title: The relationship of brevetoxin 'length' and A-ring functionality to binding and activity in neuronal sodium channels.
abstract: BACKGROUND
  Brevetoxins are polyether ladder toxins that are ichthyotoxic at nanomolar concentrations. They bind to voltage-gated sodium channels, causing four distinct electrophysiological effects: (i) a shift of activation potential; (ii) occurrence of subconductance states; (iii) induction of longer mean open times of the channel; and (iv) inhibition of channel inactivation. We set out to determine whether these functions all require the same structural elements within the brevetoxin molecules.
  
  
  RESULTS
  Several synthetically prepared structural analogs of brevetoxin B were examined in synaptosome receptor binding assays and by functional electrophysiological measurements. A truncated analog is not ichthyotoxic at micromolar concentrations, shows decreased receptor-binding affinity, and causes only a shift of activation potential without affecting mean open times or channel inactivation. An analog with the A-ring carbonyl removed binds to the receptor with nanomolar affinity, produces a shift of activation potential and inhibits inactivation, but does not induce longer mean open times. An analog in which the A-ring diol is reduced shows low binding affinity, yet populates five subconductance states.
  
  
  CONCLUSIONS
  Our data are consistent with the hypothesis that binding to sodium channels requires an elongated cigar-shaped molecule, approximately 30 A long. The four electrophysiological effects of the brevetoxins are not produced by a single structural feature, however, since they can be decoupled by using modified ligands, which are shown here to be partial sodium channel agonists. We propose a detailed model for the binding of brevetoxins to the channel which explains the differences in the effects of the brevetoxin analogs. These studies also offer the potential for developing brevetoxin antagonists.
authors.affiliation: Department of Chemistry, University of Miami, Coral Gables, FL 33124, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Gawley
authors.forename: K S
authors.initials: KS
authors.lastname: Rein
authors.forename: G
authors.initials: G
authors.lastname: Jeglitsch
authors.forename: D J
authors.initials: DJ
authors.lastname: Adams
authors.forename: E A
authors.initials: EA
authors.lastname: Theodorakis
authors.forename: J
authors.initials: J
authors.lastname: Tiebes
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: D G
authors.initials: DG
authors.lastname: Baden
mesh_terms: D000818:Animals; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D008387:Marine Toxins / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology*; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D035964:Oxocins; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000095702:Polyether Toxins
chemical_list: D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C053342:brevetoxin; D000095702:Polyether Toxins