Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling

Daigle, Tanya L.; Kearn, Christopher S.; Mackie, Ken

doi:10.1016/j.neuropharm.2007.06.005

Cited by 137 publications

(167 citation statements)

References 38 publications

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“…As described in the introduction, the binding between β-arr2 and CB 1 R as well as a role for β-arrestins in the desensitization of CB 1 R have been demonstrated by former studies (Bakshi et al, 2007;Daigle et al, 2008aDaigle et al, , 2008bJin et al, 1999;Kouznetsova et al, 2002;Nguyen et al, 2012;Singh et al, 2011). Therefore, the role of β-arr2 in CB 1 R endocytosis may seem to be a logical consequence of its recruitment to the receptor.…”

Section: Discussionmentioning

confidence: 82%

“…Although the role of β-arrestin molecules in CB 1 R-mediated ERK activation has been suggested (Daigle et al, 2008a), the exact role of this process in CB 1 R-mediated ERK activation requires additional studies. It is very likely that the class A behavior of CB 1 R is associated with a characteristic distribution of MAPK activation, nevertheless, direct studies that address these questions are needed to confirm them.…”

Section: Discussionmentioning

confidence: 99%

“…Recruitment of β-arr2 to the activated CB 1 R has also been demonstrated (Daigle et al, 2008a). Mutation of amino acids S426 and S430 was shown to inhibit receptor desensitization as well as late phase receptor endocytosis, but not β-arrestin binding (Daigle et al, 2008b;Jin et al, 1999).…”

mentioning

confidence: 92%

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Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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CB 1 cannabinoid receptor (CB 1 R) undergoes both constitutive and agonist-induced internalization, but the underlying mechanisms of these processes and the role of β-arrestins in the regulation of CB 1 R function are not completely understood. In this study, we followed CB 1 R internalization using confocal microscopy and bioluminescence resonance energy transfer measurements in HeLa and Neuro-2a cells. We found that upon activation CB 1 R binds β-arrestin2 (β-arr2), but not β-arrestin1. Furthermore, both the expression of dominant-negative β-arr2 (β-arr2-V54D) and siRNA-mediated knock-down of β-arr2 impaired the agonist-induced internalization of CB 1 R. In contrast, neither β-arr2-V54D nor β-arr2-specific siRNA had a significant effect on the constitutive internalization of CB 1 R. However, both constitutive and agonist-induced internalization of CB 1 R were impaired by siRNA-mediated depletion of clathrin heavy chain. We conclude that although clathrin is required for both constitutive and agonist-stimulated internalization of CB 1 R, β-arr2 binding is only required for agonist-induced internalization of the receptor suggesting that the molecular mechanisms underlying constitutive and agonist-induced internalization of CB 1 R are different.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Gyombolai

Boros

Hunyady

et al. 2013

Molecular and Cellular Endocrinology

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“…Blockade of AEA uptake by UCM707 abolished hyperkinesia in rodent models of HD and reduced spasticity in MS rats [178]. However, the elevation in AEA could produce psychotropic effects and tolerance upon CB 1 R activation [179], which has not been seen as a side effect of CBD [180]. Therefore, the binding of CBD to the AEA transporter will not provide a therapeutic effect in movement disorders.…”

Section: Cbd Transporter Targets In Movement Disordersmentioning

confidence: 99%

“…Although the inhibition of AEA uptake has produced anxiolytic responses in animal models, previous studies have shown that CB 1 R activation leads to psychotropic effects; this has never been observed following CBD treatment [279]. Furthermore, prolonged CB 1 R activation leads to tolerance, which has not been reported in CBD-treated animals [180]. Thus, it is unlikely that the AEA transporter is involved in the anxiolytic or antipsychotic effect of CBD.…”

Section: Cbd Transporter Targets In Psychosismentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Development of In‐Cell Western Assays Using Far‐Red Fluorophores

Moerke

Hoffman

2011

CP Chemical Biology

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The in‐cell western (ICW) technique is a cell‐based immunoassay method for quantitative measurement of protein expression or phosphorylation levels that can be used for both small molecule and siRNA screening. The method involves growth of cells in microplates, fixation, permeabilization, and staining with specific antibodies and/or cell labeling dyes. ICW assays take advantage of the properties of near‐infrared dyes to achieve higher signal‐to‐noise ratios than are possible for methods utilizing fluorophores in the visible range of the spectrum, and typically involve measurements using two fluorescent channels: one to measure levels of the target of interest, and one to measure total cell number for normalization. The ICW method is readily adaptable to high‐throughput format and has been successfully used with a variety of targets and cell lines. The protocols in this unit describe an ICW procedure for quantitative measurement of rpS6‐phosphorylation as an endpoint for monitoring mTORC1 signaling in HeLa cells. This assay can be used for small molecule or siRNA screening, and with modification is adaptable to other cell lines and targets. Curr. Protoc. Chem. Biol. 3:39‐52 © 2011 by John Wiley & Sons, Inc.

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Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling

Cited by 137 publications

References 38 publications

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Differential β-arrestin2 requirements for constitutive and agonist-induced internalization of the CB1 cannabinoid receptor

Molecular Targets of Cannabidiol in Neurological Disorders

Development of In‐Cell Western Assays Using Far‐Red Fluorophores

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