Interaction of a fragment of the cannabinoid CB1 receptor C‐terminus with arrestin‐2

Bakshi, Kunal; Mercier, Richard W.; Pavlopoulos, Spiro

doi:10.1016/j.febslet.2007.09.030

Cited by 33 publications

(41 citation statements)

References 43 publications

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“…The C-terminal tagging of β-arr1 is also not likely to cause the lack of the signal, as both β-arr1-Rluc and β-arr1-GFP constructs could be successfully used to detect β-arr1 recruitment to AT 1 R and β 2 AR. In a previous study, Bakshi et al have shown using nuclear magnetic resonance (NMR) that a C-terminal fragment of CB 1 R is able to bind β-arr1 (Bakshi et al, 2007). Our data suggest that such binding between the two molecules, even if present, must be very weak compared to β-arr2, when tested with native proteins in living cells.…”

Section: Discussionsupporting

confidence: 46%

“…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: 81%

“…It has been demonstrated that serine and threonine residues at the C-terminus of CB 1 R are involved in its β-arr2 binding and agonist-induced endocytosis (Daigle et al, 2008b;Hsieh et al, 1999). In contrast to the various studies that clearly point to an interaction between CB 1 R and β-arr2 upon agonist stimulation, no direct data have been hitherto presented concerning the β-arr1 binding of CB 1 R. In some structural studies, the association of β-arr1 with a synthesized CB 1 R C-terminus has been shown (Bakshi et al, 2007;Singh et al, 2011), however, such binding has not been demonstrated with the intact CB 1 R in living cells.…”

mentioning

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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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: Discussionsupporting

confidence: 46%

Section: Discussionmentioning

confidence: 81%

mentioning

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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“…For example, probable G-protein-coupled receptor kinase phosphorylation sites have been identified Jin et al, 1999;Daigle et al, 2008) and isolated fragments of the CB 1 R C-terminus can bind to b-arrestins (Singh et al, 2011;Bakshi et al, 2007) and GASP1 (Martini et al, 2007). Prolonged agonist exposure downregulates CB 1 Rs expressed in HEK-293 (Shapira et al, 2003) but not N18TG2 cells (McIntosh et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor–Interacting Protein 1a Modulates CB1 Receptor Signaling and Regulation

Smith

Blume

Straiker

et al. 2015

Molecular Pharmacology

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Cannabinoid CB 1 receptors (CB 1 Rs) mediate the presynaptic effects of endocannabinoids in the central nervous system (CNS) and most behavioral effects of exogenous cannabinoids. Cannabinoid receptor-interacting protein 1a (CRIP 1a ) binds to the CB 1 R C-terminus and can attenuate constitutive CB 1 R-mediated inhibition of Ca 21 channel activity. We now demonstrate cellular colocalization of CRIP 1a at neuronal elements in the CNS and show that CRIP 1a inhibits both constitutive and agonist-stimulated CB 1 Rmediated guanine nucleotide-binding regulatory protein (G-protein) activity. Stable overexpression of CRIP 1a in human embryonic kidney (HEK)-293 cells stably expressing CB 1 Rs (CB 1 -HEK), or in N18TG2 cells endogenously expressing CB 1 Rs, decreased CB 1 Rmediated G-protein activation (measured by agonist-stimulated [ activation. These effects were not attributable to differences in CB 1 R expression or endocannabinoid tone because CB 1 R levels did not differ between cell lines varying in CRIP 1a expression, and endocannabinoid levels were undetectable (CB 1 -HEK) or unchanged (N18TG2) by CRIP 1a overexpression. In CB 1 -HEK cells, 4-hour pretreatment with cannabinoid agonists downregulated CB 1 Rs and desensitized agonist-stimulated [ 35 S]GTPgS binding. CRIP 1a overexpression attenuated CB 1 R downregulation without altering CB 1 R desensitization. Finally, in cultured autaptic hippocampal neurons, CRIP 1a overexpression attenuated both depolarizationinduced suppression of excitation and inhibition of excitatory synaptic activity induced by exogenous application of cannabinoid but not by adenosine A1 agonists. These results confirm that CRIP 1a inhibits constitutive CB 1 R activity and demonstrate that CRIP 1a can also inhibit agonist-stimulated CB 1 R signaling and downregulation of CB 1 Rs. Thus, CRIP 1a appears to act as a broad negative regulator of CB 1 R function.

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“…Arrestin-1 (or visual arrestin) and arrestin-4 (or cone arrestin) modulate the action of rhodopsin (10,11) and arrestin-2 and arrestin-3 modulate nonretinal GPCRs (12,13). Recently, desensitization of the CB1 receptor was reported to be mediated by the interaction of the COOH-terminal residues (419-439) of CB1 with arrestin-2 (14), indicating that CB1 and CB2 might act as photoreceptors in nonretinal tissues. However, a role for CB1 and CB2 in skin cancer has not been reported.…”

Section: Introductionmentioning

confidence: 99%

The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development

et al. 2008

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Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UVinduced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor-KB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development. [Cancer Res 2008;68(10):3992-8]

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Interaction of a fragment of the cannabinoid CB1 receptor C‐terminus with arrestin‐2

Cited by 33 publications

References 43 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

Cannabinoid Receptor–Interacting Protein 1a Modulates CB1 Receptor Signaling and Regulation

The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development

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