Down-regulation of voltage-dependent sodium channels initiated by sodium influx in developing neurons.
To address the issue of whether regulatory feedback exists between the electrical activity of a neuron and ion-channel density, we investigated the effect of Na(+)-channel activators (scorpion alpha toxin, batrachotoxin, and veratridine) on the density of Na+ channels in fetal rat brain neurons in vitro. A partial but rapid (t1/2, 15 min) disappearance of surface Na+ channels was observed as measured by a decrease in the specific binding of [3H]saxitoxin and 125I-labeled scorpion beta toxin and a decrease in specific 22Na+ uptake. Moreover, the increase in the number of Na+ channels that normally occurs during neuronal maturation in vitro was inhibited by chronic channel activator treatment. The induced disappearance of Na+ channels was abolished by tetrodotoxin, was found to be dependent on the external Na+ concentration, and was prevented when either choline (a nonpermeant ion) or Li+ (a permeant ion) was substituted for Na+. Amphotericin B, a Na+ ionophore, and monensin were able to mimick the effect of Na(+)-channel activators, while a KCl depolarization failed to do this. This feedback regulation seems to be a neuronal property since Na(+)-channel density in cultured astrocytes was not affected by channel activator treatment or by amphotericin B. The present evidence suggests that an increase in intracellular Na+ concentration, whether elicited by Na(+)-channel activators or mediated by a Na+ ionophore, can induce a decrease in surface Na+ channels and therefore is involved in down-regulation of Na(+)-channel density in fetal rat brain neurons in vitro.
Dargent
B
B
Laboratoire de Biochimie, Centre National de la Recherche Scientifique UA 1179, Faculté de Médecine-Secteur Nord, Marseille, France.
Couraud
F
F
D029845:Amphibian Proteins; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000502:physiology*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D007700:Kinetics; D008985:Monensin / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D012530:Saxitoxin / Q000378:metabolism / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D029845:Amphibian Proteins; D002352:Carrier Proteins; D015222:Sodium Channels; C027525:saxitoxin-binding protein, Rana catesbeiana; D012530:Saxitoxin; D013779:Tetrodotoxin; D014701:Veratridine; D000666:Amphotericin B; D008985:Monensin; D012964:Sodium