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The Journal of Neuroscience, April 1, 2001, 21(7):2425-2433

Agonist-Induced Internalization and Trafficking of Cannabinoid CB₁ Receptors in Hippocampal Neurons

Angela A. Coutts¹, Sharon Anavi-Goffer¹, Ruth A. Ross¹, David J. MacEwan¹, Ken Mackie², Roger G. Pertwee¹, and Andrew J. Irving^{1, 3}

¹ Department of Biomedical Sciences, University of Aberdeen, Scotland, AB25 2ZD, United Kingdom, ² Department of Anesthesiology, University of Washington, Seattle, Washington 98195, and ³ Neurosciences Institute, Department of Pharmacology and Neuroscience, University of Dundee, Scotland, DD1 9SY, United Kingdom

Agonist-induced internalization of G-protein-coupled receptors is an important mechanism for regulating receptor abundance and availability at the plasma membrane. In this study we have used immunolabeling techniques and confocal microscopy to investigate agonist-induced internalization and trafficking of CB₁ receptors in rat cultured hippocampal neurons. The levels of cell surface CB₁ receptor immunoreactivity associated with presynaptic GABAergic terminals decreased markedly (by up to 84%) after exposure to the cannabinoid agonist (+)-WIN55212, in a concentration-dependent (0.1-1 µM) and stereoselective manner. Inhibition was maximal at 16 hr and abolished in the presence of SR141716A, a selective CB₁ receptor antagonist. Methanandamide (an analog of an endogenous cannabinoid, anandamide) also reduced cell surface labeling (by 43% at 1 µM). Differential labeling of cell surface and intracellular pools of receptor demonstrated that the reduction in cell surface immunoreactivity reflects agonist-induced internalization and suggests that the internalized CB₁ receptors are translocated toward the soma. The internalization process did not require activated G-protein (i) or (o) subunits. A different pattern of cell surface CB₁ receptor expression was observed using an undifferentiated F-11 cell line, which had pronounced somatic labeling. In these cells substantial CB₁ receptor internalization was also observed after exposure to (+)-WIN55212 (1 µM) for relatively short periods (30 min) of agonist exposure. In summary, this dynamic modulation of CB₁ receptor expression may play an important role in the development of cannabinoid tolerance in the CNS. Agonist-induced internalization at presynaptic terminals has important implications for the modulatory effects of G-protein-coupled receptors on neurotransmitter release.

Key words: internalization; cannabinoid; receptor trafficking; CB1; hippocampal; F-11

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2172425-09$05.00/0

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