CBR1

Cannabinoid receptor 1 (CBR1/CB1R) is a Gi/o-coupled G protein-coupled receptor that functions as a major regulator of endocannabinoid signaling in the central nervous system and peripheral tissues, where it modulates neurotransmitter release and synaptic activity through presynaptic mechanisms^[1]. Mechanistically, CBR1 inhibits adenylyl cyclase, regulates cyclic AMP-dependent signaling, activates mitogen-activated protein kinase pathways, and modulates voltage-gated calcium and inwardly rectifying potassium channels, thereby controlling neuronal excitability and cellular responses^[2]. Endocannabinoid-mediated CBR1 signaling acts as a feedback system that limits excessive synaptic transmission and contributes to neuronal plasticity and neuroprotection^[3]. In disease-related experimental models, CBR1 activation promotes cell-survival pathways involving PI3K/Akt/mTORC1 signaling and brain-derived neurotrophic factor expression, supporting neuronal viability in models of striatal injury and Huntington’s disease^[3]. Compared with the related cannabinoid receptor CB2, which is predominantly associated with immune tissues and immunomodulatory functions, CBR1 is highly enriched in neuronal populations and uniquely exhibits prominent ion-channel regulation^[2]. For experimental applications, selective CBR1 agonists and antagonists are widely used to distinguish receptor-specific functions, investigate feeding behavior, metabolic regulation, synaptic plasticity, and neurodegenerative mechanisms, although centrally acting antagonists have shown psychiatric liabilities in clinical development^[1][4].

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