دورية أكاديمية
أعرض في EDS

Mechanism and site of action of big dynorphin on ASIC1a.

التفاصيل البيبلوغرافية
العنوان: Mechanism and site of action of big dynorphin on ASIC1a.
المؤلفون: Borg CB; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Braun N; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Heusser SA; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Bay Y; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Weis D; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Galleano I; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Lund C; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Tian W; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.; Copenhagen Center for Glycomics, Department of Odontology, University of Copenhagen, 2200 Copenhagen, Denmark., Haugaard-Kedström LM; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Bennett EP; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.; Copenhagen Center for Glycomics, Department of Odontology, University of Copenhagen, 2200 Copenhagen, Denmark., Lynagh T; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Strømgaard K; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark., Andersen J; Department of Molecular Biology, Vipergen ApS, 1610 Copenhagen, Denmark., Pless SA; Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark; stephan.pless@sund.ku.dk.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 31; Vol. 117 (13), pp. 7447-7454. Date of Electronic Publication: 2020 Mar 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Acid Sensing Ion Channels/*metabolism , Dynorphins/*metabolism, Acid Sensing Ion Channels/genetics ; Animals ; Animals, Genetically Modified ; Binding Sites ; HEK293 Cells ; Humans ; Hydrogen-Ion Concentration ; Neurons/metabolism ; Neuropeptides/metabolism ; Neuropeptides/physiology ; Oocytes/metabolism ; Protons ; Xenopus laevis
مستخلص: Acid-sensing ion channels (ASICs) are proton-gated cation channels that contribute to neurotransmission, as well as initiation of pain and neuronal death following ischemic stroke. As such, there is a great interest in understanding the in vivo regulation of ASICs, especially by endogenous neuropeptides that potently modulate ASICs. The most potent endogenous ASIC modulator known to date is the opioid neuropeptide big dynorphin (BigDyn). BigDyn is up-regulated in chronic pain and increases ASIC-mediated neuronal death during acidosis. Understanding the mechanism and site of action of BigDyn on ASICs could thus enable the rational design of compounds potentially useful in the treatment of pain and ischemic stroke. To this end, we employ a combination of electrophysiology, voltage-clamp fluorometry, synthetic BigDyn analogs, and noncanonical amino acid-mediated photocrosslinking. We demonstrate that BigDyn binding results in an ASIC1a closed resting conformation that is distinct from open and desensitized states induced by protons. Using alanine-substituted BigDyn analogs, we find that the BigDyn modulation of ASIC1a is primarily mediated through electrostatic interactions of basic amino acids in the BigDyn N terminus. Furthermore, neutralizing acidic amino acids in the ASIC1a extracellular domain reduces BigDyn effects, suggesting a binding site at the acidic pocket. This is confirmed by photocrosslinking using the noncanonical amino acid azidophenylalanine. Overall, our data define the mechanism of how BigDyn modulates ASIC1a, identify the acidic pocket as the binding site for BigDyn, and thus highlight this cavity as an important site for the development of ASIC-targeting therapeutics.
Competing Interests: The authors declare no competing interest.
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فهرسة مساهمة: Keywords: acid-sensing ion channel; ligand–receptor interaction; neuropeptide; noncanonical amino acids; voltage-clamp fluorometry
المشرفين على المادة: 0 (ASIC1 protein, human)
0 (ASIC1 protein, mouse)
0 (Acid Sensing Ion Channels)
0 (Neuropeptides)
0 (Protons)
74913-18-1 (Dynorphins)
تواريخ الأحداث: Date Created: 20200314 Date Completed: 20200814 Latest Revision: 20210110
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7132280
DOI: 10.1073/pnas.1919323117
PMID: 32165542
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1919323117