s0218126694000296.

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Concepts of the electronically-controlled electromechanical/mechanoelectrical Steer-, Autodrive- and Autoabsorbable Wheels (SA2W) with their brushless Alternating Current-to-Alternating Current (AC-AC), Alternating Current-to-Direct Current-Alternating Current (AC-DC-AC) and/or Direct Current-to-Alternating Current (DC-AC)/Alternating Current-to-Direct Current (AC-DC) macroelectronic converter commutator (macro-commutator) wheel-hub motors/generators with the Application Specific Integrated Matrixer (ASIM) macroelectronic converter commutators (ASIM macrocommutators) and Application Specific Integrated Circuit (ASIC) microelectronic Neuro-Fuzzy (NF) computer (processor) controllers (ASIC NF microcontrollers) for environmentally-friendly tri-mode supercars (advanced ultralight hybrids) have been conceived by the first author and designed by both authors with the Cracow University of Technology’s Automotive Mechatronics Research and Development (R&D) Team. These electromechanical/mechanoelectrical wheel-hub motors/generators, respectively, for instance, can be composed of the outer rotor with the Interior Permanent Magnet (IPM) poles and the inner stator that has the three-phase armature winding. The macroelectronic converter commutator establishes the AC-AC cycloconverter, AC-DC rectifier-DC-AC inverter and/or DC-AC inverter/AC-DC rectifier ASIM macrocommutator. The microelectronic NF computer (processor) controller establishes the ASIC microcomputer-based NF microcontroller. By adopting continuous semiconductor bipolar electrical valves in the high-power ASIM, it has been able to increase the commutation (switching) frequency and reduce harmonic losses of the electromechanical/mechanoelectrical wheel-hub motors/generators, respectively.

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Holmes, Jim, A. Matthew Francis, Ian Getreu, and Michael Glover. "A Unified ASIC and LTCC Module Design Kit for High-Temperature High-Density Circuits." Additional Conferences (Device Packaging, HiTEC, HiTEN, and CICMT) 2016, CICMT (May 1, 2016): 000169–72. http://dx.doi.org/10.4071/2016cicmt-wp43.

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Abstract State of the art high temperature ASIC design requires the complement of high temperature modules and circuit boards. Certain LTCC tape systems have coefficients of thermal expansion that are well matched to advanced high temperature semiconductors such as SiC, making them an attractive option for low to mid-volume high temperature products. A computer aided process design kit that supports unified design of high temperature SiC ASICs and the corresponding LTCC module is presented herein. The CAD tools used in the design kit are open source and include basic features such as schematic capture layout drafting, design rule checking, and schematic to layout equivalency checking. In addition, advanced features are included such as automatic routing, automatic pad frame generation, and parasitic extraction for high-fidelity simulation. The kit also allows for the generation of a 3D mock-up rendering of the ASIC and LTCC co-design. Most importantly, pattern file generation for ASIC and LTCC manufacturing data formats is supported. Revision control is also easily accomplished, making collaboration within large design teams tractable. A 12-Volt high-temperature amplifier design using a SiC ASIC process and a compatible LTCC process is presented as a case study.

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de Geronimo, Gianluigi, George Iakovidis, Sorin Martoiu, and Venetios Polychronakos. "The VMM3a ASIC." IEEE Transactions on Nuclear Science 69, no. 4 (April 2022): 976–85. http://dx.doi.org/10.1109/tns.2022.3155818.

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Bray, Natasha. "ASIC inhibits addiction." Nature Reviews Neuroscience 15, no. 8 (July 9, 2014): 496. http://dx.doi.org/10.1038/nrn3789.

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López, Juan Carlos. "ASIC-nal integrator." Nature Reviews Neuroscience 3, no. 10 (October 2002): 763. http://dx.doi.org/10.1038/nrn950.

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Poikela, T., R. Ballabriga, J. Buytaert, X. Llopart, W. Wong, M. Campbell, K. Wyllie, et al. "The VeloPix ASIC." Journal of Instrumentation 12, no. 01 (January 24, 2017): C01070. http://dx.doi.org/10.1088/1748-0221/12/01/c01070.

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Bailey, A., T. Lada, and J. Preston. "Collateral ASIC test." IEEE Design & Test of Computers 14, no. 1 (1997): 55–63. http://dx.doi.org/10.1109/54.573368.

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Levitt, M. E. "ASIC testing upgraded." IEEE Spectrum 29, no. 5 (May 1992): 26–29. http://dx.doi.org/10.1109/6.135405.

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Lynagh, Timothy, Yana Mikhaleva, Janne M. Colding, Joel C. Glover, and Stephan A. Pless. "Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes." Proceedings of the National Academy of Sciences 115, no. 33 (July 30, 2018): 8430–35. http://dx.doi.org/10.1073/pnas.1806614115.

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Acid-sensing ion channels (ASICs) are proton-gated ion channels broadly expressed in the vertebrate nervous system, converting decreased extracellular pH into excitatory sodium current. ASICs were previously thought to be a vertebrate-specific branch of the DEG/ENaC family, a broadly conserved but functionally diverse family of channels. Here, we provide phylogenetic and experimental evidence that ASICs are conserved throughout deuterostome animals, showing that ASICs evolved over 600 million years ago. We also provide evidence of ASIC expression in the central nervous system of the tunicate, Oikopleura dioica. Furthermore, by comparing broadly related ASICs, we identify key molecular determinants of proton sensitivity and establish that proton sensitivity of the ASIC4 isoform was lost in the mammalian lineage. Taken together, these results suggest that contributions of ASICs to neuronal function may also be conserved broadly in numerous animal phyla.

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Springauf, Andreas, Pia Bresenitz, and Stefan Gründer. "The Interaction between Two Extracellular Linker Regions Controls Sustained Opening of Acid-sensing Ion Channel 1." Journal of Biological Chemistry 286, no. 27 (May 16, 2011): 24374–84. http://dx.doi.org/10.1074/jbc.m111.230797.

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Activation of acid-sensing ion channels (ASICs) contributes to neuronal death during stroke, to axonal degeneration during neuroinflammation, and to pain during inflammation. Although understanding ASIC gating may help to modulate ASIC activity during these pathologic situations, at present it is poorly understood. The ligand, H+, probably binds to several sites, among them amino acids within the large extracellular domain. The extracellular domain is linked to the two transmembrane domains by the wrist region that is connected to two anti-parallel β-strands, β1 and β12. Thus, the wrist region together with those β-strands may have a crucial role in transmitting ligand binding to pore opening and closing. Here we show that amino acids in the β1-β2 linker determine constitutive opening of ASIC1b from shark. The most crucial residue within the β1-β2 linker (Asp110), when mutated from aspartate to cysteine, can be altered by cysteine-modifying reagents much more readily when channels are closed than when they are desensitized. Finally, engineering of a cysteine at position 110 and at an adjacent position in the β11-β12 linker leads to spontaneous formation of a disulfide bond that traps the channel in the desensitized conformation. Collectively, our results suggest that the β1-β2 and β11-β12 linkers are dynamic during gating and tightly appose to each other during desensitization gating. Hindrance of this tight apposition leads to reopening of the channel. It follows that the β1-β2 and β11-β12 linkers modulate gating movements of ASIC1 and may thus be drug targets to modulate ASIC activity.

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Li, Ming-Hua, Selina Qiuying Liu, Koichi Inoue, Jinquan Lan, Roger P. Simon, and Zhi-Gang Xiong. "Acid-sensing ion channels in mouse olfactory bulb M/T neurons." Journal of General Physiology 143, no. 6 (May 12, 2014): 719–31. http://dx.doi.org/10.1085/jgp.201310990.

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The olfactory bulb contains the first synaptic relay in the olfactory pathway, the sensory system in which odorants are detected enabling these chemical stimuli to be transformed into electrical signals and, ultimately, the perception of odor. Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are widely expressed in neurons of the central nervous system. However, no direct electrophysiological and pharmacological characterizations of ASICs in olfactory bulb neurons have been described. Using a combination of whole-cell patch-clamp recordings and biochemical and molecular biological analyses, we demonstrated that functional ASICs exist in mouse olfactory bulb mitral/tufted (M/T) neurons and mainly consist of homomeric ASIC1a and heteromeric ASIC1a/2a channels. ASIC activation depolarized cultured M/T neurons and increased their intracellular calcium concentration. Thus, ASIC activation may play an important role in normal olfactory function.

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Zhang, Ying, Xuemei Xie, Pourya Naderi Yeganeh, Dian-Jang Lee, David Valle-Garcia, Karla F. Meza-Sosa, Caroline Junqueira, et al. "Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown." Proceedings of the National Academy of Sciences 118, no. 9 (February 24, 2021): e2022830118. http://dx.doi.org/10.1073/pnas.2022830118.

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New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM+ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2+ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti–PD-1 checkpoint inhibition.

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Lenta, Francesca, Daniela Calvo, Fabio Cossio, Giovanni Mazza, Richard Wheadon, Jürgen Becker, Kai-Thomas Brinkmann, et al. "Characterization of the radiation tolerant ToASt ASIC for the readout of the PANDA MVD strip detector." Journal of Instrumentation 19, no. 04 (April 1, 2024): C04047. http://dx.doi.org/10.1088/1748-0221/19/04/c04047.

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Abstract The ToASt ASIC is a 64-channel integrated circuit developed for the readout of the Silicon strip detector project designed to be placed in the Micro-Vertex Detector of the PANDA experiment. ToASt is implemented in a commercial 110 nm CMOS technology and can provide information on the position, time, and deposited energy of the particle passing through the detector. Its time resolution is given by its 160 MHz master clock. The ASIC has been developed in the framework of the European FAIRnet project. The chip has been characterized electrically both standalone and coupled with sensors, with focus on its noise performances. It has also been tested for radiation tolerance, both in terms of Total Ionizing Dose and Single Event Upset. In particular, this work aims to guarantee that the studied ASICs can sustain the levels of ionizing radiation expected in the PANDA experiment and to study the noise characteristics for the two polarities of the ASIC.

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Katsura, Koyo, Hideo Maejima, Shinichi Kojima, and Kazuo Minorikawa. "Development of ASIC for Graphic Systems." IEEJ Transactions on Electronics, Information and Systems 108, no. 6 (1988): 422–27. http://dx.doi.org/10.1541/ieejeiss1987.108.6_422.

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Montalbetti, Nicolas, James G. Rooney, Allison L. Marciszyn, and Marcelo D. Carattino. "ASIC3 fine-tunes bladder sensory signaling." American Journal of Physiology-Renal Physiology 315, no. 4 (October 1, 2018): F870—F879. http://dx.doi.org/10.1152/ajprenal.00630.2017.

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Acid-sensing ion channels (ASICs) are trimeric proton-activated, cation-selective neuronal channels that are considered to play important roles in mechanosensation and nociception. Here we investigated the role of ASIC3, a subunit primarily expressed in sensory neurons, in bladder sensory signaling and function. We found that extracellular acidification evokes a transient increase in current, consistent with the kinetics of activation and desensitization of ASICs, in ~25% of the bladder sensory neurons harvested from both wild-type (WT) and ASIC3 knockout (KO) mice. The absence of ASIC3 increased the magnitude of the peak evoked by extracellular acidification and reduced the rate of decay of the ASIC-like currents. These findings suggest that ASICs are assembled as heteromers and that the absence of ASIC3 alters the composition of these channels in bladder sensory neurons. Consistent with the notion that ASIC3 serves as a proton sensor, 59% of the bladder sensory neurons harvested from WT, but none from ASIC3 KO mice, fired action potentials in response to extracellular acidification. Studies of bladder function revealed that ASIC3 deletion reduces voiding volume and the pressure required to trigger micturition. In summary, our findings indicate that ASIC3 plays a role in the control of bladder function by modulating the response of afferents to filling.

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Journal articles on the topic 'ASIC'

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