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Eric Gouaux - One of the best experts on this subject based on the ideXlab platform.
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Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing Ion Channels.
Current opinion in structural biology, 2013Co-Authors: Isabelle Baconguis, Motoyuki Hattori, Eric GouauxAbstract:ATP-gated P2X receptors and Acid-Sensing Ion Channels are catIon-selective, trimeric ligand-gated Ion Channels unrelated in amino acid sequence. Nevertheless, initial crystal structures of the P2X4 receptor and Acid-Sensing Ion Channel 1a in resting/closed and in non conductive/desensitized conformatIons, respectively, revealed common elements of architecture. Recent structures of both Channels have revealed the Ion Channels in open conformatIons. Here we focus on common elements of architecture, conformatIonal change and Ion permeatIon, emphasizing general principles of structure and mechanism in P2X receptors and in Acid-Sensing Ion Channels and showing how these two sequence-disparate families of ligand-gated Ion Channel harbor unexpected similarities when viewed through a structural lens.
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structural plasticity and dynamic selectivity of acid sensing Ion Channel spider toxin complexes
Nature, 2012Co-Authors: Isabelle Baconguis, Eric GouauxAbstract:Acid-Sensing Ion Channels (ASICs) are voltage-independent, amiloride-sensitive Channels involved in diverse physiological processes ranging from nociceptIon to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of Channel activatIon. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-sectIon with dimensIons of approximately 5 by 7 A, consistent with a barrier mechanism for Ion selectivity. These studies define mechanisms for activatIon of ASICs, illuminate the basis for dynamic Ion selectivity and provide the blueprints for new therapeutic agents. Acid-Sensing Ion Channels (ASICs) are voltage-independent Ion Channels that participate in a broad range of biological processes, including nociceptIon and mechanosensatIon; here X-ray crystal structures of the complexes of chicken ASIC1a with psalmotoxin, a peptide toxin from tarantula, indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. Acid-Sensing Ion Channels (ASICs) are members of the epithelial sodium Channel/degenerin (ENaC/DEG) superfamily of voltage-independent Ion Channels. ENaCs, including ASICs, participate in a broad range of biological processes, such as nociceptIon, mechanosensatIon and regulatIon of sodium-Ion homeostasis. Here, Isabelle Baconguis and Eric Gouaux show that psalmotoxin, a peptide toxin from the tarantula, activates nonselective and sodium-selective currents in chicken ASIC1a. X-ray crystal structures of the chicken ASIC1a–psalmotoxin complexes indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. This view of an important type of Ion Channel in an open conformatIon is of relevance to the design of open-Channel blockers that might have therapeutic promise for the treatment of pain.
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Structural plasticity and dynamic selectivity of Acid-Sensing Ion Channel–spider toxin complexes
Nature, 2012Co-Authors: Isabelle Baconguis, Eric GouauxAbstract:Acid-Sensing Ion Channels (ASICs) are voltage-independent, amiloride-sensitive Channels involved in diverse physiological processes ranging from nociceptIon to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of Channel activatIon. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-sectIon with dimensIons of approximately 5 by 7 A, consistent with a barrier mechanism for Ion selectivity. These studies define mechanisms for activatIon of ASICs, illuminate the basis for dynamic Ion selectivity and provide the blueprints for new therapeutic agents. Acid-Sensing Ion Channels (ASICs) are voltage-independent Ion Channels that participate in a broad range of biological processes, including nociceptIon and mechanosensatIon; here X-ray crystal structures of the complexes of chicken ASIC1a with psalmotoxin, a peptide toxin from tarantula, indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. Acid-Sensing Ion Channels (ASICs) are members of the epithelial sodium Channel/degenerin (ENaC/DEG) superfamily of voltage-independent Ion Channels. ENaCs, including ASICs, participate in a broad range of biological processes, such as nociceptIon, mechanosensatIon and regulatIon of sodium-Ion homeostasis. Here, Isabelle Baconguis and Eric Gouaux show that psalmotoxin, a peptide toxin from the tarantula, activates nonselective and sodium-selective currents in chicken ASIC1a. X-ray crystal structures of the chicken ASIC1a–psalmotoxin complexes indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. This view of an important type of Ion Channel in an open conformatIon is of relevance to the design of open-Channel blockers that might have therapeutic promise for the treatment of pain.
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Pore Architecture and Ion Sites of Acid Sensing Ion Channels and P2X Receptors
Biophysical Journal, 2010Co-Authors: Eric B. Gonzales, Toshimitsu Kawate, Eric GouauxAbstract:Acid-Sensing Ion Channels are proton-activated, sodium-selective Channels composed of three subunits, and members of the degenerin/epithelial sodium Channel (DEG/ENaC) superfamily. These eukaryotic Channels have essential roles in sodium homeostasis, taste, and pain. Despite their roles in biology, there is little knowledge of the structural and chemical principles underlying their Ion Channel architecture and Ion-binding sites. Here we present the crystal structure of a functIonal Acid-Sensing Ion Channel in a desensitized state at 3 angstrom resolutIon, the locatIon of the desensitizatIon gate, and the trigonal antiprism coordinatIon of cesium Ions bound in the extracellular vestibule. Comparison of the Acid-Sensing Ion Channel structure with the P2X receptor reveals unanticipated similarities and mechanical principles in different ligand-gated Ion Channels.
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Pore architecture and Ion sites in Acid-Sensing Ion Channels and P2X receptors
Nature, 2009Co-Authors: Eric B. Gonzales, Toshimitsu Kawate, Eric GouauxAbstract:Acid-Sensing Ion Channels are proton-activated, sodium-selective Channels composed of three subunits, and are members of the superfamily of epithelial sodium Channels, mechanosensitive and FMRF-amide peptide-gated Ion Channels. These ubiquitous eukaryotic Ion Channels have essential roles in biological activities as diverse as sodium homeostasis, taste and pain. Despite their crucial roles in biology and their unusual trimeric subunit stoichiometry, there is little knowledge of the structural and chemical principles underlying their Ion Channel architecture and Ion-binding sites. Here we present the structure of a functIonal Acid-Sensing Ion Channel in a desensitized state at 3 A resolutIon, the locatIon and compositIon of the ∼8 A ‘thick’ desensitizatIon gate, and the trigonal antiprism coordinatIon of caesium Ions bound in the extracellular vestibule. Comparison of the Acid-Sensing Ion Channel structure with the ATP-gated P2X4 receptor reveals similarity in pore architecture and aqueous vestibules, suggesting that there are unanticipated yet common structural and mechanistic principles. P2X receptors are ATP-gated non-selective catIon Channels involved in nociceptIon and inflammatory responses, whose structures were unknown. Kawate et al. now present the crystal structure of the zebrafish P2X4 receptor in a closed state. The trimeric structure reveals some of the molecular underpinnings of ligand-binding, catIon entry and Channel gating. A related paper presents the structure of chicken Acid-Sensing Ion Channel 1 (ASIC1) in a desensitized state. Like P2X receptors, ASICs are trimeric, but they belong to an entirely different family of Ion Channels. The structure determinatIon of ASIC1 shows how Ion permeatIon and desensitizatIon may occur, and comparison of ASIC and P2X structures suggests that these functIonally distinct Channels employ similar mechanistic principles. Like P2X receptors, Acid-Sensing Ion Channels are trimeric in structure; however, they belong to an entirely different family. Here, the structure of an Acid-Sensing Ion Channel is presented and compared to the structure of P2X4, suggesting that these functIonally distinct Channels use similar mechanistic principles.
Lachlan D. Rash - One of the best experts on this subject based on the ideXlab platform.
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acid sensing Ion Channel asic structure and functIon insights from spider snake and sea anemone venoms
Neuropharmacology, 2017Co-Authors: Ben Cristoforiarmstrong, Lachlan D. RashAbstract: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. Some modulators, such as the prototypical ASIC1 modulator PcTx1 have been studied in great detail, while some of the newer members of the club remain largely unstudied. Here we review the current state of knowledge on venom derived ASIC modulators, with a particular focus on their molecular interactIon with ASICs, what they have taught us about Channel structure, and what they might still reveal about ASIC functIon and pathophysiological roles.
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discovery and molecular interactIon studies of a highly stable tarantula peptide modulator of acid sensing Ion Channel 1
Neuropharmacology, 2017Co-Authors: Sing Yan Er, Ben Cristoforiarmstrong, Pierre Escoubas, Lachlan D. RashAbstract:Abstract 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. π-TRTX-Hm3a (Hm3a) is a 37-amino acid peptide isolated from Togo starburst tarantula (Heteroscodra maculata) venom with five amino acid substitutIons compared to PcTx1, and is also three residues shorter at the C-terminus. Hm3a pH-dependently inhibited ASIC1a with an IC50 of 1–2 nM and potentiated ASIC1b with an EC50 of 46.5 nM, similar to PcTx1. Using ASIC1a to ASIC1b point mutants in rat ASIC1a revealed that Glu177 and Arg175 in the palm regIon opposite α-helix 5 play an important role in the Hm3a-ASIC1 interactIon and contribute to the subtype-dependent effects of the peptide. Despite its high sequence similarity with PcTx1, Hm3a showed higher levels of stability over 48 h. Overall, Hm3a represents a potent, highly stable tool for the study of ASICs and will be particularly useful when stability in biological fluids is required, for example in long term in vitro cell-based assays and in vivo experiments. This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’
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Molecular dynamics and functIonal studies define a hot spot of crystal contacts essential for PcTx1 inhibitIon of Acid-Sensing Ion Channel 1a.
British journal of pharmacology, 2015Co-Authors: Natalie J. Saez, Irene R Chassagnon, Mehdi Mobli, Evelyne Deplazes, Ben Cristofori-armstrong, Xiaozhen Lin, Alan E. Mark, Lachlan D. Rash, Glenn F. KingAbstract:Background and Purpose The spider‐venom peptide PcTx1 is the most potent and selective inhibitor of acid‐sensing Ion Channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interactIon should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β‐hairpin loop; conclusIons confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : Channel contacts were observed in these crystal structures, but it remains unclear which of these are functIonally important.
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understanding the molecular basis of toxin promiscuity the analgesic sea anemone peptide apetx2 interacts with acid sensing Ion Channel 3 and herg Channels via overlapping pharmacophores
Journal of Medicinal Chemistry, 2014Co-Authors: Jonas E Jensen, Mehdi Mobli, Glenn F. King, Ben Cristoforiarmstrong, Raveendra Anangi, Johan K Rosengren, Andreas Brust, Paul F Alewood, Lachlan D. RashAbstract:The sea anemone peptide APETx2 is a potent and selective blocker of Acid-Sensing Ion Channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relatIonship study of APETx2. DeterminatIon of a high-resolutIon structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interactIon with ASIC3. We show that APETx2 also inhibits the off-target hERG Channel by reducing the maximal current amplitude and shifting the voltage dependence of activatIon to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interactIon with ASIC3 and hERG. CharacterizatIon of the molecular basis of these interactIons is an important first step toward the ratIonal design of more selective APETx2 analogues.
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understanding the molecular basis of toxin promiscuity the analgesic sea anemone peptide apetx2 interacts with acid sensing Ion Channel 3 and herg Channels via overlapping pharmacophores
Journal of Medicinal Chemistry, 2014Co-Authors: Jonas E Jensen, Mehdi Mobli, Glenn F. King, Ben Cristoforiarmstrong, Raveendra Anangi, Johan K Rosengren, Andreas Brust, Paul F Alewood, Carus H Y Lau, Lachlan D. RashAbstract:The sea anemone peptide APETx2 is a potent and selective blocker of Acid-Sensing Ion Channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relatIonship study of APETx2. DeterminatIon of a high-resolutIon structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interactIon with ASIC3. We show that APETx2 also inhibits the off-target hERG Channel by reducing the maximal current amplitude and shifting the voltage dependence of activatIon to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interactIon with ASIC3 and hERG. CharacterizatIon of the molecular basis of these interactIons is an important first step toward the ratIonal design of more selective APETx2 analogues.
Isabelle Baconguis - One of the best experts on this subject based on the ideXlab platform.
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Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing Ion Channels.
Current opinion in structural biology, 2013Co-Authors: Isabelle Baconguis, Motoyuki Hattori, Eric GouauxAbstract:ATP-gated P2X receptors and Acid-Sensing Ion Channels are catIon-selective, trimeric ligand-gated Ion Channels unrelated in amino acid sequence. Nevertheless, initial crystal structures of the P2X4 receptor and Acid-Sensing Ion Channel 1a in resting/closed and in non conductive/desensitized conformatIons, respectively, revealed common elements of architecture. Recent structures of both Channels have revealed the Ion Channels in open conformatIons. Here we focus on common elements of architecture, conformatIonal change and Ion permeatIon, emphasizing general principles of structure and mechanism in P2X receptors and in Acid-Sensing Ion Channels and showing how these two sequence-disparate families of ligand-gated Ion Channel harbor unexpected similarities when viewed through a structural lens.
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structural plasticity and dynamic selectivity of acid sensing Ion Channel spider toxin complexes
Nature, 2012Co-Authors: Isabelle Baconguis, Eric GouauxAbstract:Acid-Sensing Ion Channels (ASICs) are voltage-independent, amiloride-sensitive Channels involved in diverse physiological processes ranging from nociceptIon to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of Channel activatIon. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-sectIon with dimensIons of approximately 5 by 7 A, consistent with a barrier mechanism for Ion selectivity. These studies define mechanisms for activatIon of ASICs, illuminate the basis for dynamic Ion selectivity and provide the blueprints for new therapeutic agents. Acid-Sensing Ion Channels (ASICs) are voltage-independent Ion Channels that participate in a broad range of biological processes, including nociceptIon and mechanosensatIon; here X-ray crystal structures of the complexes of chicken ASIC1a with psalmotoxin, a peptide toxin from tarantula, indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. Acid-Sensing Ion Channels (ASICs) are members of the epithelial sodium Channel/degenerin (ENaC/DEG) superfamily of voltage-independent Ion Channels. ENaCs, including ASICs, participate in a broad range of biological processes, such as nociceptIon, mechanosensatIon and regulatIon of sodium-Ion homeostasis. Here, Isabelle Baconguis and Eric Gouaux show that psalmotoxin, a peptide toxin from the tarantula, activates nonselective and sodium-selective currents in chicken ASIC1a. X-ray crystal structures of the chicken ASIC1a–psalmotoxin complexes indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. This view of an important type of Ion Channel in an open conformatIon is of relevance to the design of open-Channel blockers that might have therapeutic promise for the treatment of pain.
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Structural plasticity and dynamic selectivity of Acid-Sensing Ion Channel–spider toxin complexes
Nature, 2012Co-Authors: Isabelle Baconguis, Eric GouauxAbstract:Acid-Sensing Ion Channels (ASICs) are voltage-independent, amiloride-sensitive Channels involved in diverse physiological processes ranging from nociceptIon to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of Channel activatIon. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-sectIon with dimensIons of approximately 5 by 7 A, consistent with a barrier mechanism for Ion selectivity. These studies define mechanisms for activatIon of ASICs, illuminate the basis for dynamic Ion selectivity and provide the blueprints for new therapeutic agents. Acid-Sensing Ion Channels (ASICs) are voltage-independent Ion Channels that participate in a broad range of biological processes, including nociceptIon and mechanosensatIon; here X-ray crystal structures of the complexes of chicken ASIC1a with psalmotoxin, a peptide toxin from tarantula, indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. Acid-Sensing Ion Channels (ASICs) are members of the epithelial sodium Channel/degenerin (ENaC/DEG) superfamily of voltage-independent Ion Channels. ENaCs, including ASICs, participate in a broad range of biological processes, such as nociceptIon, mechanosensatIon and regulatIon of sodium-Ion homeostasis. Here, Isabelle Baconguis and Eric Gouaux show that psalmotoxin, a peptide toxin from the tarantula, activates nonselective and sodium-selective currents in chicken ASIC1a. X-ray crystal structures of the chicken ASIC1a–psalmotoxin complexes indicate that toxin binding triggers an expansIon of the extracellular vestibule and stabilizatIon of the open Channel pore. This view of an important type of Ion Channel in an open conformatIon is of relevance to the design of open-Channel blockers that might have therapeutic promise for the treatment of pain.
Michel Lazdunski - One of the best experts on this subject based on the ideXlab platform.
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Asic3 is a neuronal mechanosensor for pressure-induced vasodilatIon that protects against pressure ulcers.
Nature Medicine, 2012Co-Authors: Bérengère Fromy, Eric Lingueglia, Dominique Sigaudo-roussel, Jean Louis Saumet, Michel LazdunskiAbstract:Pressure-induced vasodilatIon (PIV) delays the decrease in cutaneous blood flow produced by local applicatIon of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor functIon. Individuals without a normal PIV response have a high risk of ulceratIon. Here we demonstrate that Acid-Sensing Ion Channel 3 (Asic3) is an essential neuronal sensor for the vasodilatIon response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice.
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Structural elements for the generatIon of sustained currents by the acid pain sensor ASIC3.
Journal of Biological Chemistry, 2009Co-Authors: Miguel Salinas, Michel Lazdunski, Eric LinguegliaAbstract:ASIC3 is an Acid-Sensing Ion Channel expressed in sensory neurons, where it participates in acidic and inflammatory pain. In additIon to the "classical" transient current, ASIC3 generates a sustained current essential for pain perceptIon. Using chimeras between the ASIC3 and ASIC1a Channels we show that the first transmembrane domain (TM1), combined with the N-terminal domain, is the key structural element generating the low pH (
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Acid-Sensing Ion Channel 3 in retinal functIon and survival.
Investigative Ophthalmology & Visual Science, 2009Co-Authors: Mohammed Ettaiche, Emmanuel Deval, Michel Lazdunski, Sophie Pagnotta, Eric LinguegliaAbstract:PURPOSE: Changes in extracellular pH occur in the retina and directly affect retinal activity and phototransductIon. The authors analyzed the expressIon in rodent retina of ASIC3, a sensor of extracellular acidosis, and used ASIC3 knockout mice to explore its role in retinal functIon and survival. METHODS: The expressIon and the role of ASIC3 were examined by immunolocalizatIon and by comparing retinas from wild-type and knockout mice at different ages through electroretinography, retinal histology (light and electron microscopy), expressIon of glial fibrillary acidic protein (GFAP), analysis of cell apoptosis (TUNEL assay), and patch-clamp recordings in primary cultures of retinal ganglIon cells (RGCs). RESULTS: ASIC3 is present in the rod inner segment of photoreceptors and in horizontal and some amacrine cells. ASIC3 is also detected in RGCs but does not significantly contribute to ASIC currents recorded in cultured RGCs. At 2 to 3 months, knockout mice experience a 19% enhancement of scotopic electroretinogram a-wave amplitude and a concomitant increase of b-wave amplitude without alteratIon of retinal structure. Older (8-month-old) knockout mice have 69% and 64% reductIons in scotopic a- and b-waves, respectively, and reductIons in oscillatory potential amplitudes associated with complete disorganizatIon of the retina and degenerating rod inner segments. GFAP and TUNEL staining performed at 8 and 12 months of age revealed an upregulatIon of GFAP expressIon in Müller cells and the presence of apoptotic cells in the inner and outer retina. CONCLUSIonS: InactivatIon of ASIC3 enhances visual transductIon at 2 to 3 months but induces late-onset rod photoreceptor death, suggesting an important role for ASIC3 in maintaining retinal integrity.
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deletIon of the acid sensing Ion Channel asic3 prevents gastritis induced acid hyperresponsiveness of the stomach brainstem axis
Pain, 2008Co-Authors: Thomas Wultsch, Michel Lazdunski, Evelin Painsipp, Anaid Shahbazian, Martina Mitrovic, Martin Edelsbrunner, Rainer Waldmann, Peter HolzerAbstract:Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expressIon of c-Fos. The molecular sensors relevant to the detectIon of gastric mucosal acidosis are not known. Since the Acid-Sensing Ion Channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activatIon of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by additIon of iodoacetamide (0.1%) to the drinking water for 7 days. Exposure of the gastric mucosa to HCl (0.25 M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33% (P < 0.01). Pretreatment of wild-type mice with iodoacetamide induced mild gastritis, as revealed by increased myeloperoxidase activity, and enhanced the number of NTS neurons responding to gastric HCl challenge by 41% (P < 0.01). This gastric acid hyperresponsiveness was absent in ASIC3 knockout mice but fully preserved in ASIC2 knockout mice. The current data indicate that ASIC3 plays a major role in the acid hyperresponsiveness associated with experimental gastritis. In contrast, ASIC2 appears to dampen acid-evoked input from the stomach to the NTS.
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DeletIon of the Acid-Sensing Ion Channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach-brainstem axis.
PAIN, 2007Co-Authors: Thomas Wultsch, Michel Lazdunski, Evelin Painsipp, Anaid Shahbazian, Martina Mitrovic, Martin Edelsbrunner, Rainer Waldmann, Peter HolzerAbstract:Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expressIon of c-Fos. The molecular sensors relevant to the detectIon of gastric mucosal acidosis are not known. Since the Acid-Sensing Ion Channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activatIon of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by additIon of iodoacetamide (0.1%) to the drinking water for 7days. Exposure of the gastric mucosa to HCl (0.25M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33% (P
Glenn F. King - One of the best experts on this subject based on the ideXlab platform.
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combinatIon of ambiguous and unambiguous data in the restraint driven docking of flexible peptides with haddock the binding of the spider toxin pctx1 to the acid sensing Ion Channel asic 1a
Journal of Chemical Information and Modeling, 2016Co-Authors: Evelyne Deplazes, Glenn F. King, Josephine Davies, Alexandre M J J Bonvin, Alan E. MarkAbstract:Peptides that bind to Ion Channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determinatIon of large peptide-Channel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental informatIon with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing Ion Channel (ASIC) 1a as a case study, we have examined the effect of different combinatIons of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-Channel interactIons. For this, we have analyzed over 200 000 water-refined docked structures obtained with various amounts and types of restraints of the peptide-Channel complex predicted using the docking program HADDOCK. We found that increasing the ...
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Molecular dynamics and functIonal studies define a hot spot of crystal contacts essential for PcTx1 inhibitIon of Acid-Sensing Ion Channel 1a.
British journal of pharmacology, 2015Co-Authors: Natalie J. Saez, Irene R Chassagnon, Mehdi Mobli, Evelyne Deplazes, Ben Cristofori-armstrong, Xiaozhen Lin, Alan E. Mark, Lachlan D. Rash, Glenn F. KingAbstract:Background and Purpose The spider‐venom peptide PcTx1 is the most potent and selective inhibitor of acid‐sensing Ion Channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interactIon should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β‐hairpin loop; conclusIons confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : Channel contacts were observed in these crystal structures, but it remains unclear which of these are functIonally important.
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understanding the molecular basis of toxin promiscuity the analgesic sea anemone peptide apetx2 interacts with acid sensing Ion Channel 3 and herg Channels via overlapping pharmacophores
Journal of Medicinal Chemistry, 2014Co-Authors: Jonas E Jensen, Mehdi Mobli, Glenn F. King, Ben Cristoforiarmstrong, Raveendra Anangi, Johan K Rosengren, Andreas Brust, Paul F Alewood, Lachlan D. RashAbstract:The sea anemone peptide APETx2 is a potent and selective blocker of Acid-Sensing Ion Channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relatIonship study of APETx2. DeterminatIon of a high-resolutIon structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interactIon with ASIC3. We show that APETx2 also inhibits the off-target hERG Channel by reducing the maximal current amplitude and shifting the voltage dependence of activatIon to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interactIon with ASIC3 and hERG. CharacterizatIon of the molecular basis of these interactIons is an important first step toward the ratIonal design of more selective APETx2 analogues.
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understanding the molecular basis of toxin promiscuity the analgesic sea anemone peptide apetx2 interacts with acid sensing Ion Channel 3 and herg Channels via overlapping pharmacophores
Journal of Medicinal Chemistry, 2014Co-Authors: Jonas E Jensen, Mehdi Mobli, Glenn F. King, Ben Cristoforiarmstrong, Raveendra Anangi, Johan K Rosengren, Andreas Brust, Paul F Alewood, Carus H Y Lau, Lachlan D. RashAbstract:The sea anemone peptide APETx2 is a potent and selective blocker of Acid-Sensing Ion Channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relatIonship study of APETx2. DeterminatIon of a high-resolutIon structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interactIon with ASIC3. We show that APETx2 also inhibits the off-target hERG Channel by reducing the maximal current amplitude and shifting the voltage dependence of activatIon to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interactIon with ASIC3 and hERG. CharacterizatIon of the molecular basis of these interactIons is an important first step toward the ratIonal design of more selective APETx2 analogues.
