In the central nervous system (CNS), cannabinoid receptor 1 (CB1R) is preferentially expressed in axons where it has a unique property, namely resistance to agonist-driven endocytosis. This review aims to summarize what we know about molecular mechanisms of CB1R cell surface stability in axonal compartments, how these impact CB1R signaling, and to consider their physiological consequences. This review then focuses on a potential candidate for maintaining axonal CB1R at the cell surface, Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1). SGIP1 may contribute to the polarized distribution of CB1R and modify its signaling in axons. In addition, deletion of SGIP1 results in discrete behavioral changes in modalities controlled by the endocannabinoid system in vivo. Several drugs acting directly via CB1R have important therapeutic potential, however their adverse effects limit their clinical use. Future studies might reveal chemical approaches to target the SGIP1-CB1R interaction, with the aim to exploit the endocannabinoid system pharmaceutically in a discrete way, with minimized undesired consequences.

• Klíčová slova
• axon enrichment, cannabinoid receptor 1, clathrin-mediated endocytosis, internalization, synaptic transmission,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cannabinoid receptor 1 (CB1R), a G protein-coupled receptor, plays a fundamental role in synaptic plasticity. Abnormal activity and deregulation of CB1R signaling result in a broad spectrum of pathological conditions. CB1R signaling is regulated by receptor desensitization including phosphorylation of residues within the intracellular C terminus by G protein-coupled receptor kinases (GRKs) that may lead to endocytosis. Furthermore, CB1R signaling is regulated by the protein Src homology 3-domain growth factor receptor-bound 2-like (SGIP1) that hinders receptor internalization, while enhancing CB1R association with β-arrestin. It has been postulated that phosphorylation of two clusters of serine/threonine residues, 425 SMGDS429 and 460 TMSVSTDTS468 , within the CB1R C-tail controls dynamics of the association between receptor and its interaction partners involved in desensitization. Several molecular determinants of these events are still not well understood. We hypothesized that the dynamics of these interactions are modulated by SGIP1. Using a panel of CB1Rs mutated in the aforementioned serine and threonine residues, together with an array of Bioluminescence energy transfer-based (BRET) sensors, we discovered that GRK3 forms complexes with Gβγ subunits of G proteins that largely independent of GRK3's interaction with CB1R. Furthermore, CB1R interacts only with activated GRK3. Interestingly, phosphorylation of two specific residues on CB1R triggers GRK3 dissociation from the desensitized receptor. SGIP1 increases the association of GRK3 with Gβγ subunits of G proteins, and with CB1R. Altogether, our data suggest that the CB1R signalosome complex is dynamically controlled by sequential phosphorylation of the receptor C-tail and is also modified by SGIP1.

• Klíčová slova
• G protein-coupled receptor kinase, G protein-coupled receptors, SGIP1, cannabinoid receptor 1, phosphorylation, β-arrestin,
• MeSH
• fosforylace MeSH
• kinetika MeSH
• proteiny vázající GTP * MeSH
• receptory kanabinoidní metabolismus   MeSH
• serin metabolismus   MeSH
• threonin metabolismus   MeSH
• transportní proteiny * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny vázající GTP * MeSH
• receptory kanabinoidní MeSH
• serin MeSH
• threonin MeSH
• transportní proteiny * MeSH

BACKGROUND AND PURPOSE: Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid CB1 receptors. SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB1 receptors co-localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of activated CB1 receptors in transfected heterologous cells. Consequently, the transient association of CB1 receptors with β-arrestin2 is enhanced and prolonged, and CB1 receptor-mediated ERK1/2 signalling is decreased. Because of these actions, SGIP1 may modulate affect, anxiety, pain processing, and other physiological processes controlled by the endocannabinoid system (ECS). EXPERIMENTAL APPROACH: Using a battery of behavioural tests, we investigated the consequences of SGIP1 deletion in tasks regulated by the ECS in SGIP1 constitutive knockout (SGIP1-/- ) mice. KEY RESULTS: In SGIP1-/- mice, sensorimotor gating, exploratory levels, and working memory are unaltered. SGIP1-/- mice have decreased anxiety-like behaviours. Fear extinction to tone is facilitated in SGIP1-/- females. Several cannabinoid tetrad behaviours are altered in the absence of SGIP1. SGIP1-/- males exhibit abnormal behaviours on Δ9 -tetrahydrocannabinol withdrawal. SGIP1 deletion also reduces acute nociception, and SGIP1-/- mice are more sensitive to analgesics. CONCLUSION AND IMPLICATIONS: SGIP1 was detected as a novel protein associated with CB1 receptors, and profoundly modified CB1 receptor signalling. Genetic deletion of SGIP1 particularly affected behavioural tests of mood-related assessment and the cannabinoid tetrad. SGIP1-/- mice exhibit decreased nociception and augmented responses to CB1 receptor agonists and morphine. These in vivo findings suggest that SGIP1 is a novel modulator of CB1 receptor-mediated behaviour.

• Klíčová slova
• GPCR, anxiety, cannabinoid receptor 1, endocannabinoid system, pain, tolerance,
• MeSH
• adaptorové proteiny signální transdukční fyziologie   MeSH
• afekt MeSH
• emoce MeSH
• extinkce (psychologie) MeSH
• kanabinoidy MeSH
• myši knockoutované MeSH
• myši MeSH
• nocicepce * MeSH
• receptor kanabinoidní CB1 * genetika   MeSH
• receptory kanabinoidní MeSH
• strach MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• kanabinoidy MeSH
• receptor kanabinoidní CB1 * MeSH
• receptory kanabinoidní MeSH
• SGIP1 protein, mouse MeSH Prohlížeč