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 m M ) of valproic acid (VPA) for >24 h caused a time‐dependent ( t 1/2 = 74 h) increase in [ 3 H]saxitoxin binding up to 1.4‐fold without altering the K D value; it was prevented by the simultaneous treatment with cycloheximide (an inhibitor of protein synthesis). VPA also raised Na + channel α‐ and β 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 22 Na + 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 EC 50 value of veratridine. Ptychodiscus brevis toxin‐3 allosterically potentiated veratridine‐induced 22 Na + influx by ∼2‐fold in VPA‐treated cells as in nontreated cells. Long‐term treatment with VPA augmented veratridine‐induced 45 Ca 2+ influx via voltage‐dependent Ca 2+ channels and catecholamine secretion, but had no effect on 45 Ca 2+ influx and catecholamine secretion caused by high K + (a direct activation of voltage‐dependent Ca 2+ channels). Chronic treatment with VPA also enhanced nicotine‐induced 22 Na + influx via the nicotinic receptor‐ion channel complex 1.2–1.4‐fold with little change in the EC 50 value of nicotine, thereby increasing the nicotine‐induced 45 Ca 2+ influx via voltage‐dependent Ca 2+ 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 Ca 2+ channel gating and catecholamine secretion.