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Nuclear Ca2+/calmodulin translocation activated by mu-opioid (OP3) receptor
D Wang1, L M Tolbert, K W Carlson
1Department of Biopharmaceutical Sciences and Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, 94143-0446, USA.
Journal of Neurochemistry
|March 29, 2000
Summary
Morphine activates mu-opioid receptors, causing calmodulin (CaM) to move into the nucleus. This nuclear CaM enhances gene transcription via Ca2+/CaM kinases and protein kinase C.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Calmodulin (CaM) is implicated in opioid receptor signaling.
- Opioid receptors, particularly the mu-opioid (OP3) receptor, are key targets in pain management and addiction.
- Understanding the molecular mechanisms of opioid receptor signaling is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of calmodulin (CaM) in mu-opioid (OP3) receptor signaling.
- To determine the pathway of CaM translocation to the nucleus following OP3 receptor activation.
- To explore the impact of nuclear CaM on gene transcription.
Main Methods:
- Utilized OP3-transfected human embryonic kidney (HEK)-293 cells and SH-SY5Y neuroblastoma cells.
- Stimulated OP3 receptors with morphine and measured CaM translocation using microscopy.
- Assessed Ca2+ influx and protein phosphorylation (CREB) via Western blotting and kinase assays.
- Employed a K273A mutant OP3 receptor to investigate CaM release from the plasma membrane.
Main Results:
- Morphine stimulation of OP3 receptors induced rapid CaM translocation to the nucleus, dependent on Ca2+ influx.
- Increased nuclear CaM correlated with enhanced phosphorylation of cyclic AMP-responsive element-binding protein (CREB).
- CaM release from the plasma membrane by the wild-type OP3 receptor enhanced nuclear CaM translocation, while a mutant receptor impaired this process.
Conclusions:
- Opioid receptor activation triggers a novel Ca2+/CaM signaling pathway.
- Nuclear CaM translocation, influenced by Ca2+ influx and receptor-mediated CaM release, regulates transcriptional activity.
- This pathway offers potential targets for modulating opioid receptor function and gene expression.