Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

Laprairie, Robert B.; Bagher, Amina M.; Kelly, Melanie E. M.; Dupré, Denis J.; Denovan‐Wright, Eileen M.

doi:10.1074/jbc.m114.557025

Cited by 126 publications

(175 citation statements)

References 65 publications

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“…Thus, it appears that the recruitment of b-arr1 to CB 1 R-WT is very weak, so that it challenges the limits of detectability via the (otherwise quite sensitive) BRET approach applied here. However, our results showing a significant increase in b-arr1 BRET upon 2-AG stimulus are in accordance with recent results showing higher b-arr1 recruitment by 2-AG compared with WIN55 (Laprairie et al 2014). Taken together, recruitment of b-arr1 to CB 1 R-WT is obviously lower than that of b-arr2, but both are substantially enhanced in the CB 1 R-AAY mutant.…”

Section: Discussionsupporting

confidence: 81%

“…The binding between b-arrs and CB 1 R is relatively weak, and the affinity of the receptor for b-arr2 (b-arr2) is substantially higher than that for b-arr1 (b-arr1) (Gyombolai et al 2013). Furthermore, b-arr1 recruitment of CB 1 R appears to be agonist-dependent (Laprairie et al 2014, Flores-Otero et al 2014. Interestingly, in addition to canonical G-protein-mediated intracellular effects, recent data have suggested that the existence of b-arr-mediated, G-protein-independent signaling of CB 1 R, i.e.…”

Section: Introductionmentioning

confidence: 96%

“…Data are meanGS.E.M., nZ4-7. Laprairie et al 2014). To test whether DRY mutations of CB 1 R affect the recruitment of b-arr1, we applied the same BRET-based approach as above, i.e.…”

Section: B-arr1 Recruitment Of Cb 1 R-aay Mutant Is Robustly Enhancedmentioning

confidence: 99%

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Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

Gyombolai¹,

Tóth²,

Tímár³

et al. 2014

Journal of Molecular Endocrinology

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The role of the highly conserved 'DRY' motif in the signaling of the CB 1 cannabinoid receptor (CB 1 R) was investigated by inducing single-, double-, and triple-alanine mutations into this site of the receptor. We found that the CB 1 R-R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric G o proteins (w80% of WT CB 1 R (CB 1 R-WT)). Moreover, this mutant showed an enhanced basal b-arrestin2 (b-arr2) recruitment. More strikingly, the double-mutant CB 1 R-D3.49A/R3.50A was biased toward b-arrs, as it gained a robustly increased b-arr1 and b-arr2 recruitment ability compared with the WT receptor, while its G-protein activation was decreased. In contrast, the double-mutant CB 1 R-R3.50A/Y3.51A proved to be G-protein-biased, as it was practically unable to recruit b-arrs in response to agonist stimulus, while still activating G-proteins, although at a reduced level (w70% of CB 1 R-WT). Agonist-induced ERK1/2 activation of the CB 1 R mutants showed a good correlation with their b-arr recruitment ability but not with their G-protein activation or inhibition of cAMP accumulation. Our results suggest that G-protein activation and b-arr binding of the CB 1 R are mediated by distinct receptor conformations, and the conserved 'DRY' motif plays different roles in the stabilization of these conformations, thus mediating both G-protein-and b-arr-mediated functions of CB 1 R.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

Gyombolai¹,

Tóth²,

Tímár³

et al. 2014

Journal of Molecular Endocrinology

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“…There is precedence for both ligand-and cell-type-specific differences in CB 1 R signaling Laprairie et al 2014). Ligands for CB 1 R, including the ECBs, synthetic cannabinoids such as WIN and phytocannabinoids such as Δ 9 -tetrahydrocannabinol, all bind different residues on the receptor.…”

Section: Discussionmentioning

confidence: 99%

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

et al. 2017

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Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB 1 receptor (CB 1 R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB 1 Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB 1 R/β1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.

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“…In addition, eCB, synthetic cannabinoids and phytocannabinoids exhibited biased signaling at CB 1, and activation of CB 1 by Gαi/o-and Gβγ-selective ligands might be therapeutically beneficial in HD [64][65][66]. Indeed, in vitro treatment of striatal cell model of HD with AEA normalized CB 1 protein levels and this effect was associated with improved cell viability, ATP production, BDNF-2 expression and inhibition of GABA release [64][65][66].…”

Section: The Link Between Hd and Cb 1 Receptor-mediated Protective Acmentioning

confidence: 99%

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Coccurello

Bisogno

2016

Expert Review of Clinical Pharmacology

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Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

Cited by 126 publications

References 65 publications

Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

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