Abstract
In cultured bovine adrenal chromaffin cells expressing Na V1.7 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 [ 3H]saxitoxin ([ 3H]STX) binding by ∼32% without altering the affinity of [ 3H]STX binding. This increase was prevented by cycloheximide and actinomycin D. SB216763 and SB415286 (GSK-3 inhibitors) also increased cell surface [ 3H]STX binding by ∼31%. Simultaneous treatment with LiCl and SB216763 or SB415286 did not produce an increased effect on [ 3H]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 22Na + influx as in untreated cells. However, washout of LiCl after chronic treatment enhanced veratridine-induced 22Na + influx, 45Ca 2+ influx and catecholamine secretion by ∼30%. Washout of LiCl after 24 h treatment shifted concentration–response curve of veratridine upon 22Na + influx upward, without altering its EC 50 value. Ptychodiscus brevis toxin-3 allosterically enhanced veratridine-induced 22Na + 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 V1.7 via acceleration of α-subunit gene transcription, enhancing veratridine-induced Na + influx, Ca 2+ influx and catecholamine secretion.
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