Cell-type specific signalling of the CB1 cannabinoid receptor

• Applicant: Dr. Krisztina Monory
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238098327

Type 1 cannabinoid (CB1) receptor is a G protein-coupled receptor with high expression in the brain, where it exerts its main function to suppress neurotransmitter release. Interestingly, in the cortex and hippocampus, CB1 receptor is expressed in inhibitory as well as stimulatory neurons, therefore influencing neuronal excitation as well as inhibition. In this proposal, we aim at investigating how the CB1 receptor-activated intracellular signalling is different in these two cell types. Previously, we have established that in inhibitory cells a substantial amount of CB1 receptor is coupled to a relatively low amount of G proteins. Conversely, in excitatory neurons, a low amount of CB1 receptor is present, but most of cannabinoid-activated G proteins can be found in these cells. This means that in stimulatory neurons CB1 receptor is more effectively coupled to the intracellular signalling machinery. Enhanced signalling efficiency leads to fast signal amplification, supporting the notion of spatially and temporally limited, on-demand activation of CB1 receptor. To achieve a dynamic response to receptor activation, we also hypothesize the presence of a mechanism facilitating enhanced signal deactivation / termination. beta-arrestins and regulators of G protein signalling (RGS) proteins are the most plausible candidates for this function. To explore the possible involvement of beta-arrestins and RGS proteins in cannabinoid signalling, we will study the co-expression of CB1 receptor and these proteins in the mouse brain. After identifying likely candidates, we will employ a knock-down technique to validate our hypothesis. For these studies, newly developed transgenic mice will be utilized, in which CB1 receptor is only expressed in stimulatory or inhibitory neurons, respectively. This conditional rescue technique enables us to specifically examine receptor binding and signalling properties of CB1 receptor in a given cell type. With this project, we aim at achieving a better understanding of the intricate molecular complexities of the endocannabinoid system and provide a scaffold for the development of pharmacological tools to treat diseases related to dysregulated endocannabinoid signalling.

• DFG Programme: Research Grants