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.
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.
Oliveira
Joacir Stolarz
JS
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza, 2, Milan 20126, Italy.
Redaelli
Elisa
E
Zaharenko
André J
AJ
Cassulini
Rita Restano
RR
Konno
Katsuhiro
K
Pimenta
Daniel C
DC
Freitas
José C
JC
Clare
Jeffrey J
JJ
Wanke
Enzo
E
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
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)