Lithium inhibits function of voltage-dependent sodium channels and catecholamine secretion independent of glycogen synthase kinase-3 in adrenal chromaffin cells.
Lithium has been proven to be effective in the therapy of bipolar disorder, but its mechanism of pharmacological action is not clearly defined. We examined the effects of lithium on voltage-dependent Na(+) channels, nicotinic acetylcholine receptors, and voltage-dependent Ca(2+) channels, as well as catecholamine secretion in cultured bovine adrenal chromaffin cells. Lithium chloride (LiCl) reduced veratridine-induced (22)Na(+) influx in a concentration-dependent manner, even in the presence of ouabain, an inhibitor of Na(+), K(+)-ATPase. Glycogen synthase kinase-3 (GSK-3) inhibitors (SB216763, SB415286 or the GSK-3 inhibitor IX) did not affect veratridine-induced (22)Na(+) influx, as well as inhibitory effect of LiCl on veratridine-induced (22)Na(+) influx. Enhancement of veratridine (site 2 toxin)-induced (22)Na(+) influx caused by alpha-scorpion venom (site 3 toxin), beta-scorpion venom (site 4 toxin), or Ptychodiscus brevis toxin-3 (site 5 toxin), still occurred in the presence of LiCl in the same manner as in the control cells. LiCl also reduced veratridine-induced (45)Ca(2+) influx and catecholamine secretion. In contrast, LiCl (< or = 30 mM) had no effect on nicotine-induced (22)Na(+) influx, (45)Ca(2+) influx and catecholamine secretion, as well as on high K(+)-induced (45)Ca(2+) influx and catecholamine secretion. Chronic treatment with LiCl at 100mM (but not at < or = 30 mM) significantly reduced cell viability in a time-dependent manner. These results suggest that lithium selectively inhibits Na(+) influx thorough Na(+) channels and subsequent Ca(2+) influx and catecholamine secretion, independent of GSK-3 inhibition.
Yanagita
Toshihiko
T
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan. yanagita@med.miyazaki-u.ac.jp
Maruta
Toyoaki
T
Uezono
Yasuhito
Y
Satoh
Shinya
S
Yoshikawa
Norie
N
Nemoto
Takayuki
T
Kobayashi
Hideyuki
H
Wada
Akihiko
A
D000311:Adrenal Glands / Q000166:cytology*; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D018021:Lithium Chloride / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology
D018692:Antimanic Agents; D002395:Catecholamines; D004791:Enzyme Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014701:Veratridine; D012964:Sodium; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D002118:Calcium