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Morphine- and CaMKII-dependent enhancement of GIRK channel signaling in hippocampal neurons

Nassirpour, Rounak
Bahima, Laia
Luján, Rafael
Slesinger, Paul A
Published in Journal of Neuroscience. 2010, vol. 30, no. 40, p. 13419-30
Abstract G-protein-gated inwardly rectifying potassium (GIRK) channels, which help control neuronal excitability, are important for the response to drugs of abuse. Here, we describe a novel pathway for morphine-dependent enhancement of GIRK channel signaling in hippocampal neurons. Morphine treatment for ∼20 h increased the colocalization of GIRK2 with PSD95, a dendritic spine marker. Western blot analysis and quantitative immunoelectron microscopy revealed an increase in GIRK2 protein and targeting to dendritic spines. In vivo administration of morphine also produced an upregulation of GIRK2 protein in the hippocampus. The mechanism engaged by morphine required elevated intracellular Ca(2+) and was insensitive to pertussis toxin, implicating opioid receptors that may couple to Gq G-proteins. Met-enkephalin, but not the μ-selective (DAMGO) and δ-selective (DPDPE) opioid receptor agonists, mimicked the effect of morphine, suggesting involvement of a heterodimeric opioid receptor complex. Peptide (KN-93) inhibition of CaMKII prevented the morphine-dependent change in GIRK localization, whereas expression of a constitutively activated form of CaMKII mimicked the effects of morphine. Coincident with an increase in GIRK2 surface expression, functional analyses revealed that morphine treatment increased the size of serotonin-activated GIRK currents and Ba(2+)-sensitive basal K(+) currents in neurons. These results demonstrate plasticity in neuronal GIRK signaling that may contribute to the abusive effects of morphine.
Keywords Analgesics, Opioid/pharmacologyAnimalsAnimals, NewbornCalcium Signaling/drug effects/physiologyCalcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors/physiologyCells, CulturedG Protein-Coupled Inwardly-Rectifying Potassium Channels/physiologyHippocampus/drug effects/enzymology/metabolismMorphine/pharmacologyMorphine Dependence/metabolism/physiopathologyNeurons/drug effects/enzymology/metabolismRatsRats, Sprague-DawleySignal Transduction/drug effects/physiologyUp-Regulation/drug effects/physiology
PMID: 20926668
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Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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NASSIRPOUR, Rounak et al. Morphine- and CaMKII-dependent enhancement of GIRK channel signaling in hippocampal neurons. In: Journal of Neuroscience, 2010, vol. 30, n° 40, p. 13419-30. doi: 10.1523/JNEUROSCI.2966-10.2010 https://archive-ouverte.unige.ch/unige:26929

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Deposited on : 2013-03-25

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