Acid-Sensing Ion Channel - Explore the Science & Experts | ideXlab

Scan Science and Technology

Contact Leading Edge Experts & Companies

Acid-Sensing Ion Channel

The Experts below are selected from a list of 15549 Experts worldwide ranked by ideXlab platform

Acid-Sensing Ion Channel – Free Register to Access Experts & Abstracts

Eric Gouaux – One of the best experts on this subject based on the ideXlab platform.

  • Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing Ion Channels.
    Current opinion in structural biology, 2013
    Co-Authors: Isabelle Baconguis, Motoyuki Hattori, Eric Gouaux

    Abstract:

    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.

  • structural plasticity and dynamic selectivity of acid sensing Ion Channel spider toxin complexes
    Nature, 2012
    Co-Authors: Isabelle Baconguis, Eric Gouaux

    Abstract:

    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.

  • Structural plasticity and dynamic selectivity of Acid-Sensing Ion Channel–spider toxin complexes
    Nature, 2012
    Co-Authors: Isabelle Baconguis, Eric Gouaux

    Abstract:

    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.

Lachlan D. Rash – One of the best experts on this subject based on the ideXlab platform.

  • acid sensing Ion Channel asic structure and functIon insights from spider snake and sea anemone venoms
    Neuropharmacology, 2017
    Co-Authors: Ben Cristoforiarmstrong, Lachlan D. Rash

    Abstract:

    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.

  • discovery and molecular interactIon studies of a highly stable tarantula peptide modulator of acid sensing Ion Channel 1
    Neuropharmacology, 2017
    Co-Authors: Sing Yan Er, Ben Cristoforiarmstrong, Pierre Escoubas, Lachlan D. Rash

    Abstract:

    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.’

  • 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, 2015
    Co-Authors: Natalie J. Saez, Irene R Chassagnon, Mehdi Mobli, Evelyne Deplazes, Ben Cristofori-armstrong, Xiaozhen Lin, Alan E. Mark, Lachlan D. Rash, Glenn F. King

    Abstract:

    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.

Isabelle Baconguis – One of the best experts on this subject based on the ideXlab platform.

  • Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing Ion Channels.
    Current opinion in structural biology, 2013
    Co-Authors: Isabelle Baconguis, Motoyuki Hattori, Eric Gouaux

    Abstract:

    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.

  • structural plasticity and dynamic selectivity of acid sensing Ion Channel spider toxin complexes
    Nature, 2012
    Co-Authors: Isabelle Baconguis, Eric Gouaux

    Abstract:

    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.

  • Structural plasticity and dynamic selectivity of Acid-Sensing Ion Channel–spider toxin complexes
    Nature, 2012
    Co-Authors: Isabelle Baconguis, Eric Gouaux

    Abstract:

    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.