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Modulation of carbachol-stimulated AP-1 DNA binding activity by therapeutic agents for bipolar disorder in human
1Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1057 Sparks Center, Birmingham, AL 35294-0017, USA.
Abstract:
Lithium, carbamazepine and sodium valproate are mood stabilizers used in the treatment of bipolar disorder, and although their mechanisms of action remain unknown, signal transduction systems and the associated modulation of gene expression may constitute significant actions. We examined if acute or chronic treatments with these agents modulated the activation of the AP-1 transcription factor or the increased intracellular calcium levels in human neuroblastoma SH-SY5Y cells caused by stimulation with carbachol. AP-1 activation stimulated by carbachol was reduced by pretreatment for 1 h, 24 h or 7 days with 1 mM lithium by 15%, 37%, and 60%, respectively, and with 0.05 mM carbamazepine by 3%, 21%, and 46%, respectively, but not by pretreatment with 0.5 mM sodium valproate. AP-1 DNA binding activity stimulated by carbachol or by phorbol ester-induced activation of protein kinase C was inhibited by the protein kinase C inhibitor Ro31-8220, but phorbol ester-stimulated AP-1 activation was unaltered by 7-day pretreatments with lithium or carbamazepine. Activation of AP-1 by carbachol was dependent on calcium, as it was inhibited by treatment with the extracellular calcium chelator EGTA, the intracellular calcium chelator BAPTA-AM, and the calcium/calmodulin kinase II inhibitor KN62. Pretreatment for 7 days with lithium or carbamazepine had no significant effect on carbachol-stimulated increases in intracellular calcium levels, but reduced the stimulation of AP-1 by the calcium ionophore ionomycin by 30% to 40%. Thus, chronic treatment with the antibipolar agents lithium and carbamazepine attenuates carbachol-stimulated AP-1 DNA binding activity, and these agents preferentially inhibit signaling cascades activated by the calcium rather than the protein kinase C arm of the phosphoinositide signaling pathway.
Insights
Lithium and carbamazepine, used for bipolar disorder, reduce AP-1 activation by inhibiting calcium signaling pathways. Sodium valproate showed no effect on this mood stabilizer mechanism.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Mood stabilizers like lithium, carbamazepine, and sodium valproate are crucial for bipolar disorder treatment.
- Their precise mechanisms of action are not fully understood, but may involve signal transduction and gene expression modulation.
- Activating transcription factor-1 (AP-1) and intracellular calcium levels are potential targets for these drugs.
Purpose of the Study:
- To investigate if acute or chronic treatments with lithium, carbamazepine, and sodium valproate modulate AP-1 activation and intracellular calcium levels.
- To explore the role of calcium and protein kinase C (PKC) signaling in carbachol-stimulated AP-1 activation.
- To elucidate the specific signaling pathways targeted by these mood stabilizers.
Main Methods:
- Human neuroblastoma SH-SY5Y cells were used to examine the effects of mood stabilizers on carbachol-stimulated AP-1 activation.
- AP-1 DNA binding activity was measured after pretreatment with lithium, carbamazepine, or sodium valproate.
- Intracellular calcium levels were assessed, and the roles of calcium and PKC were investigated using specific inhibitors and calcium ionophores.
Main Results:
- Chronic lithium and carbamazepine treatments significantly reduced carbachol-stimulated AP-1 activation in a time-dependent manner.
- Sodium valproate did not affect carbachol-induced AP-1 activation.
- While AP-1 activation by carbachol is calcium-dependent, chronic lithium and carbamazepine treatments did not alter carbachol-stimulated calcium increases but reduced ionomycin-stimulated AP-1 activation, suggesting a preferential inhibition of calcium-mediated signaling.
Conclusions:
- Chronic administration of lithium and carbamazepine attenuates carbachol-stimulated AP-1 DNA binding activity in neuroblastoma cells.
- These mood stabilizers preferentially inhibit signaling cascades activated by calcium, rather than the protein kinase C pathway.
- The findings provide insights into the molecular mechanisms underlying the efficacy of lithium and carbamazepine in bipolar disorder treatment.