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Acid-sensing ion channels

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https://www.readbyqxmd.com/read/28528673/acid-sensing-ion-channel-pharmacology-past-present-and-future-%C3%A2
#1
Lachlan D Rash
pH is one of the most strictly controlled parameters in mammalian physiology. An extracellular pH of ~7.4 is crucial for normal physiological processes, and perturbations to this have profound effects on cell function. Acidic microenvironments occur in many physiological and pathological conditions, including inflammation, bone remodeling, ischemia, trauma, and intense synaptic activity. Cells exposed to these conditions respond in different ways, from tumor cells that thrive to neurons that are either suppressed or hyperactivated, often fatally...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28522561/immediate-and-delayed-potentiating-effects-of-tumor-necrosis-factor-alpha-on-trpv1-sensitivity-of-rat-vagal-pulmonary-sensory-neurons
#2
Chun-Chun Hsu, You Shuei Lin, Ruei-Lung Lin, Lu-Yuan Lee
We studied acute effects of tumor necrosis factor-alpha (TNFα) on the sensitivity of isolated rat vagal pulmonary sensory neurons. Our results showed: 1) A brief pretreatment with a low dose of TNFα (1.44 nM, 9 min) enhanced the sensitivity of transient receptor potential vanilloid type 1 (TRPV1) receptors in these neurons in two distinct phases: the inward current evoked by capsaicin was amplified (∆=247%) immediately following the TNFα pretreatment, which gradually declined toward control and then increased again reaching another peak (∆=384%) after 60-90 min...
May 18, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28518134/asic1-and-asic3-contribute-to-acidity-induced-emt-of-pancreatic-cancer-through-activating-ca-2-rhoa-pathway
#3
Shuai Zhu, Hai-Yun Zhou, Shi-Chang Deng, Shi-Jiang Deng, Chi He, Xiang Li, Jing-Yuan Chen, Yan Jin, Zhuang-Li Hu, Fang Wang, Chun-You Wang, Gang Zhao
Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca(2+) concentration ([Ca(2+)]i)...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28516122/two-electrode-voltage-clamp-recordings-in-xenopus-laevis-oocytes-reconstitution-of-abscisic-acid-activation-of-slac1-anion-channel-via-pyl9-aba-receptor
#4
Cun Wang, Jingbo Zhang, Julian I Schroeder
Two-Electrode Voltage-Clamp (TEVC) recording in Xenopus laevis oocytes provides a powerful method to investigate the functions and regulation of ion channel proteins. This approach provides a well-known tool to characterize ion channels or transporters expressed in Xenopus laevis oocytes. The plasma membrane of the oocyte is impaled by two microelectrodes, one for voltage sensing and the other one for current injection. Here we list a protocol that allows robust reconstitution of multi-component signaling pathways...
January 20, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28515089/the-n-terminus-regulates-voltage-dependent-gating-of-calhm-ion-channels
#5
Jessica E Tanis, Zhongming Ma, J Kevin Foskett
CALHM1 and its C. elegans (ce) homolog, CLHM-1, belong to a new family of physiologically important ion channels that are regulated by voltage and extracellular Ca(2+) (Ca(2+)o), but lack a canonical voltage-sensing domain. Consequently, the intrinsic voltage-dependent gating mechanisms for CALHM channels are unknown. Here, we performed voltage-clamp experiments on ceCLHM-1 chimeric, deletion, insertion and point mutants to assess the role of the N-terminus (NT) in CALHM channel gating. Analyses of chimeric channels in which the ceCLHM-1 and human (h)CALHM1 N-termini were interchanged showed that the hCALHM1 NT destabilized channel-closed states, whereas the ceCLHM-1 NT had a stabilizing effect...
May 17, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28498103/a-selectivity-filter-at-the-intracellular-end-of-the-acid-sensing-ion-channel-pore
#6
Timothy Lynagh, Emelie Flood, Céline Boiteux, Matthias Wulf, Vitaly V Komnatnyy, Janne M Colding, Toby W Allen, Stephan A Pless
Increased extracellular proton concentrations during neurotransmission are converted to excitatory sodium influx by acid-sensing ion channels (ASICs). 10-fold sodium/potassium selectivity in ASICs has long been attributed to a central constriction in the channel pore, but experimental verification is lacking due to the sensitivity of this structure to conventional manipulations. Here, we explored the basis for ion selectivity by incorporating unnatural amino acids into the channel, engineering channel stoichiometry and performing free energy simulations...
May 12, 2017: ELife
https://www.readbyqxmd.com/read/28462470/evidence-that-activation-of-asic1a-by-acidosis-increases-osteoclast-migration-and-adhesion-by-modulating-integrin-pyk2-src-signaling-pathway
#7
X Li, J-X Ye, M-H Xu, M-D Zhao, F-L Yuan
Activated acid-sensing ion channel 1a (ASIC1a) is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. These results indicated that ASIC1a activation by extracellular acid may cause osteoclast migration and adhesion through Ca(2+)-dependent integrin/Pyk2/Src signaling pathway. INTRODUCTION: Osteoclast adhesion and migration are responsible for osteoporotic bone loss. Acidic conditions promote osteoclastogenesis. ASIC1a in osteoclasts is associated with acid-induced osteoclastogenesis through modulating transcription factor NFATc1 activation...
May 1, 2017: Osteoporosis International
https://www.readbyqxmd.com/read/28461138/distribution-of-asic4-transcripts-in-the-adult-wild-type-mouse-brain
#8
M Hoshikawa, A Kato, H Hojo, Y Shibata, N Kumamoto, M Watanabe, S Ugawa
Acid-sensing ion channel 4 (ASIC4) belongs to the ASIC gene family of neuronal proton-gated cation channels, and is the least understood subtype among the members. Previous studies of ASIC4 expression in the mammalian central nervous system have shown that ASIC4 is abundantly expressed in the spinal cord and in various brain regions, such as the cerebral cortex, the hippocampus, and the cerebellum. However, the detailed distribution of ASIC4 transcripts in mammalian brains still remains to be elucidated. In the present study, radioactive in situ hybridization histochemistry with an ASIC4-specific cRNA probe was performed on wild-type mouse brains, followed by X-gal staining experiments with Asic4-lacZ reporter mice Asic4(tm1a(KOMP)Mbp)...
April 29, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28457973/acid-sensing-ion-channel-asic-structure-and-function-insights-from-spider-snake-and-sea-anemone-venoms
#9
REVIEW
Ben Cristofori-Armstrong, Lachlan D Rash
Acid-sensing ion channels (ASICs) are proton-activated cation channels that are expressed in a variety of neuronal and non-neuronal tissues. As proton-gated channels, they have been implicated in many pathophysiological conditions where pH is perturbed. Venom derived compounds represent the most potent and selective modulators of ASICs described to date, and thus have been invaluable as pharmacological tools to study ASIC structure, function, and biological roles. There are now ten ASIC modulators described from animal venoms, with those from snakes and spiders favouring ASIC1, while the sea anemones preferentially target ASIC3...
April 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28430192/a-monodisperse-transmembrane-%C3%AE-helical-peptide-barrel
#10
Kozhinjampara R Mahendran, Ai Niitsu, Lingbing Kong, Andrew R Thomson, Richard B Sessions, Derek N Woolfson, Hagan Bayley
The fabrication of monodisperse transmembrane barrels formed from short synthetic peptides has not been demonstrated previously. This is in part because of the complexity of the interactions between peptides and lipids within the hydrophobic environment of a membrane. Here we report the formation of a transmembrane pore through the self-assembly of 35 amino acid α-helical peptides. The design of the peptides is based on the C-terminal D4 domain of the Escherichia coli polysaccharide transporter Wza. By using single-channel current recording, we define discrete assembly intermediates and show that the pore is most probably a helix barrel that contains eight D4 peptides arranged in parallel...
May 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28428534/expression-of-acid-sensing-ion-channels-in-renal-tubular-epithelial-cells-and-their-role-in-patients-with-henoch-sch%C3%A3-nlein-purpura-nephritis
#11
Li-Ping Yuan, Yan Bo, Zhang Qin, Hua Ran, Wang Li, Yu-Fei Li, Gui Ming
BACKGROUND Acid-sensing ion channels (ASICs) are ligand-gated cation channels activated by extracellular protons. However, the role of ASICs in kidney diseases remains uncertain. This study investigated ASICs expression in kidney tissues and their role in the development of Henoch-Schönlein purpura nephritis (HSPN). MATERIAL AND METHODS The expression of ASIC subunits was examined by immunochemical techniques in the kidney tissue from HSPN patients. Acid-induced ASICs expression in cultured renal tubular epithelial cells was determined by quantitative RT-PCR analysis...
April 21, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28402882/gating-charge-calculations-by-computational-electrophysiology-simulations
#12
Jan-Philipp Machtens, Rodolfo Briones, Claudia Alleva, Bert L de Groot, Christoph Fahlke
Electrical cell signaling requires adjustment of ion channel, receptor, or transporter function in response to changes in membrane potential. For the majority of such membrane proteins, the molecular details of voltage sensing remain insufficiently understood. Here, we present a molecular dynamics simulation-based method to determine the underlying charge movement across the membrane-the gating charge-by measuring electrical capacitor properties of membrane-embedded proteins. We illustrate the approach by calculating the charge transfer upon membrane insertion of the HIV gp41 fusion peptide, and validate the method on two prototypical voltage-dependent proteins, the Kv1...
April 11, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28396446/identification-of-a-cono-rfamide-from-the-venom-of-conus-textile-that-targets-asic3-and-enhances-muscle-pain
#13
Catharina Reimers, Cheng-Han Lee, Hubert Kalbacher, Yuemin Tian, Chih-Hsien Hung, Axel Schmidt, Lea Prokop, Silke Kauferstein, Dietrich Mebs, Chih-Cheng Chen, Stefan Gründer
Acid-sensing ion channels (ASICs) are proton-gated Na(+) channels that are expressed throughout the nervous system. ASICs have been implicated in several neuronal disorders, like ischemic stroke, neuronal inflammation, and pathological pain. Several toxins from venomous animals have been identified that target ASICs with high specificity and potency. These toxins are extremely useful in providing protein pharmacophores and to characterize function and structure of ASICs. Marine cone snails contain a high diversity of toxins in their venom such as conotoxins, which are short polypeptides stabilized by disulfide bonds, and conopeptides, which have no or only one disulfide bond...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28384246/proton-and-non-proton-activation-of-asic-channels
#14
Ivan Gautschi, Miguel Xavier van Bemmelen, Laurent Schild
The Acid-Sensing Ion Channels (ASIC) exhibit a fast desensitizing current when activated by pH values below 7.0. By contrast, non-proton ligands are able to trigger sustained ASIC currents at physiological pHs. To analyze the functional basis of the ASIC desensitizing and sustained currents, we have used ASIC1a and ASIC2a mutants with a cysteine in the pore vestibule for covalent binding of different sulfhydryl reagents. We found that ASIC1a and ASIC2a exhibit two distinct currents, a proton-induced desensitizing current and a sustained current triggered by sulfhydryl reagents...
2017: PloS One
https://www.readbyqxmd.com/read/28362083/ultrasensitive-and-selective-sensing-of-selenium-using-nitrogen-rich-ligand-interfaced-carbon-quantum-dots
#15
Pooja Devi, Anupma Thakur, Shweta Chopra, Navneet Kaur, Praveen Kumar, Narinder Singh, Mahesh Kumar, Sonnada Math Shivaprasad, Manoj K Nayak
This work reports a label-free, ultrasensitive, and selective optical chemosensory system for trace level detection of selenite (SeO3(2-)), the most toxic form of selenium, in water. The probe, i.e., carbon quantum dots (CQDs), is designed from citric acid by means of pyrolysis and is interfaced with a newly synthesized nitrogen-rich ligand to create a selective sensor platform (functionalized CQDs, fCQDs) for selenite in a water matrix. Spectral (NMR, UV-vis, photoluminescence, Raman, and Fourier transform infrared analyses) and structural (high-resolution transmission electron microscopy) characteristics of the designed new probe were investigated...
April 6, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28327374/discovery-and-molecular-interaction-studies-of-a-highly-stable-tarantula-peptide-modulator-of-acid-sensing-ion-channel-1
#16
REVIEW
Sing Yan Er, Ben Cristofori-Armstrong, Pierre Escoubas, Lachlan D Rash
Acute pharmacological inhibition of acid-sensing ion channel 1a (ASIC1a) is efficacious in rodent models in alleviating symptoms of neurological diseases such as stroke and multiple sclerosis. Thus, ASIC1a is a promising therapeutic target and selective ligands that modulate it are invaluable research tools and potential therapeutic leads. Spider venoms have provided an abundance of voltage-gated ion channel modulators, however, only one ASIC modulator (PcTx1) has so far been isolated from this source. Here we report the discovery, characterization, and chemical stability of a second spider venom peptide that potently modulates ASIC1a and ASIC1b, and investigate the molecular basis for its subtype selectivity...
March 18, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28321113/acid-sensing-ion-channel-1a-in-the-amygdala-is-involved-in-pain-and-anxiety-related-behaviours-associated-with-arthritis
#17
Youssef Aissouni, Abderrahim El Guerrab, Al Mahdy Hamieh, Jérémy Ferrier, Maryse Chalus, Diane Lemaire, Stéphanie Grégoire, Monique Etienne, Alain Eschalier, Denis Ardid, Eric Lingueglia, Fabien Marchand
Chronic pain is associated with anxiety and depression episodes. The amygdala plays a key role in the relationship between emotional responses and chronic pain. Here, we investigated the role of Acid-Sensing Ion Channels 1a within the basolateral amygdala (BLA), in pain and associated anxiety in a rat model of monoarthritis (MoAr). Administration within the BLA of PcTx1 or mambalgin-1, two specific inhibitors of ASIC1a-containing channels significantly inhibited pain and anxiety-related behaviours in MoAr rats...
March 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28320963/conformational-dynamics-and-role-of-the-acidic-pocket-in-asic-ph-dependent-gating
#18
Sabrina Vullo, Gaetano Bonifacio, Sophie Roy, Niklaus Johner, Simon Bernèche, Stephan Kellenberger
Acid-sensing ion channels (ASICs) are proton-activated Na(+) channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28320941/potent-neuroprotection-after-stroke-afforded-by-a-double-knot-spider-venom-peptide-that-inhibits-acid-sensing-ion-channel-1a
#19
Irène R Chassagnon, Claudia A McCarthy, Yanni K-Y Chin, Sandy S Pineda, Angelo Keramidas, Mehdi Mobli, Vi Pham, T Michael De Silva, Joseph W Lynch, Robert E Widdop, Lachlan D Rash, Glenn F King
Stroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28303465/pharmacotherapy-in-generalized-anxiety-disorder-novel-experimental-medicine-models-and-emerging-drug-targets
#20
REVIEW
David S Baldwin, Ruihua Hou, Robert Gordon, Nathan T M Huneke, Matthew Garner
Many pharmacological and psychological approaches have been found efficacious in patients with generalized anxiety disorder (GAD), but many treatment-seeking patients will not respond and others will relapse despite continuing with interventions that initially had beneficial effects. Other patients will respond but then stop treatment early because of untoward effects such as sexual dysfunction, drowsiness, and weight gain. There is much scope for the development of novel approaches that could have greater overall effectiveness or acceptability than currently available interventions or that have particular effectiveness in specific clinical subgroups...
April 2017: CNS Drugs
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