Abstract
The endocannabinoid system (ECS) acts as a negative feedback mechanism to suppress synaptic transmission and plays a major role in a diverse range of brain functions including, for example, the regulation of mood, energy balance, and learning and memory. The function and dysfunction of the ECS are strongly implicated in multiple psychiatric, neurological, and neurodegenerative diseases. Cannabinoid type 1 receptor (CB1R) is the most abundant G protein-coupled receptor (GPCR) expressed in the brain and, as for any synaptic receptor, CB1R needs to be in the right place at the right time to respond appropriately to changing synaptic circumstances. While CB1R is found intracellularly throughout neurons, its surface expression is highly polarized to the axonal membrane, consistent with its functional expression at presynaptic sites. Surprisingly, despite the importance of CB1R, the interacting proteins and molecular mechanisms that regulate the highly polarized distribution and function of CB1R remain relatively poorly understood. Here we set out what is currently known about the trafficking pathways and protein interactions that underpin the surface expression and axonal polarity of CB1R, and highlight key questions that still need to be addressed.
Highlights
Information transfer at synapses is almost always mediated by neurotransmitter released from the presynaptic terminal activating specific postsynaptic receptors
This review focuses on the trafficking and polarized surface expression of Cannabinoid type 1 receptor (CB1R) but, intriguingly, CB1R expressed at the plasma membrane comprises only ∼20% of total CB1R (McIntosh et al, 1998; Leterrier et al, 2006; Rozenfeld and Devi, 2008)
Cannabinoid type 1 receptor is trafficked to the plasma membrane via the secretory pathway but, like many other G protein-coupled receptor (GPCR), CB1R does not have a canonical, cleavable signal peptide (Andersson et al, 2003)
Summary
Information transfer at synapses is almost always mediated by neurotransmitter released from the presynaptic terminal activating specific postsynaptic receptors. Cannabinoid type 1 receptor surface expression in neurons is highly polarized to axons and presynaptic sites, where ligand binding results in the downregulation of presynaptic release through coupling to a variety of downstream signaling pathways (Figure 1). CB1R has a wide intracellular distribution but its plasma membrane surface expression is highly polarized toward the axonal compartment (Figure 1; Irving et al, 2000; Coutts et al, 2001; Leterrier et al, 2006; McDonald et al, 2007a; Fletcher-Jones et al, 2019). For recent reviews see Djeungoue-Petga and Hebert-Chatelain (2017), Busquets-Garcia et al (2018)
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