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Titolo:
THE RELATIONSHIP OF BREVETOXIN LENGTH AND A-RING FUNCTIONALITY TO BINDING AND ACTIVITY IN NEURONAL SODIUM-CHANNELS
Autore:
GAWLEY RE; REIN KS; JEGLITSCH G; ADAMS DJ; THEODORAKIS EA; TIEBES J; NICOLAOU KC; BADEN DG;
Indirizzi:
UNIV MIAMI,DEPT CHEM,POB 249118 CORAL GABLES FL 33124 NIEHS,MARINE & FRESHWATER BIOMED SCI CTR MIAMI FL 33149 UNIV MIAMI,SCH MED,DEPT MOLEC & CELLULAR PHARMACOL MIAMI FL 33101 SCRIPPS CLIN & RES INST,DEPT CHEM LA JOLLA CA 92037 UNIV CALIF SAN DIEGO,DEPT CHEM & BIOCHEM LA JOLLA CA 92093
Titolo Testata:
Chemistry & biology
fascicolo: 8, volume: 2, anno: 1995,
pagine: 533 - 541
SICI:
1074-5521(1995)2:8<533:TROBLA>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT-BRAIN SYNAPTOSOMES; RECEPTOR;
Keywords:
BREVETOXIN; PATCH-CLAMP; SINGLE SODIUM CHANNEL CURRENTS; SUBCONDUCTANCE STATES; SYNAPTOSOME BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
20
Recensione:
Indirizzi per estratti:
Citazione:
R.E. Gawley et al., "THE RELATIONSHIP OF BREVETOXIN LENGTH AND A-RING FUNCTIONALITY TO BINDING AND ACTIVITY IN NEURONAL SODIUM-CHANNELS", Chemistry & biology, 2(8), 1995, pp. 533-541

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, similar to 30 Angstrom long. The four electrophysiological effects of the brevetoxins are not produced by a singlestructural 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 thechannel which explains the differences in the effects of the brevetoxin analogs. These studies also offer the potential for developing brevetoxin antagonists.

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Documento generato il 02/04/20 alle ore 00:17:43