Neurotoxin-sensitive sodium channels in neurons developing in vivo and in vitro.
Fetal mouse brain cells were investigated by 22Na+ flux assays with the aim to determine the ontogenetic time course of appearance of functional voltage-sensitive sodium channels. Their pharmacological properties were assessed by measurement of the response to known neurotoxins, acting at site 1, 2, or 3 of the Na+ channel. Brain cell suspensions, prepared at 11-19 d of prenatal development in vivo, and fetal brain neurons in culture were explored. In vivo neurotoxin-sensitive Na+ influx becomes detectable at 12 d of gestation, in concordance with the time of appearance of saturable binding sites for alpha-scorpion toxin (alpha-ScTx) and saxitoxin. Progression in fetal age or in time in vitro is accompanied by an increase in the initial rate and in the amplitude of Na+ uptake stimulated by batrachotoxin or veratridine. The general pharmacological properties of developing Na+ channels are very similar to the known properties of voltage-dependent Na+ channels in adult nerve: Batrachotoxin acts as a full channel agonist and veratridine as a partial agonist. Their respective apparent affinities are increased in presence of alpha-ScTx, in agreement with the known positive cooperativity of toxins acting at sites 2 and 3 of the Na+ channel. alpha-ScTx alone induces a small increase in Na+ permeability; its effect is greatly amplified in the presence of batrachotoxin or veratridine. The apparent affinity of alpha-ScTx is reduced by cell depolarization. Tetrodotoxin and saxitoxin block the increase in Na+ permeability induced by batrachotoxin, veratridine, and alpha-ScTx.(ABSTRACT TRUNCATED AT 250 WORDS)
F
F
Couraud
N
N
Martin-Moutot
A
A
Koulakoff
Y
Y
Berwald-Netter
D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D011247:Pregnancy; D012530:Saxitoxin / Q000494:pharmacology; D012604:Scorpion Venoms / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology
D007473:Ion Channels; D009498:Neurotoxins; D012604:Scorpion Venoms; D012530:Saxitoxin; D013779:Tetrodotoxin; D014701:Veratridine; D012964:Sodium