Signalling and production in the endocannabinoid system

Cannabinoid receptors (CB1and CB2) are involved in many physiological processes. Located in the cell membrane, 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. One involves a protein, beta-arrestin which dampens cellular response to a variety of stimuli. However, the details of these interactions are unknown.

The project ' CB1R ARRESTIN is unravelling the mechanisms of cannabinoid regulation. In the course of the project, two CB2 receptor mutants were studied. One mutation is overrepresented in patients with major depression, alcoholism, and autoimmune disorders, while the other is associated with bipolar disorder.

The study of mutant receptors in vitro for binding with beta-arrestin, revealed that both were different to the binding in the wild-type receptor. After confirming the specificity of binding, , the researchers overexpressed CB2 receptor 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 of differences between mutants. CB1R ARRESTIN research analysed the functions of several of these proteins.

In addition, novel approaches studied the expression of CB2 in neuronal cells and its participation in the regulation of the neuronal functions. A cell-specific method of protein purification was developed, allowing for in vitro separation of the proteins with different cell-origin even if the cell lysates were mixed. Obtaining protein expression profiles of specific cells instead of cell mixtures in tissues can lead to discovery of novel therapeutic targets in the future.

Taking part in so many physiological processes, the pharmacalogical manipulation of the endocannabinoid system has great potential in a large number of diseases and conditions.