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Novel mechanism of blocking axonal Na + channels by three macrocyclic polyamine analogues and two spider toxins
Author(s) -
Yakehiro Masuhide,
Furukawa Yasuo,
Koike Tohru,
Kimura Eiichi,
Nakajima Terumi,
Yamaoka Kaoru,
Seyama Issei
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703765
Subject(s) - cyclam , polyamine , chemistry , biophysics , gating , depolarization , spider toxin , sodium channel , stereochemistry , patch clamp , sodium , biochemistry , receptor , biology , organic chemistry , glutamate receptor , metal
The mechanism of Na + channel block by three macrocyclic polyamine derivatives and two spider toxins was studied with voltage clamp and internal perfusion method in squid axons. All these chemicals specifically block Na + channels in the open state only from the internal surface, and do not affect K + channels. The blocking effect is enhanced as the depolarizing pulse becomes larger. Blocked channels are unable to shift to the inactivated state. In the case of cyclam and guanidyl‐side armed cyclam (G‐cyclam), quick release of these chemicals from the binding sites is proven by the increase in the tail current and prolongation of the time course of the off gating current. On the other hand, in the presence of N‐4 and the spider toxins, their detachment was delayed significantly. Molecular requirements for the block of Na + channels by these molecules are the presence of positive charge and hydrophobicity.British Journal of Pharmacology (2001) 132 , 63–72; doi: 10.1038/sj.bjp.0703765