The present address of Dr. N. Ozaki is Department of Pharmacology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun 920-02, Japan.
Lithium Increases Transcription Factor Binding to AP-1 and Cyclic AMP-Responsive Element in Cultured Neurons and Rat Brain
Article first published online: 18 NOV 2002
Journal of Neurochemistry
Volume 69, Issue 6, pages 2336–2344, December 1997
How to Cite
Ozaki, N. and Chuang, D.-M. (1997), Lithium Increases Transcription Factor Binding to AP-1 and Cyclic AMP-Responsive Element in Cultured Neurons and Rat Brain. Journal of Neurochemistry, 69: 2336–2344. doi: 10.1046/j.1471-4159.1997.69062336.x
- Issue published online: 18 NOV 2002
- Article first published online: 18 NOV 2002
- Received May 16, 1997; revised manuscript received August 4, 1997; accepted August 5, 1997.
- Cyclic AMP-responsive element binding protein;
- Cerebellar granule cells
Abstract: We have investigated whether lithium has effects on transcription factor binding to consensus DNA sequences of AP-1 and cyclic AMP-responsive element (CRE) in cultured rat neurons and in vivo. Treatment of rat cerebellar granule cells (CGC) with lithium chloride induced a concentration-dependent increase in AP-1 and CRE binding activities with maximal effects at therapeutically relevant concentrations of 0.5 and 1.0 mM. Time-course studies show that lithium's effects on AP-1 and CRE binding were biphasic within the first 24 h of treatment in immature CGC in culture and persistent in mature CGC, lasting as long as 7 days. These actions were concurrent with an increase in the mRNA levels of c-fos and c-jun, as well as the protein levels of c-Fos, c-Jun, and phosphorylated CRE binding protein (p-CREB). Gel supershift assays using transcription factor-specific antibodies revealed that p-CREB, Jun D, and a Fos family protein(s) are components of the AP-1 binding complex in untreated and lithium-treated CGC. Chronic dietary treatment of rats with lithium carbonate for 4 weeks also significantly increased AP-1 and CRE binding activity in the frontal cortex, hippocampus, amygdala, and cerebellum. Similar to the results obtained in CGC, p-CREB, Jun D, and Fos family proteins are present in the AP-1 binding sites in the frontal cortex and hippocampus of untreated and lithium-treated rats. Lithium-induced activation of transcription factor binding to AP-1 and CRE sites in vivo and in vitro provides a new avenue to study the mechanisms of action of lithium in the treatment of manic depressive illness.
Abbreviations used: CGC, cerebellar granule cells; CRE, cyclic AMP-responsive element; CREB, CRE binding protein; DIV, days in vitro; ECL, enhanced chemiluminescence; IEG, immediate early genes; IMPase, inositol monophosphatase; mAChR, muscarinic acetylcholine receptors; MAPK, mitogen-activated protein kinase; p-CREB, phosphorylated CRE binding protein; PKC, protein kinase C; SDS, sodium dodecyl sulfate; SSC, saline-sodium citrate.