og:image: https://www.pnas.org/sites/default/files/highwire/pnas/116/3.cover-source.jpg citation_mjid: pnas;116/3/1059 article:published_time: 2019-01-15 og:site_name: PNAS citation_reference: citation_journal_title=J Biol Chem;citation_author=P. Chen;citation_author=A. Dendorfer;citation_author=RK. Finol-Urdaneta;citation_author=H. Terlau;citation_author=BM. Olivera;citation_title=Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: Evaluation of cardioprotective effects of kappaM-conotoxins;citation_volume=285;citation_year=2010;citation_pmid=20220134;citation_doi=10.1074/jbc.M109.068486 citation_journal_title: Proceedings of the National Academy of Sciences type: article og:description: Most ion channels are multimeric (typically comprising 3?5 subunits). The subunits are encoded by homologous members of a gene family, generating an enormous set of possible heteromeric combinations. In this study, we provide evidence that the preferred target of conopeptide ?M-RIIIJ is a heteromeric Kv1 channel consisting of three Kv1.2 subunits and one Kv1.1 or Kv1.6 subunit. We define the molecular interaction of ?M-RIIIJ with these asymmetric Kv1 channels and show that in dorsal root ganglia (DRG) neurons, different ?M-RIIIJ concentrations can distinguish discrete subpopulations of neurons. Our results highlight the potential of natural products and venom components, such as conopeptides, to generally elucidate native physiological roles of specific heteromeric ion channel isoforms at the cellular, circuit, and systems level. citation_author_email: olivera@biology.utah.edu citation_issn: 0027-8424 citation_full_html_url: https://www.pnas.org/content/116/3/1059.full citation_public_url: https://www.pnas.org/content/116/3/1059 dc:title: Conotoxin ?M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels | PNAS Content-Encoding: UTF-8 citation_pdf_url: https://www.pnas.org/content/pnas/116/3/1059.full.pdf citation_section: Biological Sciences citation_num_pages: 6 citation_lastpage: 1064 citation_journal_abbrev: PNAS DC.Identifier: 10.1073/pnas.1813161116 DC.Rights: © 2019 . Published under the PNAS license. citation_author: Sönke Cordeiro citation_abstract_html_url: https://www.pnas.org/content/116/3/1059.abstract citation_issue: 3 HW.identifier: /pnas/116/3/1059.atom citation_doi: 10.1073/pnas.1813161116 citation_volume: 116 Content-Language: en Generator: Drupal 7 (http://drupal.org) format-detection: telephone=no citation_author_orcid: http://orcid.org/0000-0003-2157-4532 DC.AccessRights: restricted citation_publication_date: 2019/01/15 citation_title: Conotoxin ?M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels citation_author_institution: Christian-Albrechts-University Kiel citation_publisher: National Academy of Sciences citation_id: 116/3/1059 title: Conotoxin ?M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels | PNAS DC.Description: Most ion channels are multimeric (typically comprising 3?5 subunits). The subunits are encoded by homologous members of a gene family, generating an enormous set of possible heteromeric combinations. In this study, we provide evidence that the preferred target of conopeptide ?M-RIIIJ is a heteromeric Kv1 channel consisting of three Kv1.2 subunits and one Kv1.1 or Kv1.6 subunit. We define the molecular interaction of ?M-RIIIJ with these asymmetric Kv1 channels and show that in dorsal root ganglia (DRG) neurons, different ?M-RIIIJ concentrations can distinguish discrete subpopulations of neurons. Our results highlight the potential of natural products and venom components, such as conopeptides, to generally elucidate native physiological roles of specific heteromeric ion channel isoforms at the cellular, circuit, and systems level. Content-Type-Hint: text/html; charset=utf-8 DC.Format: text/html DC.Publisher: National Academy of Sciences DC.Contributor: Sönke Cordeiro Content-Type: application/xhtml+xml; charset=UTF-8 X-Parsed-By: org.apache.tika.parser.DefaultParser og:type: article article:section: Biological Sciences citation_pmid: 30593566 citation_article_type: Research Article og:title: Conotoxin ?M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels citation_abstract:

The vast complexity of native heteromeric K+ channels is largely unexplored. Defining the composition and subunit arrangement of individual subunits in native heteromeric K+ channels and establishing their physiological roles is experimentally challenging. Here we systematically explored this ?zone of ignorance? in molecular neuroscience. Venom components, such as peptide toxins, appear to have evolved to modulate physiologically relevant targets by discriminating among closely related native ion channel complexes. We provide proof-of-principle for this assertion by demonstrating that ?M-conotoxin RIIIJ (?M-RIIIJ) from Conus radiatus precisely targets ?asymmetric? Kv channels composed of three Kv1.2 subunits and one Kv1.1 or Kv1.6 subunit with 100-fold higher apparent affinity compared with homomeric Kv1.2 channels. Our study shows that dorsal root ganglion (DRG) neurons contain at least two major functional Kv1.2 channel complexes: a heteromer, for which ?M-RIIIJ has high affinity, and a putative Kv1.2 homomer, toward which ?M-RIIIJ is less potent. This conclusion was reached by (i) covalent linkage of members of the mammalian Shaker-related Kv1 family to Kv1.2 and systematic assessment of the potency of ?M-RIIIJ block of heteromeric K+ channel-mediated currents in heterologous expression systems; (ii) molecular dynamics simulations of asymmetric Kv1 channels providing insights into the molecular basis of ?M-RIIIJ selectivity and potency toward its targets; and (iii) evaluation of calcium responses of a defined population of DRG neurons to ?M-RIIIJ. Our study demonstrates that bioactive molecules present in venoms provide essential pharmacological tools that systematically target specific heteromeric Kv channel complexes that operate in native tissues.

DC.Title: Conotoxin ?M-RIIIJ, a tool targeting asymmetric heteromeric Kv1 channels issue_cover_image: https://www.pnas.org/sites/default/files/highwire/pnas/116/3.cover-source.jpg citation_firstpage: 1059 viewport: initial-scale=1, maximum-scale=1, width=device-width, user-scalable=yes citation_funding_source: citation_funder_id=100000057;citation_grant_number=GM 048677; HW.pisa: pnas;116/3/1059 DC.Language: en DC.Date: 2019-01-15 category: research-article og:url: https://www.pnas.org/content/116/3/1059