COMPARATIVE-ANALYSIS OF THE EFFECTS OF SYNTHETIC DERIVATIVES OF BATRACHOTOXIN ON SODIUM CURRENTS IN FROG NODE OF RANVIER

被引:8
作者
KHODOROV, BI [1 ]
YELIN, EA [1 ]
ZABOROVSKAYA, LD [1 ]
MAKSUDOV, MZ [1 ]
TIKHOMIROVA, OB [1 ]
LEONOV, VN [1 ]
机构
[1] MM SHEMYAKIN BIOORGAN CHEM INST,MOSCOW 117312,USSR
关键词
BATRACHOTOXIN DERIVATIVES; NA CHANNELS; ACTIVATION; INACTIVATION; BLOCKADE; NERVE MEMBRANE; NODE OF RANVIER;
D O I
10.1007/BF00711639
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
1. In voltage-clamp experiments on frog myelinated nerve fibers, the effects of nine synthetic derivatives of batrachotoxin (BTX) obtained from 7,8-dihydrobatrachotoxinin A (DBTX-A) on Na+ currents (I(Na)) have been investigated. 2. Both of 20-alpha-esters of DBTX-A with 2,4,5-trimethylpyrrol-3-carboxylic acid (DBTX-P) and benzoic acid (DBTX) at a 10(-5) M concentration caused modification of I(Na) qualitatively similar to that induced by BTX. 3. The quaternary derivative of DBTX (QDBTX) produced such changes in I(Na) only at a 5.10(-4) M concentration, apparently due to its much lower lipid solubility. 4. Replacement of a -CH2- by a -C = O. group in the homomorpholine ring near the tertiary nitrogen atom abolished the DBTX activity, strongly suggesting the necessity of tertiary nitrogen protonation for the toxin interaction with the channel receptor. 5. Transfer of an 11-hydroxygroup from the alpha- to the beta-position in the DBTX molecule did not decrease its activity in spite of the fact that in the beta-position this group is sterically very hindered. The activity of 11-beta-DBTX is at variance with the prediction of Codding's (1983) "oxygen triad" hypothesis. 6. DBTX-A and compounds obtained from DBTX by oxidation of the 11 alpha-hydroxygroup (K-DBTX), acetylation (Ac-DBTX), or reduction of the hemiketal moiety (H2DBTX) even at a concentration as high as 10(-3) M were able to modify only a very small fraction of the Na channels. However, a clear-cut reversible blocking action on both normal and modified Na channels was observed. 7. These results led us to conclude that BTX modifies the Na channels only in the charged form and hemiketal and 20-alpha-ester moieties provide adequate disposition of toxin on the receptor surface. The inability of H2DBTX, DBTX-A, and K-DBTX and Ac-DBTX to modify most of the Na channels can be explained by a low "probability of correct disposition" of these ligands on the receptor surface.
引用
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页码:59 / 81
页数:23
相关论文
共 29 条
[1]  
ALBUQUERQUE EX, 1976, SPECIFICITY ACTION B, V1, P297
[2]  
ANGELIDES KJ, 1984, J BIOL CHEM, V259, P6117
[3]   BATRACHOTOXININ-A 20-ALPHA-BENZOATE - A NEW RADIOACTIVE LIGAND FOR VOLTAGE SENSITIVE SODIUM-CHANNELS [J].
BROWN, GB ;
TIESZEN, SC ;
DALY, JW ;
WARNICK, JE ;
ALBUQUERQUE, EX .
CELLULAR AND MOLECULAR NEUROBIOLOGY, 1981, 1 (01) :19-40
[4]   INTERACTION OF BATRACHOTOXININ-A BENZOATE WITH VOLTAGE-SENSITIVE SODIUM-CHANNELS - THE EFFECTS OF PH [J].
BROWN, GB ;
DALY, JW .
CELLULAR AND MOLECULAR NEUROBIOLOGY, 1981, 1 (04) :361-371
[5]  
BROWN GB, 1986, J NEUROSCI, V6, P2064
[6]   BATRACHOTOXIN - A WINDOW ON THE ALLOSTERIC NATURE OF THE VOLTAGE-SENSITIVE SODIUM-CHANNEL [J].
BROWN, GB .
INTERNATIONAL REVIEW OF NEUROBIOLOGY, 1988, 29 :77-116
[8]  
CATTERALL WA, 1981, J BIOL CHEM, V256, P8922
[9]  
CATTERALL WA, 1977, J BIOL CHEM, V252, P8660