Chronic lithium treatment up-regulates cell surface NaV1.7 sodium channels via inhibition of glycogen synthase kinase-3 in adrenal chromaffin cells: Enhancement of Na+ influx, Ca2+ influx and catecholamine secretion after lithium withdrawal

Abstract In cultured bovine adrenal chromaffin cells expressing Na V 1.7 isoform of voltage-dependent Na + channels, we have previously reported that lithium chloride (LiCl) inhibits function of Na + channels independent of glycogen synthase kinase-3 (GSK-3) (Yanagita et al., 2007). Here, we further examined the effects of chronic lithium treatment on Na + channels. LiCl treatment (1–30 mM, ≥12 h) increased cell surface [ 3 H]saxitoxin ([ 3 H]STX) binding by ∼32% without altering the affinity of [ 3 H]STX binding. This increase was prevented by cycloheximide and actinomycin D. SB216763 and SB415286 (GSK-3 inhibitors) also increased cell surface [ 3 H]STX binding by ∼31%. Simultaneous treatment with LiCl and SB216763 or SB415286 did not produce an increased effect on [ 3 H]STX binding compared with either treatment alone. LiCl increased Na + channel α-subunit mRNA level by 32% at 24 h. LiCl accelerated α-subunit gene transcription by 35% without altering α-subunit mRNA stability. In LiCl-treated cells, LiCl inhibited veratridine-induced 22 Na + influx as in untreated cells. However, washout of LiCl after chronic treatment enhanced veratridine-induced 22 Na + influx, 45 Ca 2+ influx and catecholamine secretion by ∼30%. Washout of LiCl after 24 h treatment shifted concentration–response curve of veratridine upon 22 Na + influx upward, without altering its EC 50 value. Ptychodiscus brevis toxin-3 allosterically enhanced veratridine-induced 22 Na + influx by two-fold in untreated and LiCl-treated cells. Whole-cell patch-clamp analysis indicated that I – V curve and steady-state inactivation/activation curves were comparable between untreated and LiCl-treated cells. Thus, GSK-3 inhibition by LiCl up-regulated cell surface Na V 1.7 via acceleration of α-subunit gene transcription, enhancing veratridine-induced Na + influx, Ca 2+ influx and catecholamine secretion.