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Balancing Arc synthesis, mRNA decay, and proteasomal degradation: maximal protein expression triggered by rapid eye movement sleep-like bursts of muscarinic cholinergic receptor stimulation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Jun 22; Vol. 287 (26), pp. 22354-66. Date of Electronic Publication: 2012 May 14. - Publication Year :
- 2012
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Abstract
- Cholinergic signaling induces Arc/Arg3.1, an immediate early gene crucial for synaptic plasticity. However, the molecular mechanisms that dictate Arc mRNA and protein dynamics during and after cholinergic epochs are little understood. Using human SH-SY5Y neuroblastoma cells, we show that muscarinic cholinergic receptor (mAchR) stimulation triggers Arc synthesis, whereas translation-dependent RNA decay and proteasomal degradation strictly limit the amount and duration of Arc expression. Chronic application of the mAchR agonist, carbachol (Cch), induces Arc transcription via ERK signaling and release of calcium from IP(3)-sensitive stores. Arc translation requires ERK activation, but not changes in intracellular calcium. Proteasomal degradation of Arc (half-life ∼37 min) was enhanced by thapsigargin, an inhibitor of the endoplasmic calcium-ATPase pump. Similar mechanisms of Arc protein regulation were observed in cultured rat hippocampal slices. Functionally, we studied the impact of cholinergic epoch duration and temporal pattern on Arc protein expression. Acute Cch treatment (as short as 2 min) induces transient, moderate Arc expression, whereas continuous treatment of more than 30 min induces maximal expression, followed by rapid decline. Cholinergic activity associated with rapid eye movement sleep may function to facilitate long term synaptic plasticity and memory. Employing a paradigm designed to mimic intermittent rapid eye movement sleep epochs, we show that application of Cch in a series of short bursts generates persistent and maximal Arc protein expression. The results demonstrate dynamic, multifaceted control of Arc synthesis during mAchR signaling, and implicate cholinergic epoch duration and repetition as critical determinants of Arc expression and function in synaptic plasticity and behavior.
- Subjects :
- Animals
Carbachol metabolism
Carbachol pharmacology
Cell Line
Cell Line, Tumor
Hippocampus metabolism
Humans
Memory
Models, Biological
Neuronal Plasticity
Rats
Rats, Wistar
Receptors, Cholinergic metabolism
Signal Transduction
Sleep
Sleep, REM
Time Factors
Cytoskeletal Proteins metabolism
Gene Expression Regulation
Nerve Tissue Proteins metabolism
Proteasome Endopeptidase Complex metabolism
RNA, Messenger metabolism
Synapses metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22584581
- Full Text :
- https://doi.org/10.1074/jbc.M112.376491