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Contribution of beta-arrestin-dependent receptor signaling to the physiological regulation of the endocannabinoid system

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The endocannabinoid system regulation

Cannabinoid receptors are a promising therapeutic target for a number of conditions, including psychological and movement disorders, obesity, neuropathic pain and cancer.

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Located in the cell membrane, cannabinoid receptors (CB1and CB2) are involved in many physiological processes. These receptors can be activated by endocannabinoids (produced by the body), as well as plant or synthetic cannabinoids. The endocannabinoid system can be regulated by several pathways and one involves a protein, beta-arrestin which dampens cellular response to a variety of stimuli. The EU-funded project CB1R ARRESTIN (Contribution of beta-arrestin-dependent receptor signaling to the physiological regulation of the endocannabinoid system) has looked at two CB2 receptor mutants. One mutation is overrepresented in patients with major depression, alcoholism, and autoimmune disorders, while the other is associated with bipolar disorder. Study of two CB2 mutant receptors in vitro for binding with beta-arrestin, revealed significant differences in their binding compared to the wild-type receptors. After confirming the specificity of binding, the researchers overexpressed CB2 receptors in a cell line and isolated interacting protein candidates. Mass spectrometry identified the interacting partners of the wild-type CB2 and the mutant receptors. Over 2 000 interacting proteins binding CB2 were identified, with a few dozen differences between mutants. CB1R ARRESTIN research then analysed the functions of several of these proteins. In a Parkinson's disease model, the researchers investigated whether a CB2 inverse agonist can improve movement or inhibit dyskinesia, involuntary muscle movements. Recent research has shown that CB2 agonists inhibit cocaine-induced locomotion. Results suggest that beta-arrestin prevents the actions of the CB2 receptor that contribute to increased dyskinesia during chronic L-DOPA treatment. Further investigation of the molecular mechanisms involved may lead to the discovery of new therapies for dyskinesia, a major side-effect of L-DOPA therapy. For future research, project members developed a modified but safe adeno-associated virus (AAV) construct as well as a NES-BirA transgenic mouse model. Diverting the protein into the cytoplasm, this should enable research into the individual proteomes of dopamine receptor expressing neurons, D2 or D1, in the mouse striatum. Understanding the protein expression profiles of specific cells should provide insight into many systems that could lead to the discovery of new therapeutic options. An animal experiment protocol has been submitted for approval so in vivo studies can be conducted.


Endocannabinoid system, beta-arrestin, CB2 receptor, dopamine receptor expressing neurons, adeno-associated virus, NES-BirA

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