PT  - JOURNAL ARTICLE
AU  - Angel Y. F. Kam
AU  - Dezhi Liao
AU  - Horace H. Loh
AU  - Ping-Yee Law
TI  - Morphine Induces AMPA Receptor Internalization in Primary Hippocampal Neurons via Calcineurin-Dependent Dephosphorylation of GluR1 Subunits
AID  - 10.1523/JNEUROSCI.4255-10.2010
DP  - 2010 Nov 10
TA  - The Journal of Neuroscience
PG  - 15304--15316
VI  - 30
IP  - 45
4099  - http://www.jneurosci.org/content/30/45/15304.short
4100  - http://www.jneurosci.org/content/30/45/15304.full
SO  - J. Neurosci.2010 Nov 10; 30
AB  - Chronic morphine treatment resulting in the alteration of postsynaptic levels of AMPA receptors, thereby modulating synaptic strength, has been reported. However, the mechanism underlying such drug-induced synaptic modification has not been resolved. By monitoring the GluR1 trafficking in primary hippocampal neurons using the pHluorin-GluR1 imaging and biotinylation studies, we observed that prolonged morphine exposure significantly induced loss of synaptic and extrasynaptic GluR1 by internalization. The morphine-induced GluR1 endocytosis was independent of neural network activities or NMDA receptor activities, as neither blocking the sodium channels with tetrodotoxin nor NMDA receptors with dl-APV altered the effects of morphine. Instead, morphine-induced GluR1 endocytosis is attributed to a change in the phosphorylation state of the GluR1 at Ser845 as morphine significantly decreased the dephosphorylation of GluR1 at this site. Such changes in Ser845 phosphorylation required morphine-induced activation of calcineurin, based on the observations that a calcineurin inhibitor, FK506, completely abrogated the dephosphorylation, and morphine treatment led to an increase in calcineurin enzymatic activity, even in the presence of dl-APV. Importantly, pretreatment with FK506 and overexpression of the GluR1 mutants, S845D (phospho-mimic) or S845A (phospho-blocking) attenuated the morphine-induced GluR1 endocytosis. Therefore, the calcineurin-mediated GluR1-S845 dephosphorylation is critical for the morphine-induced changes in the postsynaptic AMPA receptor level. Together, these findings reveal a novel molecular mechanism for opioid-induced neuronal adaptation and/or synaptic impairment.