Multiple mechanisms of CB1 cannabinoid receptors regulation.
ABSTRACT 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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ABSTRACT: The type 1 cannabinoid receptor (CB1 receptor) is considered to be the most abundant G protein-coupled receptor (GPCR) in the mammalian brain. The presence and highly compartmentalized cellular distribution of CB1 receptors in neurons localized to corticolimbic areas, basal ganglia, cerebellum, and brainstem accounts for the majority of behavioral actions associated with cannabinoid drugs. The discovery of endocannabinoids led to an avalanche of data showing that signaling at this GPCR is critical for, e.g., neurogenesis, neural development, synaptic plasticity, learning and memory, food intake, and energy metabolism. In contrast, deficient CB1 receptor expression or coupling to downstream signal transduction cascades contributes to the neuropathogenesis of a broad variety of neurological and metabolic disorders with selective pharmacological modulation of CB1 receptor availability and activity being a prime target for therapeutic intervention. Here, we summarize contemporary knowledge on the regulation of CB1 receptor expression in the central nervous system and describe the contextdependent recruitment of second messengers to this receptor. Finally, we present the concept that CB1 receptor bioavailability together with its momentary signaling activity on neuronal membranes defines the efficacy of endocannabinoid signaling such that a fine-tuned control of synaptic efficacy and plasticity may be achieved.12/2007: pages 59-73;
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ABSTRACT: CB1 cannabinoid receptor (CB1R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB1R function are not completely understood. In this study, we followed CB1R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB1R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB1R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB1R. However, both constitutive and agonist-induced internalization of CB1R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB1R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB1R are different.Molecular and Cellular Endocrinology 03/2013; · 4.04 Impact Factor
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ABSTRACT: Die therapeutische Anwendbarkeit von Cannabinoiden, den Inhaltsstoffen von Cannabis sativa L., wurde in zahlreichen Studien gezielt untersucht. Tierexperimente ergaben, dass Cannabinoide das schmerzassoziierte Verhalten ndern, immunsuppressive Eigenschaften besitzen, Tumorwachstum hemmen, Sensibilisierungsprozesse modulieren und Lern- bzw. Gedchtnisprozesse beeinflussen. Diese Effekte werden ber 2 membranstndige Cannabinoidrezeptoren vermittelt und als Mechanismen eine Blockade der Ionenkanle, Hemmung der Adenylatzyklase und retrograde Hemmung der Neurotransmitterausschttung diskutiert.Klinische Studien mit oral verabreichten Cannabinoiden ergaben positive Resultate bei der Therapie von multipler Sklerose, bei Gewichtsverlust, belkeit und Erbrechen whrend einer Chemotherapie und bei nicht therapierbarem Juckreiz. Bei der Behandlung chronischer Schmerzzustnde liegen gegenstzliche Befunde vor, und eindeutige Therapieerfolge konnten—wegen unerwnschter Nebenwirkungen—nur z.T. erzielt werden. Weitere multizentrisch angelegte Studien stehen daher noch aus, um Cannabinoide als neuartige Therapeutika zur Behandlung chronischer Schmerzen beurteilen zu knnen.The therapeutic use of cannabinoids, the components of cannabis sativa L., was investigated in numerous researches in detail. Animal studies revealed that cannabinoid receptor agonists alter pain-associated behaviour, have immune-suppressive properties, suppress tumor growth, modulate sensitisation processes and influence memory and learning. Those effects are mediated by two membrane-bound cannabinoid receptors and as mechanisms of signal transduction blockade of ion channels, inhibition of adenylate cyclase and retrograde inhibition of neurotransmitter release are currently being discussed.In clinical studies oral administration of cannabinoids indicated beneficial results during the therapy of multiple sclerosis, weight loss, nausea and vomiting due to chemotherapy, and intractable pruritus. However, therapy of chronic pain conditions revealed conflicting results and unequivocal success could not have been delivered due to unwanted side effects. Further multicentre studies are required to estimate cannabinoids as novel therapeutic tools for the treatment of chronic pain.Der Schmerz 11/2005; 19(6):528-534. · 1.02 Impact Factor