Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells

Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1...

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Bibliographic Details
Published in:Biochemical journal 2005-06, Vol.388 (Pt 2), p.465-473
Main Authors: Small-Howard, Andrea L, Shimoda, Lori M N, Adra, Chaker N, Turner, Helen
Format: Article
Language:English
Subjects:
Adenylyl Cyclases - metabolism
Animals
Arachidonic Acids - pharmacology
Bornanes - pharmacology
Cell Line
Colforsin - pharmacology
Cyclic AMP - biosynthesis
Cytosol - drug effects
Cytosol - metabolism
Down-Regulation
GTP-Binding Protein alpha Subunits, Gi-Go - physiology
Humans
Indoles - pharmacology
Ligands
Mast Cells - drug effects
Mast Cells - metabolism
Morpholines - pharmacology
Pertussis Toxin - pharmacology
Pyrazoles - pharmacology
Receptor, Cannabinoid, CB1 - agonists
Receptor, Cannabinoid, CB1 - physiology
Receptor, Cannabinoid, CB2 - agonists
Receptor, Cannabinoid, CB2 - physiology
Signal Transduction
Time Factors
Transcription, Genetic
Up-Regulation
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Summary:Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune system cells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the Galpha(i/o)-coupled CB1 is paradoxical, and our results indicate that it may be attributed to CB1-mediated transcriptional regulation of specific adenylate cyclase isoenzymes that exhibit superactivatable kinetics. Taken together, these results reveal the complexity in signalling of natively co-expressed cannabinoid receptors and suggest that some anti-inflammatory effects of CB1 ligands may be attributable to sustained cAMP elevation that, in turn, causes suppression of mast cell degranulation.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20041682