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Acid-sensing ion channels

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https://www.readbyqxmd.com/read/28430192/a-monodisperse-transmembrane-%C3%AE-helical-peptide-barrel
#1
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
#2
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
#3
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
#4
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 10, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28300265/catalytic-routes-to-fuels-from-c1-and-oxygenate-molecules
#12
Shuai Wang, Iker Agirrezabal-Telleria, Aditya Bhan, Dante Simonetti, Kazuhiro Takanabe, Enrique Iglesia
This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C-C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges...
March 16, 2017: Faraday Discussions
https://www.readbyqxmd.com/read/28298159/biological-behavior-of-human-nucleus-pulposus-mesenchymal-stem-cells-in-response-to-changes-in-the-acidic-environment-during-intervertebral-disc-degeneration
#13
Jianjun Liu, Hui Tao, Cailiang Shen, Xiaoying Liu, Hanbang Wang, Fulong Dong, Renjie Zhang, Jie Li, Peng Ge, Peiwen Song, Huaqing Zhang, Peng Xu
An acidic environment is vital for the maintenance of cellular activities but can be affected tremendously during intervertebral disc degeneration. The effect of changes in the acidity of the environment on human nucleus pulposus mesenchymal stem cells (NP-MSCs) is unknown, however. Thus, this study aimed to observe the biological effects of acidic conditions mimicking a degenerated intervertebral disc on NP-MSCs in vitro. NP-MSCs were isolated from patients with lumbar disc herniation and were further identified by their immunophenotypes and multilineage differentiation...
March 16, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28294983/on-the-emerging-role-of-the-taste-receptor-type-1-t1r-family-of-nutrient-sensors-in-the-musculoskeletal-system
#14
REVIEW
Shoichiro Kokabu, Jonathan W Lowery, Takashi Toyono, Tsuyoshi Sato, Tetsuya Yoda
The special sense of taste guides and guards food intake and is essential for body maintenance. Salty and sour tastes are sensed via ion channels or gated ion channels while G protein-coupled receptors (GPCRs) of the taste receptor type 1 (T1R) family sense sweet and umami tastes and GPCRs of the taste receptor type 2 (T2R) family sense bitter tastes. T1R and T2R receptors share similar downstream signaling pathways that result in the stimulation of phospholipase-C-β2. The T1R family includes three members that form heterodimeric complexes to recognize either amino acids or sweet molecules such as glucose...
March 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28283476/alveolar-non-selective-channels-are-asic1a-%C3%AE-enac-channels-and-contribute-to-afc
#15
Phi T Trac, Tiffany L Thai, Valerie Linck, Li Zou, Megan M Greenlee, Qiang Yue, Otor K Al-Khalili, Abdel A Alli, Amity F Eaton, Douglas C Eaton
A thin fluid layer in alveoli is normal and results from a balance of fluid entry and fluid uptake by transepithelial salt and water reabsorption. Conventional wisdom suggests the reabsorption is via epithelial Na(+) channels (ENaC), but if all Na(+) reabsorption was via ENaC, then amiloride, an ENaC inhibitor, should block AFC. But amiloride blocks only half of AFC. The reason for failure to block is clear from single channel measurements from alveolar epithelial cells: ENaC channels are observed, but another channel is present at the same frequency that is non-selective for Na(+) over K(+), has a larger conductance, and shorter open and closed times...
March 10, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28265090/deactivation-kinetics-of-acid-sensing-ion-channel-1a-are-strongly-ph-sensitive
#16
David M MacLean, Vasanthi Jayaraman
Acid-sensing ion channels (ASICs) are trimeric cation-selective ion channels activated by protons in the physiological range. Recent reports have revealed that postsynaptically localized ASICs contribute to the excitatory postsynaptic current by responding to the transient acidification of the synaptic cleft that accompanies neurotransmission. In response to such brief acidic transients, both recombinant and native ASICs show extremely rapid deactivation in outside-out patches when jumping from a pH 5 stimulus to a single resting pH of 8...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28263552/polyelectrolyte-layer-by-layer-assembly-on-organic-electrochemical-transistors
#17
Anna-Maria Pappa, Sahika Inal, Kirsty Roy, Yi Zhang, Charalampos Pitsalidis, Adel Hama, Jolien Pas, George G Malliaras, Roisin M Owens
Oppositely charged polyelectrolyte multilayers (PEMs) were built up in a layer-by-layer (LbL) assembly on top of the conducting polymer channel of an organic electrochemical transistor (OECT), aiming to combine the advantages of well-established PEMs with a high performance electronic transducer. The multilayered film is a model system to investigate the impact of biofunctionalization on the operation of OECTs comprising a poly(3,4-ethylenedioxythiophene) polystyrenesulfonate (PEDOT:PSS) film as the electrically active layer...
March 29, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28259560/4-chlorophenylguanidine-is-an-asic3-agonist-and-positive-allosteric-modulator
#18
Amruta S Agharkar, Eric B Gonzales
Acid-sensing ion channels (ASICs) are proton-sensitive sodium channels that open in response to lowered extracellular pH and are expressed in the central and peripheral nervous systems. The ASIC3 subtype is found primarily in the periphery where the channel mediates pain signals caused by ischemia and inflammation. Here, we provide identify 4-chlorophenylguanidine (4-CPG) as an ASIC3 positive allosteric modulator and newest member of the growing group of guanidine modulators of ASICs. Furthermore, the 4-CPG reversed the effects of ASIC3 desensitization...
February 17, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28254778/regulation-of-stomatal-immunity-by-interdependent-functions-of-a-pathogen-responsive-mpk3-mpk6-cascade-and-abscisic-acid
#19
Jianbin Su, Mengmeng Zhang, Lawrence Zhang, Tiefeng Sun, Yidong Liu, Wolfgang Lukowitz, Juan Xu, Shuqun Zhang
Activation of mitogen-activated protein kinases (MAPKs) is one of the earliest responses after plants sense an invading pathogen. Here, we show that MPK3 and MPK6, two Arabidopsis thaliana pathogen-responsive MAPKs, and their upstream MAPK kinases, MKK4 and MKK5, are essential to both stomatal and apoplastic immunity. Loss of function of MPK3 and MPK6, or their upstream MKK4 and MKK5, abolishes pathogen/microbe-associated molecular pattern- and pathogen-induced stomatal closure. Gain-of-function activation of MPK3/MPK6 induces stomatal closure independently of abscisic acid (ABA) biosynthesis and signaling...
March 2017: Plant Cell
https://www.readbyqxmd.com/read/28237818/quercetin-inhibits-acid-sensing-ion-channels-through-a-putative-binding-site-in-the-central-vestibular-region
#20
Mohona Mukhopadhyay, Anurag Singh, S Sachchidanand, Amal Kanti Bera
Acid-sensing ion channels (ASICs) are associated with many pathophysiological processes, such as neuronal death during ischemic stroke, epileptic seizure and nociception. However, there is a dearth of ASIC-specific therapeutic blockers. Here we report that quercetin, a plant flavonoid, which is known for its neuroprotective effect, reversibly inhibits homomeric rat ASIC1a, ASIC2a and ASIC3 with an IC50 of about 2µM. Also, quercetin prevents low pH-induced intracellular calcium rise and cell death in HEK-293 cells, which have endogenous expression of ASIC1a and 2a...
February 22, 2017: Neuroscience
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