ABSTRACT
Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the brain by engaging Type 1 cannabinoid receptor (CB1R). Accruing evidence supports that cannabinoid action relies on context-dependent factors, such as the biological characteristics of the target cell, suggesting that cell population-intrinsic molecular cues modulate CB1R-dependent signaling. Here, by using a yeast two-hybrid-based high-throughput screening, we identified BiP as a potential CB1R-interacting protein. We next found that CB1R and BiP interact specifically in vitro, and mapped the interaction site within the CB1R C-terminal (intracellular) domain and the BiP C-terminal (substrate-binding) domain-α. BiP selectively shaped agonist-evoked CB1R signaling by blocking an "alternative" Gq/11 protein-dependent signaling module while leaving the "classical" Gi/o protein-dependent inhibition of the cAMP pathway unaffected. In situ proximity ligation assays conducted on brain samples from various genetic mouse models of conditional loss or gain of CB1R expression allowed to map CB1R-BiP complexes selectively on terminals of GABAergic neurons. Behavioral studies using cannabinoid-treated male BiP+/- mice supported that CB1R-BiP complexes modulate cannabinoid-evoked anxiety, one of the most frequent undesired effects of cannabis. Together, by identifying BiP as a CB1R-interacting protein that controls receptor function in a signaling pathway- and neuron population-selective manner, our findings may help to understand the striking context-dependent actions of cannabis in the brain.SIGNIFICANCE STATEMENT Cannabis use is increasing worldwide, so innovative studies aimed to understand its complex mechanism of neurobiological action are warranted. Here, we found that cannabinoid CB1 receptor (CB1R), the primary molecular target of the bioactive constituents of cannabis, interacts specifically with an intracellular protein called BiP. The interaction between CB1R and BiP occurs selectively on terminals of GABAergic (inhibitory) neurons, and induces a remarkable shift in the CB1R-associated signaling profile. Behavioral studies conducted in mice support that CB1R-BiP complexes act as fine-tuners of anxiety, one of the most frequent undesired effects of cannabis use. Our findings open a new conceptual framework to understand the striking context-dependent pharmacological actions of cannabis in the brain.
Subject(s)
Brain/metabolism , Cannabinoids/metabolism , GABAergic Neurons/metabolism , Heat-Shock Proteins/metabolism , Receptor, Cannabinoid, CB1/metabolism , Signal Transduction/physiology , Animals , Endoplasmic Reticulum Chaperone BiP , HEK293 Cells , Heat-Shock Proteins/genetics , Humans , Mice , Mice, Knockout , Receptor, Cannabinoid, CB1/geneticsABSTRACT
BACKGROUND: The quality of life (QOL) of the elderly can be influenced by numerous factors. We assessed QOL, cognitive functions, depression and clinical data in elderly aged 65 and over with the aim of analysing factors affecting their QOL. METHODS: Semi-structured interviews were conducted with elderly over the age of 65, and their QOL, cognitive functions and depressive symptoms were assessed by validated clinical tests and screening tools. RESULTS: The correlation between QOL scales and cognitive tests was not significant. In contrast, the results of depression scales showed significant negative correlation with the scores of the QOL scales. A better QOL was determined by lower age, lack of depressive symptoms, and higher scores in the QOL-AD (Alzheimer's disease) scale. Depressive mood has much more negative impact on the QOL of the elderly than cognitive impairment. CONCLUSIONS: Our results demonstrated a close correlation between QOL and depressive mood in the elderly. The early detection and effective management of affective and cognitive symptoms in the elderly can not only restore mental health but may also improve their QOL.
