Journal ArticleDOI
Involvement of the 90-kDa heat shock protein (Hsp-90) in CB2 cannabinoid receptor-mediated cell migration: a new role of Hsp-90 in migration signaling of a G protein-coupled receptor.
TLDR
The data indicate that Hsp90 may serve as scaffold to keep the CB2 receptor and its signaling components, including Gαi2, in proximity, thus facilitating CB2-mediated signaling to cell migration through the Gi-Rac1 pathway.Abstract:
The endocannabinoid 2-arachidonoylglycerol (2-AG) enhances cell migration through the CB2 cannabinoid receptor. In this study, using an immunoprecipitation and mass spectrometry-based proteomic approach, we first identified the 90-kDa heat shock protein (Hsp90), a chaperone protein with novel signaling functions, as a CB2-interacting protein. The CB2/Hsp90 interaction was confirmed in human embryonic kidney 293 cells expressing transfected CB2 and in differentiated HL-60 cells expressing endogenous CB2, by coimmunoprecipitation and Western blot experiments, as well as by treatment with geldanamycin (GA), a specific Hsp90 inhibitor. Disruption of the CB2/Hsp90 interaction by treatment with GA or reducing Hsp90 levels with specific short interfering RNAs markedly inhibited 2-AG-induced cell migration, demonstrating that Hsp90 is crucial for 2-AG-induced cell migration. 2-AG treatment resulted in a CB2-mediated stimulation of Rac1 activity, and treatment with GA blocked 2AG-induced activation of Rac1. It is noteworthy that expression of the dominant-negative form of Rac1 reduced 2-AG-induced cell migration. These data demonstrate that 2-AG-induced activation of Rac1 is essential for 2-AG-induced cell migration, and the CB2/Hsp90 interaction is needed for 2-AG-induced activation of Rac1. Furthermore, 2-AG-induced Rac1 activation was sensitive to pertussis toxin treatment, hence involving G(i) proteins. In addition, treatment with GA significantly inhibited the CB2/Galpha(i2) interaction. As a whole, our data indicate that Hsp90 may serve as scaffold to keep the CB2 receptor and its signaling components, including Galpha(i2), in proximity, thus facilitating CB2-mediated signaling to cell migration through the G(i)-Rac1 pathway. By demonstrating that Hsp90 is essential for CB2-mediated signaling to cell migration, this study reveals a novel role of Hsp90 in the signaling events mediated by a G protein-coupled receptor.read more
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Journal ArticleDOI
The CB2 receptor and its role as a regulator of inflammation.
TL;DR: The CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases, suggesting that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions.
Journal ArticleDOI
An introduction to the endocannabinoid system: from the early to the latest concepts
TL;DR: The complexity of the endocannabinoid system and of its physiological and pathological function is outlined in this introductory chapter, for a better understanding of the subsequent chapters in this special issue.
Journal ArticleDOI
Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities.
TL;DR: The ability to selectively manipulate physiological functions, through activation of defined signalling cascades, will in all likelihood help in the development of efficacious and safe cannabinoid-based therapeutics for a variety of indications.
Journal ArticleDOI
Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor.
TL;DR: The data shows that the presence of the polymorphisms at both positions 63 and 316 produce alterations in the CB2 receptor functions, which strengthen the idea that the CB1 polymorphic receptors may contribute to the etiology of certain diseases.
Journal ArticleDOI
The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction
TL;DR: Overall, Hsps are important regulators of receptor signaling that are receiving increasing interest and exploration, particularly as Hsp90 inhibitors progress toward clinical approval for the treatment of cancer.
References
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Structure of a cannabinoid receptor and functional expression of the cloned cDNA
TL;DR: The cloning and expression of a complementary DNA that encodes a G protein-coupled receptor that is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana are suggested.
Journal ArticleDOI
Molecular characterization of a peripheral receptor for cannabinoids
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Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
Raphael Mechoulam,Shimon Ben-Shabat,Lumir Hanus,Moshe Ligumsky,Norbert E. Kaminski,Anthony R. Schatz,Asher Gopher,Shlomo Almog,Billy R. Martin,David R. Compton,Roger G. Pertwee,Graeme Griffin,Michael Bayewitch,Jacob Barg,Zvi Vogel +14 more
TL;DR: Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature.
Journal ArticleDOI
2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
Takayuki Sugiura,Sachiko Kondo,Akihiro Sukagawa,Shinji Nakane,A. Shinoda,K. Itoh,Atsushi Yamashita,Keizo Waku +7 more
TL;DR: 2-Arachidonoylglycerol was shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments and may be an endogenous cannabinoid receptor ligand in the brain.
Journal ArticleDOI
Rho and Rac Take Center Stage
TL;DR: This work will describe how the activity of Rho proteins is regulated downstream from growth factor receptors and cell adhesion molecules by guanine nucleotide exchange factors and GTPase activating proteins.