{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:45:21Z","timestamp":1792043121799,"version":"4.4.0"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"13","license":[{"start":{"date-parts":[[2020,9,12]],"date-time":"2020-09-12T00:00:00Z","timestamp":1599868800000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R139-2012-12390"],"award-info":[{"award-number":["R139-2012-12390"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","award":["R218-2016-1490"],"award-info":[{"award-number":["R218-2016-1490"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EC | Horizon 2020 Marie Sklodowska-Curie","award":["834274"],"award-info":[{"award-number":["834274"]}]},{"DOI":"10.13039\/501100001645","name":"Boehringer Ingelheim Fonds","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/501100001645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001732","name":"Danish National Research Foundation","doi-asserted-by":"crossref","award":["DNRF107"],"award-info":[{"award-number":["DNRF107"]}],"id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,31]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1073\/pnas.1919323117","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T19:35:16Z","timestamp":1584041716000},"page":"7447-7454","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":48,"title":["Mechanism and site of action of big dynorphin on ASIC1a"],"prefix":"10.1073","volume":"117","author":[{"given":"Christian B.","family":"Borg","sequence":"first","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Heusser","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Bay","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iacopo","family":"Galleano","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Lund","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-3947","authenticated-orcid":false,"given":"Weihua","family":"Tian","sequence":"additional","affiliation":[{"name":"Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;"},{"name":"Copenhagen Center for Glycomics, Department of Odontology, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M.","family":"Haugaard-Kedstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric P.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark;"},{"name":"Copenhagen Center for Glycomics, Department of Odontology, University of Copenhagen, 2200 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4888-4098","authenticated-orcid":false,"given":"Timothy","family":"Lynagh","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2206-4737","authenticated-orcid":false,"given":"Kristian","family":"Str\u00f8mgaard","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Vipergen ApS, 1610 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6654-114X","authenticated-orcid":false,"given":"Stephan A.","family":"Pless","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,3,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrn.2017.56","article-title":"Functional consequences of neuropeptide and small-molecule co-transmission","volume":"18","author":"Nusbaum M. P.","year":"2017","unstructured":"M. P. Nusbaum, D. M. Blitz, E. Marder, Functional consequences of neuropeptide and small-molecule co-transmission. Nat. Rev. Neurosci. 18, 389\u2013403 (2017).","journal-title":"Nat. Rev. Neurosci."},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neuron.2012.09.014","article-title":"Neuropeptide transmission in brain circuits","volume":"76","author":"van den Pol A. N.","year":"2012","unstructured":"A. N. van den Pol, Neuropeptide transmission in brain circuits. Neuron 76, 98\u2013115 (2012).","journal-title":"Neuron"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1126\/science.6120570","article-title":"Dynorphin is a specific endogenous ligand of the kappa opioid receptor","volume":"215","author":"Chavkin C.","year":"1982","unstructured":"C. Chavkin, I. F. James, A. Goldstein, Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215, 413\u2013415 (1982).","journal-title":"Science"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.2741\/1522","article-title":"Pathobiology of dynorphins in trauma and disease","volume":"10","author":"Hauser K. F.","year":"2005","unstructured":"K. F. Hauser ., Pathobiology of dynorphins in trauma and disease. Front. Biosci. 10, 216\u2013235 (2005).","journal-title":"Front. Biosci."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.pharmthera.2009.05.006","article-title":"30 years of dynorphins\u2014New insights on their functions in neuropsychiatric diseases","volume":"123","author":"Schwarzer C.","year":"2009","unstructured":"C. Schwarzer, 30 years of dynorphins\u2014New insights on their functions in neuropsychiatric diseases. Pharmacol. Ther. 123, 353\u2013370 (2009).","journal-title":"Pharmacol. Ther."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0014-2999(89)90149-0","article-title":"A direct non-opiate interaction of dynorphin-(1-13) with the N-methyl-D-aspartate (NMDA) receptor","volume":"170","author":"Massardier D.","year":"1989","unstructured":"D. Massardier, P. F. Hunt, A direct non-opiate interaction of dynorphin-(1-13) with the N-methyl-D-aspartate (NMDA) receptor. Eur. J. Pharmacol. 170, 125\u2013126 (1989).","journal-title":"Eur. J. Pharmacol."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"4602","DOI":"10.1523\/JNEUROSCI.15-06-04602.1995","article-title":"The mechanism of action for the block of NMDA receptor channels by the opioid peptide dynorphin","volume":"15","author":"Chen L.","year":"1995","unstructured":"L. Chen, Y. Gu, L. Y. Huang, The mechanism of action for the block of NMDA receptor channels by the opioid peptide dynorphin. J. Neurosci. 15, 4602\u20134611 (1995).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1113\/jphysiol.1995.sp020541","article-title":"The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat","volume":"482","author":"Chen L.","year":"1995","unstructured":"L. Chen, Y. Gu, L. Y. Huang, The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat. J. Physiol. 482, 575\u2013581 (1995).","journal-title":"J. Physiol."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0304-3940(98)00293-6","article-title":"Dynorphin uses a non-opioid mechanism to potentiate N-methyl-D-aspartate currents in single rat periaqueductal gray neurons","volume":"247","author":"Lai S. L.","year":"1998","unstructured":"S. L. Lai, Y. Gu, L. Y. Huang, Dynorphin uses a non-opioid mechanism to potentiate N-methyl-D-aspartate currents in single rat periaqueductal gray neurons. Neurosci. Lett. 247, 115\u2013118 (1998).","journal-title":"Neurosci. Lett."},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"14371","DOI":"10.1523\/JNEUROSCI.2186-09.2009","article-title":"Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death","volume":"29","author":"Sherwood T. W.","year":"2009","unstructured":"T. W. Sherwood, C. C. Askwith, Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death. J. Neurosci. 29, 14371\u201314380 (2009).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature11494","article-title":"Black mamba venom peptides target acid-sensing ion channels to abolish pain","volume":"490","author":"Diochot S.","year":"2012","unstructured":"S. Diochot ., Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature 490, 552\u2013555 (2012).","journal-title":"Nature"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nature10607","article-title":"A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain","volume":"479","author":"Bohlen C. J.","year":"2011","unstructured":"C. J. Bohlen ., A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature 479, 410\u2013414 (2011).","journal-title":"Nature"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/nn1940","article-title":"A tarantula peptide against pain via ASIC1a channels and opioid mechanisms","volume":"10","author":"Mazzuca M.","year":"2007","unstructured":"M. Mazzuca ., A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat. Neurosci. 10, 943\u2013945 (2007).","journal-title":"Nat. Neurosci."},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.cell.2004.08.026","article-title":"Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels","volume":"118","author":"Xiong Z. G.","year":"2004","unstructured":"Z. G. Xiong ., Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell 118, 687\u2013698 (2004).","journal-title":"Cell"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1073\/pnas.1614728114","article-title":"Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a","volume":"114","author":"Chassagnon I. R.","year":"2017","unstructured":"I. R. Chassagnon ., Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc. Natl. Acad. Sci. U.S.A. 114, 3750\u20133755 (2017).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"E7469","DOI":"10.1073\/pnas.1807233115","article-title":"Selection of an ASIC1a-blocking combinatorial antibody that protects cells from ischemic death","volume":"115","author":"Qiang M.","year":"2018","unstructured":"M. Qiang ., Selection of an ASIC1a-blocking combinatorial antibody that protects cells from ischemic death. Proc. Natl. Acad. Sci. U.S.A. 115, E7469\u2013E7477 (2018).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"e05682","DOI":"10.7554\/eLife.05682","article-title":"Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction","volume":"4","author":"Wang Y. Z.","year":"2015","unstructured":"Y. Z. Wang ., Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. eLife 4, e05682 (2015).","journal-title":"eLife"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"9723","DOI":"10.1523\/JNEUROSCI.1665-11.2011","article-title":"Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death","volume":"31","author":"Sherwood T. W.","year":"2011","unstructured":"T. W. Sherwood, K. G. Lee, M. G. Gormley, C. C. Askwith, Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J. Neurosci. 31, 9723\u20139734 (2011).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1146\/annurev-pharmtox-010715-103042","article-title":"The emerging role of spinal dynorphin in chronic pain: A therapeutic perspective","volume":"56","author":"Podvin S.","year":"2016","unstructured":"S. Podvin, T. Yaksh, V. Hook, The emerging role of spinal dynorphin in chronic pain: A therapeutic perspective. Annu. Rev. Pharmacol. Toxicol. 56, 511\u2013533 (2016).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1085\/jgp.200509303","article-title":"The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity","volume":"126","author":"Chen X.","year":"2005","unstructured":"X. Chen, H. Kalbacher, S. Gr\u00fcnder, The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J. Gen. Physiol. 126, 71\u201379 (2005).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/ncomms1917","article-title":"Structure of the acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1","volume":"3","author":"Dawson R. J.","year":"2012","unstructured":"R. J. Dawson ., Structure of the acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nat. Commun. 3, 936 (2012).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature11375","article-title":"Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes","volume":"489","author":"Baconguis I.","year":"2012","unstructured":"I. Baconguis, E. Gouaux, Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. Nature 489, 400\u2013405 (2012).","journal-title":"Nature"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.cell.2013.11.008","article-title":"Genetically encoded chemical probes in cells reveal the binding path of urocortin-I to CRF class B GPCR","volume":"155","author":"Coin I.","year":"2013","unstructured":"I. Coin ., Genetically encoded chemical probes in cells reveal the binding path of urocortin-I to CRF class B GPCR. Cell 155, 1258\u20131269 (2013).","journal-title":"Cell"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"9026","DOI":"10.1021\/ja027007w","article-title":"Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli","volume":"124","author":"Chin J. W.","year":"2002","unstructured":"J. W. Chin ., Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli. J. Am. Chem. Soc. 124, 9026\u20139027 (2002).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1085\/jgp.201912372","article-title":"The contribution of voltage clamp fluorometry to the understanding of channel and transporter mechanisms","volume":"151","author":"Cowgill J.","year":"2019","unstructured":"J. Cowgill, B. Chanda, The contribution of voltage clamp fluorometry to the understanding of channel and transporter mechanisms. J. Gen. Physiol. 151, 1163\u20131172 (2019).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1085\/jgp.201311053","article-title":"Protonation controls ASIC1a activity via coordinated movements in multiple domains","volume":"143","author":"Bonifacio G.","year":"2014","unstructured":"G. Bonifacio, C. I. Lelli, S. Kellenberger, Protonation controls ASIC1a activity via coordinated movements in multiple domains. J. Gen. Physiol. 143, 105\u2013118 (2014).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1085\/jgp.200509409","article-title":"Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent","volume":"127","author":"Chen X.","year":"2006","unstructured":"X. Chen, H. Kalbacher, S. Gr\u00fcnder, Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. J. Gen. Physiol. 127, 267\u2013276 (2006).","journal-title":"J. Gen. Physiol."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1126\/science.6128791","article-title":"Nonopiate effects of dynorphin and des-Tyr-dynorphin","volume":"218","author":"Walker J. M.","year":"1982","unstructured":"J. M. Walker, H. C. Moises, D. H. Coy, G. Baldrighi, H. Akil, Nonopiate effects of dynorphin and des-Tyr-dynorphin. Science 218, 1136\u20131138 (1982).","journal-title":"Science"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.lfs.2003.12.005","article-title":"Non-opioid actions of opioid peptides","volume":"75","author":"Wollemann M.","year":"2004","unstructured":"M. Wollemann, S. Benyhe, Non-opioid actions of opioid peptides. Life Sci. 75, 257\u2013270 (2004).","journal-title":"Life Sci."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature06163","article-title":"Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH","volume":"449","author":"Jasti J.","year":"2007","unstructured":"J. Jasti, H. Furukawa, E. B. Gonzales, E. Gouaux, Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature 449, 316\u2013323 (2007).","journal-title":"Nature"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1111\/bph.13267","article-title":"Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a","volume":"172","author":"Saez N. J.","year":"2015","unstructured":"N. J. Saez ., Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a. Br. J. Pharmacol. 172, 4985\u20134995 (2015).","journal-title":"Br. J. Pharmacol."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nchembio.167","article-title":"FTIR analysis of GPCR activation using azido probes","volume":"5","author":"Ye S.","year":"2009","unstructured":"S. Ye, T. Huber, R. Vogel, T. P. Sakmar, FTIR analysis of GPCR activation using azido probes. Nat. Chem. Biol. 5, 397\u2013399 (2009).","journal-title":"Nat. Chem. Biol."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"13358","DOI":"10.1073\/pnas.1818845116","article-title":"Gating modules of the AMPA receptor pore domain revealed by unnatural amino acid mutagenesis","volume":"116","author":"Poulsen M. H.","year":"2019","unstructured":"M. H. Poulsen, A. Poshtiban, V. Klippenstein, V. Ghisi, A. J. R. Plested, Gating modules of the AMPA receptor pore domain revealed by unnatural amino acid mutagenesis. Proc. Natl. Acad. Sci. U.S.A. 116, 13358\u201313367 (2019).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"11261","DOI":"10.1038\/ncomms11261","article-title":"Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter","volume":"7","author":"Rannversson H.","year":"2016","unstructured":"H. Rannversson ., Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter. Nat. Commun. 7, 11261 (2016).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature24031","article-title":"Expanding and reprogramming the genetic code","volume":"550","author":"Chin J. W.","year":"2017","unstructured":"J. W. Chin, Expanding and reprogramming the genetic code. Nature 550, 53\u201360 (2017).","journal-title":"Nature"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1074\/jbc.M705118200","article-title":"Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a","volume":"283","author":"Sherwood T. W.","year":"2008","unstructured":"T. W. Sherwood, C. C. Askwith, Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a. J. Biol. Chem. 283, 1818\u20131830 (2008).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"8430","DOI":"10.1073\/pnas.1806614115","article-title":"Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes","volume":"115","author":"Lynagh T.","year":"2018","unstructured":"T. Lynagh, Y. Mikhaleva, J. M. Colding, J. C. Glover, S. A. Pless, Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes. Proc. Natl. Acad. Sci. U.S.A. 115, 8430\u20138435 (2018).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1073\/pnas.1620560114","article-title":"Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating","volume":"114","author":"Vullo S.","year":"2017","unstructured":"S. Vullo ., Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating. Proc. Natl. Acad. Sci. U.S.A. 114, 3768\u20133773 (2017).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nature25782","article-title":"Gating mechanisms of acid-sensing ion channels","volume":"555","author":"Yoder N.","year":"2018","unstructured":"N. Yoder, C. Yoshioka, E. Gouaux, Gating mechanisms of acid-sensing ion channels. Nature 555, 397\u2013401 (2018).","journal-title":"Nature"},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"18000","DOI":"10.1038\/s41598-018-36125-5","article-title":"Screening of 109 neuropeptides on ASICs reveals no direct agonists and dynorphin A, YFMRFamide and endomorphin-1 as modulators","volume":"8","author":"Vyvers A.","year":"2018","unstructured":"A. Vyvers, A. Schmidt, D. Wiemuth, S. Gr\u00fcnder, Screening of 109 neuropeptides on ASICs reveals no direct agonists and dynorphin A, YFMRFamide and endomorphin-1 as modulators. Sci. Rep. 8, 18000 (2018).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1124\/mol.118.112375","article-title":"The conorfamide RPRFa stabilizes the open conformation of acid-sensing ion channel 3 via the nonproton ligand-sensing domain","volume":"94","author":"Reiners M.","year":"2018","unstructured":"M. Reiners ., The conorfamide RPRFa stabilizes the open conformation of acid-sensing ion channel 3 via the nonproton ligand-sensing domain. Mol. Pharmacol. 94, 1114\u20131124 (2018).","journal-title":"Mol. Pharmacol."},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1038\/s41598-018-37426-5","article-title":"Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides","volume":"9","author":"Bargeton B.","year":"2019","unstructured":"B. Bargeton ., Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides. Sci. Rep. 9, 2599 (2019).","journal-title":"Sci. Rep."},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1113\/jphysiol.2005.095810","article-title":"The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a","volume":"570","author":"Salinas M.","year":"2006","unstructured":"M. Salinas ., The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a. J. Physiol. 570, 339\u2013354 (2006).","journal-title":"J. Physiol."},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/bs.vh.2019.05.006","article-title":"Structure and dynamics of dynorphin peptide and its receptor","volume":"111","author":"Ferr\u00e9 G.","year":"2019","unstructured":"G. Ferr\u00e9, G. Czaplicki, P. Demange, A. Milon, Structure and dynamics of dynorphin peptide and its receptor. Vitam. Horm. 111, 17\u201347 (2019).","journal-title":"Vitam. Horm."},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"11852","DOI":"10.1073\/pnas.1510117112","article-title":"NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor","volume":"112","author":"O\u2019Connor C.","year":"2015","unstructured":"C. O\u2019Connor ., NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor. Proc. Natl. Acad. Sci. U.S.A. 112, 11852\u201311857 (2015).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/nrn3529","article-title":"Acid-sensing ion channels in pain and disease","volume":"14","author":"Wemmie J. A.","year":"2013","unstructured":"J. A. Wemmie, R. J. Taugher, C. J. Kreple, Acid-sensing ion channels in pain and disease. Nat. Rev. Neurosci. 14, 461\u2013471 (2013).","journal-title":"Nat. Rev. Neurosci."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nn.3750","article-title":"Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity","volume":"17","author":"Kreple C. J.","year":"2014","unstructured":"C. J. Kreple ., Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat. Neurosci. 17, 1083\u20131091 (2014).","journal-title":"Nat. Neurosci."},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/npp.2008.142","article-title":"Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone","volume":"34","author":"Wittmann W.","year":"2009","unstructured":"W. Wittmann ., Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone. Neuropsychopharmacology 34, 775\u2013785 (2009).","journal-title":"Neuropsychopharmacology"},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1038\/sj.npp.1300959","article-title":"Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice","volume":"31","author":"Kuzmin A.","year":"2006","unstructured":"A. Kuzmin, N. Madjid, L. Terenius, S. O. Ogren, G. Bakalkin, Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 31, 1928\u20131937 (2006).","journal-title":"Neuropsychopharmacology"},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1073\/pnas.0308753101","article-title":"Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior","volume":"101","author":"Wemmie J. A.","year":"2004","unstructured":"J. A. Wemmie ., Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior. Proc. Natl. Acad. Sci. U.S.A. 101, 3621\u20133626 (2004).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","first-page":"eaau3075","DOI":"10.1126\/sciadv.aau3075","article-title":"Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates","volume":"4","author":"Wang Q.","year":"2018","unstructured":"Q. Wang ., Fear extinction requires ASIC1a-dependent regulation of hippocampal-prefrontal correlates. Sci. Adv. 4, eaau3075 (2018).","journal-title":"Sci. Adv."},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1523\/JNEUROSCI.4009-13.2014","article-title":"ASIC1a activation enhances inhibition in the basolateral amygdala and reduces anxiety","volume":"34","author":"Pidoplichko V. I.","year":"2014","unstructured":"V. I. Pidoplichko ., ASIC1a activation enhances inhibition in the basolateral amygdala and reduces anxiety. J. Neurosci. 34, 3130\u20133141 (2014).","journal-title":"J. Neurosci."},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"6207","DOI":"10.1073\/pnas.77.10.6207","article-title":"Immunoreactive dynorphin in pituitary and brain","volume":"77","author":"Goldstein A.","year":"1980","unstructured":"A. Goldstein, V. E. Ghazarossian, Immunoreactive dynorphin in pituitary and brain. Proc. Natl. Acad. Sci. U.S.A. 77, 6207\u20136210 (1980).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_54_2","first-page":"1248","article-title":"Levels of endogenous opioids and effects of an opiate antagonist during regional cerebral ischemia in rats","volume":"247","author":"Andrews B. T.","year":"1988","unstructured":"B. T. Andrews, T. K. McIntosh, M. F. Gonzales, P. R. Weinstein, A. I. Faden, Levels of endogenous opioids and effects of an opiate antagonist during regional cerebral ischemia in rats. J. Pharmacol. Exp. Ther. 247, 1248\u20131254 (1988).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.bcp.2019.03.004","article-title":"The modulation of acid-sensing ion channel 1 by PcTx1 is pH-, subtype- and species-dependent: Importance of interactions at the channel subunit interface and potential for engineering selective analogues","volume":"163","author":"Cristofori-Armstrong B.","year":"2019","unstructured":"B. Cristofori-Armstrong, N. J. Saez, I. R. Chassagnon, G. F. King, L. D. Rash, The modulation of acid-sensing ion channel 1 by PcTx1 is pH-, subtype- and species-dependent: Importance of interactions at the channel subunit interface and potential for engineering selective analogues. Biochem. Pharmacol. 163, 381\u2013390 (2019).","journal-title":"Biochem. Pharmacol."},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","first-page":"25977","DOI":"10.18632\/oncotarget.10774","article-title":"Over-expression of ASIC1a promotes proliferation via activation of the \u03b2-catenin\/LEF-TCF axis and is associated with disease outcome in liver cancer","volume":"8","author":"Jin C.","year":"2017","unstructured":"C. Jin ., Over-expression of ASIC1a promotes proliferation via activation of the \u03b2-catenin\/LEF-TCF axis and is associated with disease outcome in liver cancer. Oncotarget 8, 25977\u201325988 (2017).","journal-title":"Oncotarget"},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","unstructured":"C. B. Borg . Mechanism and site of action of big dynorphin on ASIC1a [Data set]. Zenodo. http:\/\/doi.org\/10.5281\/zenodo.3686254. Deposited 24 February 2020.","DOI":"10.1101\/816264"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1919323117","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1919323117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T16:56:34Z","timestamp":1654620994000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1919323117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,12]]},"references-count":57,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2020,3,31]]}},"alternative-id":["10.1073\/pnas.1919323117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1919323117","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/816264","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,12]]},"assertion":[{"value":"2020-03-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}