OVERPRODUCTION OF VOLTAGE-DEPENDENT NA+ CHANNELS IN THE DEVELOPING BRAIN OF GENETICALLY SEIZURE-SUSCEPTIBLE E1-MICE

被引:34
作者
SASHIHARA, S
YANAGIHARA, N
KOBAYASHI, H
IZUMI, F
TSUJI, S
MURAI, Y
MITA, T
机构
[1] UNIV OCCUPAT & ENVIRONM HLTH,SCH MED,DEPT NEUROL,KITAKYUSHU,FUKUOKA 807,JAPAN
[2] UNIV OCCUPAT & ENVIRONM HLTH,SCH MED,DEPT PHARMACOL,KITAKYUSHU,FUKUOKA 807,JAPAN
关键词
D O I
10.1016/0306-4522(92)90490-S
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We used E1 mice, a ddY mouse-derived, autosomal mutant strain and a model of hereditary sensory-precipitated epilepsy, to test the hypothesis that epileptic susceptibility may be associated with the activity of voltage-dependent ion channels. We examined the saxitoxin binding capacity of the receptor site 1 of the Na+ channel alpha-subunit, the expression activity of the Na+ channel mRNA, the veratridine-induced Na-22(+) influx in the brain synaptosomes, and the regional distribution of Na+ channels in the brain. Compared with control ddY mice, in E1 mice which have not experienced seizures, the number of Na+ channels in the brain synaptosomes increased by approximately 20% starting at the fourth postnatal week through the adult stage as determined by [H-3]saxitoxin binding assay. Northern blot hybridization analysis showed excess expression of Na+ channel mRNA (by 30-40%) coincidentally with Na+ channel increases. Regional analysis using the saxitoxin binding assay demonstrated approximately 1.3-fold denser distribution of Na+ channels in the cortex and cerebellum but not the hippocampus and midbrain including thalamus of E1 mice compared to ddY mice. Scatchard plot analysis for saxitoxin binding in the cortex of E1 mouse brains revealed higher maximum binding capacity (B(max)) values (ddY, 4.43 +/- 0.28 pmol/mg protein; E1, 5.43 +/- 0.25 pmol/mg protein) without a change in K(d) (ddY, 1.05 +/- 0.03 nM; E1, 1.03 +/- 0.01 nM). Lastly, veratridine-evoked Na-22(+) influx, sensitive to tetrodotoxin, was increased approximately 45% in the cortical synaptosomes in six-week-old E1 mice. These results suggest that E1 brains characteristically produce an excess of voltage-dependent Na+ channels which is responsible for hyperexcitability of the central nervous system and may account for the predisposition of E1 mice to epileptic seizures.
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页码:285 / 291
页数:7
相关论文
共 36 条
[1]   NA+-CHANNEL-ASSOCIATED SCORPION TOXIN RECEPTOR-SITES AS PROBES FOR NEURONAL EVOLUTION INVIVO AND INVITRO [J].
BERWALDNETTER, Y ;
MARTINMOUTOT, N ;
KOULAKOFF, A ;
COURAUD, F .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1981, 78 (02) :1245-1249
[2]   ULTRASTRUCTURAL VISUALIZATION OF NA+-CHANNEL ASSOCIATED [I125] ALPHA-SCORPION TOXIN BINDING-SITES ON FETAL MOUSE NERVE-CELLS IN CULTURE [J].
BOUDIER, JA ;
BERWALDNETTER, Y ;
DELLMANN, HD ;
BOUDIER, JL ;
COURAUD, F ;
KOULAKOFF, A ;
CAU, P .
DEVELOPMENTAL BRAIN RESEARCH, 1985, 20 (01) :137-142
[3]  
CATTERALL WA, 1986, ANNU REV BIOCHEM, V55, P953, DOI 10.1146/annurev.biochem.55.1.953
[4]  
CATTERALL WA, 1979, J BIOL CHEM, V254, P1379
[5]   STRUCTURE AND FUNCTION OF VOLTAGE-SENSITIVE ION CHANNELS [J].
CATTERALL, WA .
SCIENCE, 1988, 242 (4875) :50-61
[6]  
CHAPMAN AG, 1987, NEUROTRANSMITTERS EP, P9
[7]   ISOLATION OF BIOLOGICALLY-ACTIVE RIBONUCLEIC-ACID FROM SOURCES ENRICHED IN RIBONUCLEASE [J].
CHIRGWIN, JM ;
PRZYBYLA, AE ;
MACDONALD, RJ ;
RUTTER, WJ .
BIOCHEMISTRY, 1979, 18 (24) :5294-5299
[8]  
COURAUD F, 1986, J NEUROSCI, V6, P192
[9]   CELLULAR MECHANISMS OF EPILEPSY - A STATUS-REPORT [J].
DICHTER, MA ;
AYALA, GF .
SCIENCE, 1987, 237 (4811) :157-164
[10]   GENERALIZED CORTICO-RETICULAR EPILEPSIES - SOME CONSIDERATIONS ON PATHOPHYSIOLOGY OF GENERALIZED BILATERALLY SYNCHRONOUS SPIKE AND WAVE DISCHARGE [J].
GLOOR, P .
EPILEPSIA, 1968, 9 (03) :249-&