Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Interactions of the C-11 hydroxyl of tetrodotoxin with the sodium channel outer vestibule.
Choudhary G
,
Yotsu-Yamashita M
,
Shang L
,
Yasumoto T
,
Dudley SC
.
???displayArticle.abstract???
The highly selective sodium channel blocker, tetrodotoxin (TTX) has been instrumental in characterization of voltage-gated sodium channels. TTX occludes the ion-permeation pathway at the outer vestibule of the channel. In addition to a critical guanidinium group, TTX possesses six hydroxyl groups, which appear to be important for toxin block. The nature of their interactions with the outer vestibule remains debatable, however. The C-11 hydroxyl (C-11 OH) has been proposed to interact with the channel through a hydrogen bond to a carboxyl group, possibly from domain IV. On the other hand, previous experiments suggest that TTX interacts most strongly with pore loops of domains I and II. Energetic localization of the C-11 OH was undertaken by thermodynamic mutant cycle analysis assessing the dependence of the effects of mutations of the adult rat skeletal muscle Na(+) channel (rNa(v)1.4) and the presence of C-11 OH on toxin IC(50). Xenopus oocytes were injected with the mutant or native Na(+) channel mRNA, and currents were measured by two-electrode voltage clamp. Toxin blocking efficacy was determined by recording the reduction in current upon toxin exposure. Mutant cycle analysis revealed that the maximum interaction of the C-11 OH was with domain IV residue D1532 (DeltaDeltaG: 1.0 kcal/mol). Furthermore, C-11 OH had significantly less interaction with several domain I, II, and III residues. The pattern of interactions suggested that C-11 was closest to domain IV, probably involved in a hydrogen bond with the domain IV carboxyl group. Incorporating this data, a new molecular model of TTX binding is proposed.
Choudhary,
Energetic localization of saxitoxin in its channel binding site.
2002, Pubmed,
Xenbase
Choudhary,
Energetic localization of saxitoxin in its channel binding site.
2002,
Pubmed
,
Xenbase
Dudley,
mu-conotoxin GIIIA interactions with the voltage-gated Na(+) channel predict a clockwise arrangement of the domains.
2000,
Pubmed
Faiman,
On the choice of reference mutant states in the application of the double-mutant cycle method.
1996,
Pubmed
Heinemann,
Calcium channel characteristics conferred on the sodium channel by single mutations.
1992,
Pubmed
,
Xenbase
Kao,
Actions of 4-epitetrodotoxin and anhydrotetrodotoxin on the squid axon.
1985,
Pubmed
Kao,
Structure-activity relations of tetrodotoxin, saxitoxin, and analogues.
1986,
Pubmed
Kirsch,
Differential effects of sulfhydryl reagents on saxitoxin and tetrodotoxin block of voltage-dependent Na channels.
1994,
Pubmed
Li,
Latent specificity of molecular recognition in sodium channels engineered to discriminate between two "indistinguishable" mu-conotoxins.
2001,
Pubmed
Li,
Clockwise domain arrangement of the sodium channel revealed by (mu)-conotoxin (GIIIA) docking orientation.
2001,
Pubmed
Lipkind,
KcsA crystal structure as framework for a molecular model of the Na(+) channel pore.
2000,
Pubmed
Mosher,
The chemistry of tetrodotoxin.
1986,
Pubmed
Nakamura,
Tetrodotoxin derivatives in puffer fish.
1985,
Pubmed
Nanda,
Aromatic interactions in homeodomains contribute to the low quantum yield of a conserved, buried tryptophan.
2000,
Pubmed
Nanda,
Hydrophobic clustering in acid-denatured IL-2 and fluorescence of a Trp NH-pi H-bond.
2000,
Pubmed
Narahashi,
Tetrodotoxin derivatives: chemical structure and blockage of nerve membrane conductance.
1967,
Pubmed
Penzotti,
Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis.
2001,
Pubmed
,
Xenbase
Penzotti,
Differences in saxitoxin and tetrodotoxin binding revealed by mutagenesis of the Na+ channel outer vestibule.
1998,
Pubmed
,
Xenbase
Ritchie,
Characterization of exchange-labeled saxitoxin and the origin of linear uptake by excitable tissue.
1977,
Pubmed
Stephan,
The microI skeletal muscle sodium channel: mutation E403Q eliminates sensitivity to tetrodotoxin but not to mu-conotoxins GIIIA and GIIIB.
1994,
Pubmed
,
Xenbase
Sun,
On the structural basis for size-selective permeation of organic cations through the voltage-gated sodium channel. Effect of alanine mutations at the DEKA locus on selectivity, inhibition by Ca2+ and H+, and molecular sieving.
1997,
Pubmed
Sunami,
Sodium channel selectivity filter regulates antiarrhythmic drug binding.
1997,
Pubmed
,
Xenbase
Terlau,
Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II.
1991,
Pubmed
,
Xenbase
Wu,
11-Oxo-tetrodotoxin and a specifically labelled 3H-tetrodotoxin.
1996,
Pubmed
Yang,
Actions of 6-epitetrodotoxin and 11-deoxytetrodotoxin on the frog skeletal muscle fiber.
1992,
Pubmed
Yang,
Actions of chiriquitoxin on frog skeletal muscle fibers and implications for the tetrodotoxin/saxitoxin receptor.
1992,
Pubmed
Yotsu-Yamashita,
Effects of specific modifications of several hydroxyls of tetrodotoxin on its affinity to rat brain membrane.
1999,
Pubmed
