2. Academic Validation
  3. Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels

Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels

  • J Biol Chem. 2010 Feb 5;285(6):4130-4142. doi: 10.1074/jbc.M109.054718.
Elisa Redaelli 1,  Rita Restano Cassulini 2,  Deyanira Fuentes Silva 3,  Herlinda Clement 4,  Emanuele Schiavon 1,  Fernando Z Zamudio 4,  George Odell 4,  Annarosa Arcangeli 5,  Jeffrey J Clare 6,  Alejandro Alagón 4,  Ricardo C Rodríguez de la Vega 7,  Lourival D Possani 4,  Enzo Wanke 8
Affiliations

Affiliations

  • 1 From the Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy.
  • 2 From the Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy; the Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, México.
  • 3 the Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Coyoacán DF 04510, México.
  • 4 the Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, México.
  • 5 the Dipartimento di Patologia e Oncologia Sperimentali, Università di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
  • 6 Gene Expression and Protein Biochemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, United Kingdom, and.
  • 7 the Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, México; the Structural and Computational Biology/Genome Biology Units, European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg 69117, Germany.
  • 8 From the Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy. Electronic address: enzo.wanke@unimib.it.
PMID: 19955179 DOI: 10.1074/jbc.M109.054718
Abstract

Venom-derived peptide modulators of ion channel gating are regarded as essential tools for understanding the molecular motions that occur during the opening and closing of ion channels. In this study, we present the characterization of five spider toxins on 12 human voltage-gated ion channels, following observations about the target promiscuity of some spider toxins and the ongoing revision of their "canonical" gating-modifying mode of action. The Peptides were purified de novo from the venom of Grammostola rosea tarantulas, and their sequences were confirmed by Edman degradation and mass spectrometry analysis. Their effects on seven tetrodotoxin-sensitive Na(+) channels, the three human ether-à-go-go (hERG)-related K(+) channels, and two human Shaker-related K(+) channels were extensively characterized by electrophysiological techniques. All the Peptides inhibited ion conduction through all the Na(+) channels tested, although with distinctive patterns. The Peptides also affected the three pharmaceutically relevant hERG isoforms differently. At higher concentrations, all Peptides also modified the gating of the Na(+) channels by shifting the activation to more positive potentials, whereas more complex effects were recorded on hERG channels. No effects were evident on the two Shaker-related K(+) channels at concentrations well above the IC(50) value for the affected channels. Given the sequence diversity of the tested Peptides, we propose that tarantula toxins should be considered both as multimode and target-promiscuous ion channel modulators; both features should not be ignored when extracting mechanistic interpretations about ion channel gating. Our observations could also aid in future structure-function studies and might help the development of novel ion channel-specific drugs.

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