Multiple mechanisms of CB1 cannabinoid receptors regulation

The Mauerberger Chair in Neuropharmacology, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Brain Research (Impact Factor: 2.84). 09/2003; 980(2):197-205. DOI: 10.1016/S0006-8993(03)02970-6
Source: PubMed


Agonist-induced regulation of cannabinoid CB1 receptors was examined in HEK-293 cells transfected with CB1 receptors and in neuroblastoma N18TG2 cells that naturally express CB1 receptors. In HEK-293 cells, CB1 receptors internalization proceeded, in parallel, via clathrin-coated pits and caveolae. Simultaneous disruption of both pathways induced compensatory endocytic mechanism(s). In N18TG2 cells, endocytosis was not mediated by caveolae-like membrane domains. Heterologous, opioid-induced, downregulation of CB1 receptors was evident in HEK-293 but not N18TG2 cells. The data demonstrate the existence of multiple pathways of CB1 receptors regulation.

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    • "Lipid raft/caveolae have been proposed to compartmentalize the endocannabinoid signalling machinery in several cellular systems (Keren and Sarne, 2003; McFarland et al., 2004; 2008 Bari et al., 2005a,b; 2006; 2008; McFarland and Barker, 2005; Sarnataro et al., 2005, 2006; Oddi et al., 2007; Placzek et al., 2008; Rimmerman et al., 2008; Maccarrone et al., 2009). Specifically, several lines of evidence support an association of the cannabinoid CB 1 receptor (nomenclature follows Alexander et al., 2011) with lipid raft/caveolae including: (i) CB1 receptor C-terminal acylation domain is required for proper interactions with lipid raft-associated G proteins (Mukhopadhyay et al., 1999; Barnett-Norris et al., 2005; Fay et al., 2005; Xie and Chen, 2005); (ii) CB1 receptor internalization in human embryonic kidney 293 cells-CB1 transfected cells that occurs via both caveolae and clathrin-coated pits (Keren and Sarne, 2003); (iii) increased CB1 receptor binding and signalling following cholesterol depletion in C6 glioma cells (Bari et al., 2005a,b; 2006); (iv) CB1 receptor association with lipid raft fractions/ non-lipid raft fractions in MDA-MB- 231 breast cancer cells which depends on receptor activation/ antagonism (Sarnataro et al., 2005; 2006); and (v) CB1 receptor localization within lipid rafts in human endothelial cells, and CB1 receptor co-localization with caveolin-1 in C6 glioma cells (Bari et al., 2006; 2008). "
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    British Journal of Pharmacology 03/2011; 165(8):2436-49. DOI:10.1111/j.1476-5381.2011.01380.x · 4.84 Impact Factor
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    • "CB1 receptor endocytosis is important in resensitization, as indicated by the finding that blockade of endocytic recycling enhances WIN55,212-2-induced desensitization of CB1 receptormediated cAMP inhibition (Wu et al., 2008). Longer agonist exposure (1.5 h) promotes down-regulation of CB1 receptors (Hsieh et al., 1999), as can briefer exposure to very high concentrations of agonists (Keren and Sarne, 2003; Martini et al., 2007). CB1 receptor down-regulation is associated with co-localization of the receptor with lysosomal markers, lysosome-associated membrane protein (LAMP)1 and 2 (Martini et al., 2007). "
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    • "somes (Hsieh et al. 1999; Leterrier et al. 2004; Martini et al. 2007). However, the endocytotic mechanism of CB1 receptors is not completely understood although recent findings suggest that several pathways including clathrincoated pits and caveolae might be involved in this process (Keren and Sarne 2003). Following CB1R activation and desensitization, the receptors are internalized, and then are either degraded in lysosomes or recycled back to the membrane for reactivation. "
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    Journal of Neurochemistry 03/2008; 104(4):1132-43. DOI:10.1111/j.1471-4159.2007.05063.x · 4.28 Impact Factor
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