THE RELATIONSHIP OF BREVETOXIN LENGTH AND A-RING FUNCTIONALITY TO BINDING AND AC

2020-03-25 08:51:53

channel potential binding activation brevetoxin

责任者: GAWLEY, RE;REIN, KS;JEGLITSCH, G;ADAMS, DJ;THEODORAKIS, EA;TIEBES, J;NICOLAOU, KC;BADEN, DG 单位: NIEHS, MARINE & FRESHWATER BIOMED SCI CTR, MIAMI, FL 33149 USA.;UNIV MIAMI, SCH MED, DEPT MOLEC & CELLULAR PHARMACOL, MIAMI, FL 33101 USA.;Scripps Res Inst, DEPT CHEM, LA JOLLA, CA 92037 USA.;UNIV CAL 来源出处: CHEMISTRY & BIOLOGY, v 2, AUG 1995, p 533- 541 摘要: 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, similar to 30 Angstrom 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. 关键词: BREVETOXIN; PATCH-CLAMP; SINGLE SODIUM CHANNEL CURRENTS; SUBCONDUCTANCE STATES; SYNAPTOSOME BINDING STATES; SYNAPTOSOME BINDING; RAT-BRAIN SYNAPTOSOMES; RECEPTOR