Up-regulation of sodium channel subunit mRNAs and their cell surface expression by antiepileptic valproic acid: activation of calcium channel and catecholamine secretion in adrenal chromaffin cells.
Treatment of cultured bovine adrenal chromaffin cells with a therapeutic concentration (0.6 mM) of valproic acid (VPA) for > 24 h caused a time-dependent (t1/2 = 74 h) increase in [3H]saxitoxin binding up to 1.4-fold without altering the KD value; it was prevented by the simultaneous treatment with cycloheximide (an inhibitor of protein synthesis). VPA also raised Na+ channel alpha- and beta 1-subunit mRNA levels 1.4- and 1.7-fold at 24 h, and 1.6- and 1.8-fold at 72 h, respectively. Chronic (but not acute) exposure to VPA enhanced 22Na+ influx caused by various concentrations of veratridine 1.4-2.1-fold, even when assayed in the presence of Na+,K(+)-ATPase inhibitor, but did not change the EC50 value of veratridine. Ptychodiscus brevis toxin-3 allosterically potentiated veratridine-induced 22Na+ influx by approximately 2-fold in VPA-treated cells as in nontreated cells. Long-term treatment with VPA augmented veratridine-induced 45Ca2+ influx via voltage-dependent Ca2+ channels and catecholamine secretion, but had no effect on 45Ca2+ influx and catecholamine secretion caused by high K+ (a direct activation of voltage-dependent Ca2+ channels). Chronic treatment with VPA also enhanced nicotine-induced 22Na+ influx via the nicotinic receptor-ion channel complex 1.2-1.4-fold with little change in the EC50 value of nicotine, thereby increasing the nicotine-induced 45Ca2+ influx via voltage-dependent Ca2+ channels and catecholamine secretion. These results suggest that chronic treatment with VPA up-regulates cell surface expression of Na+ channels via the transcription/translation-dependent mechanisms, and probably of nicotinic receptors, thereby resulting in the enhancement of Ca2+ channel gating and catecholamine secretion.
Yamamoto
R
R
Department of Pharmacology, Miyazaki Medical College, Japan.
Yanagita
T
T
Kobayashi
H
H
Yokoo
H
H
Wada
A
A
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects; D019439:Chromaffin Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015640:Ion Channel Gating / Q000502:physiology; D008387:Marine Toxins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D009498:Neurotoxins / Q000494:pharmacology; D035964:Oxocins; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012530:Saxitoxin / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics*; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology; D000095702:Polyether Toxins
D000927:Anticonvulsants; D002118:Calcium; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D002395:Catecholamines; D008387:Marine Toxins; D008565:Membrane Proteins; D009498:Neurotoxins; D035964:Oxocins; D011188:Potassium; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D012530:Saxitoxin; D015222:Sodium Channels; D014316:Tritium; D014635:Valproic Acid; D014701:Veratridine; C053342:brevetoxin; D000095702:Polyether Toxins