title: Lithium chloride at a therapeutic concentration reduces Ca2+ response in protein kinase C down-regulated human astrocytoma cells.
abstract: Since the therapeutic efficacy of Li+ in the treatment of mood disorder is observed only after chronic administration, we examined whether long-term Li+ treatment with a therapeutic concentration affected the elevation of intracellular-free Ca2+ concentration ([Ca2+]i) induced by carbachol, a muscarinic receptor agonist, in 1321N1 human astrocytoma cells. Carbachol caused [Ca2+]i elevation through phosphoinositide hydrolysis in a concentration-dependent manner. Treatment of the cells with phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, for 2 min resulted in a reduction of the carbachol-induced [Ca2+]i elevation. However, PMA did not reduce the carbachol-induced [Ca2+]i elevation in cells treated with PMA for 48 h, reflecting the down-regulation of protein kinase C. Although Li+ at a therapeutic concentration (1 mM) did not affect the carbachol-induced [Ca2+]i elevation in normal cells, it potently inhibited the [Ca2+]i elevation in protein kinase C down-regulated cells. This inhibitory action of Li+ was observed in a concentration- and time-dependent manner. When protein kinase C activity was directly determined, Li+ treatment did not restore protein kinase C activity in protein kinase C down-regulated cells. [3H]Quinuclidinyl benzylate, a muscarinic receptor ligand, bound to membranes derived from normal and protein kinase C down-regulated cells with a similar Kd and Bmax, and Li+ did not affect these parameters of [3H]quinuclidinyl benzylate binding. These results indicated that Li+ at a therapeutic concentration reduced the muscarinic receptor-mediated increased in [Ca2+]i under the protein kinase C-deficient condition without affecting muscarinic receptor or protein kinase C activity.
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Kurita
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Mashiko
authors.forename: Mayumi
authors.initials: M
authors.lastname: Rai
authors.forename: Tadanori
authors.initials: T
authors.lastname: Kumasaka
authors.forename: Sou ichi
authors.initials: Si
authors.lastname: Kouno
authors.forename: Shin ichi
authors.initials: Si
authors.lastname: Niwa
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakahata
mesh_terms: D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D014316:Tritium; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D011493:Protein Kinase C; D018021:Lithium Chloride; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium