A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3
Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins...
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| Veröffentlicht in: | PLoS biology 2023-08, Vol.21 (8), p.e3002217 |
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| creator | Hackney, Celeste M Flórez Salcedo, Paula Mueller, Emilie Koch, Thomas Lund Kjelgaard, Lau D Watkins, Maren Zachariassen, Linda G Tuelung, Pernille Sønderby McArthur, Jeffrey R Adams, David J Kristensen, Anders S Olivera, Baldomero Finol-Urdaneta, Rocio K Safavi-Hemami, Helena Morth, Jens Preben Ellgaard, Lars |
| description | Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins. |
| doi_str_mv | 10.1371/journal.pbio.3002217 |
| format | Article |
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The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.3002217</identifier><identifier>PMID: 37535677</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biology and Life Sciences ; Calcium Channels ; Calcium channels (R-type) ; Calcium channels (voltage-gated) ; Calcium compounds ; Calcium influx ; Calcium ions ; Calcium signalling ; Channel gating ; Chemical bonds ; Chemical inhibitors ; Chronic pain ; Cluster analysis ; Cone snails ; Conotoxins ; Conotoxins - chemistry ; Conotoxins - pharmacology ; Crystal structure ; Dorsal root ganglia ; FDA approval ; Health aspects ; Investigations ; Ion channels ; Kinases ; Medicine and Health Sciences ; Mice ; Mollusks ; Multidisciplinary research ; Neurons ; Neurotoxic agents ; Peptides ; Peptides - chemistry ; Physical Sciences ; Physiological aspects ; Potassium channels (voltage-gated) ; Proteins ; Sensory Receptor Cells - metabolism ; Snails ; Social Sciences ; Testing ; Toxins ; Venom</subject><ispartof>PLoS biology, 2023-08, Vol.21 (8), p.e3002217</ispartof><rights>Copyright: © 2023 Hackney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Hackney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. 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The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. 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| ispartof | PLoS biology, 2023-08, Vol.21 (8), p.e3002217 |
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| language | eng |
| recordid | cdi_plos_journals_2865506127 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central |
| subjects | Animals Biology and Life Sciences Calcium Channels Calcium channels (R-type) Calcium channels (voltage-gated) Calcium compounds Calcium influx Calcium ions Calcium signalling Channel gating Chemical bonds Chemical inhibitors Chronic pain Cluster analysis Cone snails Conotoxins Conotoxins - chemistry Conotoxins - pharmacology Crystal structure Dorsal root ganglia FDA approval Health aspects Investigations Ion channels Kinases Medicine and Health Sciences Mice Mollusks Multidisciplinary research Neurons Neurotoxic agents Peptides Peptides - chemistry Physical Sciences Physiological aspects Potassium channels (voltage-gated) Proteins Sensory Receptor Cells - metabolism Snails Social Sciences Testing Toxins Venom |
| title | A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T04%3A23%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20previously%20unrecognized%20superfamily%20of%20macro-conotoxins%20includes%20an%20inhibitor%20of%20the%20sensory%20neuron%20calcium%20channel%20Cav2.3&rft.jtitle=PLoS%20biology&rft.au=Hackney,%20Celeste%20M&rft.date=2023-08-03&rft.volume=21&rft.issue=8&rft.spage=e3002217&rft.pages=e3002217-&rft.issn=1545-7885&rft.eissn=1545-7885&rft_id=info:doi/10.1371/journal.pbio.3002217&rft_dat=%3Cgale_plos_%3EA765118417%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2865506127&rft_id=info:pmid/37535677&rft_galeid=A765118417&rft_doaj_id=oai_doaj_org_article_f3193ac4359d4247b682641281507d58&rfr_iscdi=true |