Lithium-induced decrease in spontaneous Ca2+ oscillations in single GH3 rat pituitary cells.
1. Measurement of [Ca2+]i in single rat pituitary GH3 cells by dynamic single cell imaging techniques demonstrated that under basal conditions there is a large variation in the temporal pattern of [Ca2+]i signalling between individual cells ranging from high frequency asynchronous oscillations to quiescence. 2. We have reported previously that treatment of GH3 cells with 1 mM Li+ (a concentration used therapeutically in the treatment of manic depression) for 7 days reduces basal and thyrotrophin-releasing hormone (TRH)-stimulated levels of mass inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. In the present study, we show that this is associated with a reduction in the number of cells exhibiting basal Ca2+ oscillations over a sampling period of 60 s, whereas the maximum amplitude of oscillations is unaffected. 3. The pattern of [Ca2+]i responses to the agonist TRH varied considerably between individual cells, making quantitation of the responses difficult; however, data obtained from measurements made on a population of cells showed that increases in peak [Ca2+]i induced by high concentrations of TRH were reduced in cells treated with 1 mM Li+ for 7 days relative to control cells. 4. The sensitivity of the phosphoinositide pathway to [Ca2+]i was investigated by loading GH3 cells with BAPTA/AM at a concentration sufficient to lower 'basal' [Ca2+]i in a population of cells and to inhibit agonist-stimulated increases in [Ca2+]i. Under these conditions, basal and TRH-stimulated mass Ins(1,4,5)P3 levels were unaffected. 5. These results demonstrate that a 7-day Li+ treatment leads to an alteration in Ca2+ signalling, in particular by reducing the number of cells exhibiting high frequency Ca2+ oscillations under basal conditions. The significance of these results to the clinical effectiveness of Li+ in the treatment of manic depression is discussed.
Varney
M A
MA
University Department of Pharmacology, Oxford.
Galione
A
A
Watson
S P
SP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D004533:Egtazic Acid; D013973:Thyrotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; D011388:Prolactin; D008094:Lithium; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium