title: Binding specificity of sea anemone toxins to Nav 1.1-1.6 sodium channels: unexpected contributions from differences in the IV/S3-S4 outer loop.
abstract: Sea anemones are an important source of various biologically active peptides, and it is known that ATX-II from Anemonia sulcata slows sodium current inactivation. Using six different sodium channel genes (from Nav1.1 to Nav1.6), we investigated the differential selectivity of the toxins AFT-II (purified from Anthopleura fuscoviridis) and Bc-III (purified from Bunodosoma caissarum) and compared their effects with those recorded in the presence of ATX-II. Interestingly, ATX-II and AFT-II differ by only one amino acid (L36A) and Bc-III has 70% similarity. The three toxins induced a low voltage-activated persistent component primarily in the Nav1.3 and Nav1.6 channels. An analysis showed that the 18 dose-response curves only partially fit the hypothesized binding of Lys-37 (sea anemone toxin Anthopleurin B) to the Asp (or Glu) residue of the extracellular IV/S3-S4 loop in cardiac (or nervous) Na+ channels, thus suggesting the substantial contribution of some nearby amino acids that are different in the various channels. As these channels are atypically expressed in mammalian tissues, the data not only suggest that the toxicity is highly dependent on the channel type but also that these toxins and their various physiological effects should be considered prototype models for the design of new and specific pharmacological tools.
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza, 2, Milan 20126, Italy.
authors.forename: Joacir Stolarz
authors.initials: JS
authors.lastname: Oliveira
authors.forename: Elisa
authors.initials: E
authors.lastname: Redaelli
authors.forename: André J
authors.initials: AJ
authors.lastname: Zaharenko
authors.forename: Rita Restano
authors.initials: RR
authors.lastname: Cassulini
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Konno
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Pimenta
authors.forename: José C
authors.initials: JC
authors.lastname: Freitas
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Clare
authors.forename: Enzo
authors.initials: E
authors.lastname: Wanke
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003064:Cnidarian Venoms / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D006801:Humans; D007668:Kidney; D008387:Marine Toxins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012615:Sea Anemones; D017385:Sequence Homology; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D003064:Cnidarian Venoms; D008387:Marine Toxins; D010455:Peptides; D015222:Sodium Channels; C083402:anemone toxin BcIII (Bunodosoma caissarum); C052366:AFT-II toxin; C028800:toxin II (Anemonia sulcata)