RRC ID 43828
Author Ushijima K, Koyanagi S, Sato Y, Ogata T, Matsunaga N, Fujimura A, Ohdo S.
Title Role of activating transcription factor-4 in 24-hour rhythm of serotonin transporter expression in the mouse midbrain.
Journal Mol Pharmacol
Abstract Serotonin (5-HT) transporter (5-HTT) plays a key role in the control of 5-HT neuronal activity by reuptaking extracellular 5-HT from the synapse cleft. We have previously demonstrated that 5-HTT mRNA expression levels and its uptake activity in the mouse midbrain are significantly higher in the dark phase than those in the light phase. However, the molecular mechanisms of time-dependent expression of 5-HTT have not been clarified. In this study, expression of 5-HTT mRNA in the mouse midbrain showed a significant 24-h rhythm and was higher in the dark phase. Although such an oscillation was eliminated by a Clock gene mutation, CLOCK and BMAL1 did not activate 5-HTT transcription in the luciferase reporter assay. Activating transcription factor-4 (ATF4), a member of the ATF/cAMP response element (CRE)-binding protein family, is a component responsible for sustaining circadian oscillations of CRE-mediated gene expression. ATF4 significantly activated 5-HTT transcription in vitro and time dependently bound to the CRE site in the 5-HTT promoter in the mouse midbrain. In addition, mutation of the Clock gene disrupted temporal binding of ATF4 to the CRE site in the 5-HTT promoter. These results indicated that the circuit of circadian-basis molecular regulation between the clockwork system and mouse 5-HTT gene was connected by the ATF4 signaling pathway.
Volume 82(2)
Pages 264-70
Published 2012-8-1
DOI 10.1124/mol.112.079079
PII mol.112.079079
PMID 22572884
MeSH Activating Transcription Factor 4 / genetics Activating Transcription Factor 4 / metabolism Activating Transcription Factor 4 / physiology* Animals CLOCK Proteins / biosynthesis* Circadian Rhythm / physiology* Cyclic AMP Response Element-Binding Protein / metabolism Gene Expression Regulation / physiology* Male Mesencephalon / metabolism* Mice Mice, Inbred ICR Mutation Promoter Regions, Genetic Protein Binding / genetics Protein Binding / physiology Serotonin Plasma Membrane Transport Proteins / biosynthesis* Serotonin Plasma Membrane Transport Proteins / genetics Serotonin Plasma Membrane Transport Proteins / metabolism Signal Transduction / physiology
IF 3.664
Times Cited 13
Human and Animal Cells C-1300N(RCB2620)