UP-REGULATION OF SODIUM-CHANNEL SUBUNIT MESSENGER-RNAS 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 therapeut ic concentration (0.6 mM) of valproic acid (VPA) for >24 h caused a ti me-dependent (t(1/2) = 74 h) increase in [H-3]saxitoxin binding up to 1.4-fold without altering the K-D value; it was prevented by the simul taneous treatment with cycloheximide (an inhibitor of protein synthesi s). 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, respectivel y. Chronic (but not acute) exposure to VPA enhanced Na-22(+) influx ca used 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 EC(50) value of veratridine. Ptychodiscus brevis toxin-3 alloster ically potentiated veratridine-induced Na-22(+) influx by similar to 2 -fold in VPA-treated cells as in nontreated cells. Long-term treatment with VPA augmented veratridine-induced Ca-45(2+) influx via voltage-d ependent Ca2+ channels and catecholamine secretion, but had no effect on Ca-45(2+) influx and catecholamine secretion caused by high K+ (a d irect activation of voltage-dependent Ca2+ channels). Chronic treatmen t with VPA also enhanced nicotine-induced Na-22(+) influx via the nico tinic receptor-ion channel complex 1.2-1.4-fold with little change in the EC(50) value of nicotine, thereby increasing the nicotine-induced Ca-45(2+) influx via voltage-dependent Ca2+ channels and catecholamine secretion. These results suggest that chronic treatment with VPA up-r egulates 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 cate cholamine secretion.