Antagonism of Dopamine Receptor 2 Long Affects Cannabinoid Receptor 1 Signaling in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

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

doi:10.1124/mol.116.103465

Cited by 37 publications

(26 citation statements)

References 71 publications

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“…These potential physical interactions are obviously cell-type-specific, and can modify the signaling of different pools of CB 1 receptors. In this sense, two recent studies showed how (i) heteromers between CB 1 receptors and adenosine A 2A displays a striking G protein-coupling signaling profile where the stimulation of both receptors reduces the downstream signaling ( Moreno et al , 2017 ); (ii) the formation of heteromers between CB 1 receptors and D2 receptors changes the agonist-mediated CB 1 receptor signaling and coupling ( Bagher et al , 2016 ). More research is needed to better understand the functional impact of the formation of homomers or heteromers between CB 1 receptors and other brain receptors in physiology and pathology.…”

Section: Signaling Of Cb 1 Receptors In the Brain:mentioning

confidence: 99%

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Busquets-García

Bains

Marsicano

2017

Neuropsychopharmacol.

261

218

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Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the central nervous system (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino-acid transmitters, neuropeptides, and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the eCB system (ECS) is continuously evolving and challenging long-held conventions. Here we will briefly summarize findings on the current canonical view of the ‘ECS’ and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, while clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level.

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Section: Signaling Of Cb 1 Receptors In the Brain:mentioning

confidence: 99%

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Busquets-García

Bains

Marsicano

2017

Neuropsychopharmacol.

261

218

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“…Moreover, ligand bias can be influenced by receptor oligomerization in specific cells or tissues. For instance, CB1-dependent Gα q signaling has been reported to occur through CB1-D2 (type 2 dopamine receptor) dimerization [136].…”

Section: Cb1 Biased Ligandsmentioning

confidence: 99%

Structural Insights into CB1 Receptor Biased Signaling

Al-Zoubi

Morales

Reggio

2019

IJMS

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The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.

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“…Despite longstanding consensus as to its canonical Gα i ‐mediated signalling pathway, the type one cannabinoid receptor (CB) is among several GPCRs now understood to transduce signals through more than one G protein effector – a capacity sometimes referred to as ‘promiscuous G protein coupling’ (reviewed in Maudsley et al, ). Environmental and pharmacological conditions that have been found to affect CB 1 receptor signalling in this way include blockade of the canonical Gα i pathway with pertussis toxin (PTX) (Glass and Felder, ; Bonhaus et al, ; Scotter et al, ), the class of CB 1 agonist (Bonhaus et al, ; Lauckner et al, ), receptor oligomers (Kearn et al, ; Bagher et al, ) and cell background (McIntosh et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, co‐immunoprecipitation data led Kearn et al () to propose that the CB 1 receptor signalling switch is derived pleiotropically, from altered protein conformations caused by a physical interaction between D 2 and CB 1 receptors – a receptor heterodimer. Characterization of the CB 1 /D 2 receptor heterodimer has continued using other approaches (Marcellino et al, ; Przybyla and Watts, ; Bagher et al, ). It remains noteworthy that the two hypotheses of the signalling switch mechanism need not be mutually exclusive, and both promiscuous (low‐efficacy activation of a non‐preferred G protein species due to lack of availability of the preferred species; i.e.…”

Section: Introductionmentioning

confidence: 99%

Gα_s signalling of the CB₁ receptor and the influence of receptor number

Finlay

Cawston

Grimsey

et al. 2017

British J Pharmacology

118

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CB receptor coupling to opposing G proteins is determined by both receptor and G protein expression levels, which underpins a mechanism for non-canonical signalling in a fashion consistent with Gα signalling. CB receptors mediate opposite consequences in endpoints such as tumour viability depending on expression levels; our results may help to explain such effects at the level of G protein coupling.

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Antagonism of Dopamine Receptor 2 Long Affects Cannabinoid Receptor 1 Signaling in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

Abstract: ABSTRACT

Cited by 37 publications

References 71 publications

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Structural Insights into CB1 Receptor Biased Signaling

Gα_s signalling of the CB₁ receptor and the influence of receptor number

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Antagonism of Dopamine Receptor 2 Long Affects Cannabinoid Receptor 1 Signaling in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

Abstract: ABSTRACT

Cited by 37 publications

References 71 publications

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

Structural Insights into CB1 Receptor Biased Signaling

Gαs signalling of the CB1 receptor and the influence of receptor number

Contact Info

Product

Resources

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Gα_s signalling of the CB₁ receptor and the influence of receptor number