Lithium chloride at a therapeutic concentration reduces Ca2+ response in protein kinase C down-regulated human astrocytoma cells.
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.
Kurita
Masatake
M
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Hikarigaoka 1, Fukushima, Japan.
Mashiko
Hirobumi
H
Rai
Mayumi
M
Kumasaka
Tadanori
T
Kouno
Sou ichi
Si
Niwa
Shin ichi
Si
Nakahata
Norimichi
N
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
D014316:Tritium; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D011493:Protein Kinase C; D018021:Lithium Chloride; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium