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 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.
Small-Howard
Andrea L
AL
Laboratory of Cell Biology and Immunology, Center for Biomedical Research at the Queen's Medical Center, Honolulu, HI 96813, USA.
Shimoda
Lori M N
LM
Adra
Chaker N
CN
Turner
Helen
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D001095:Arachidonic Acids; D001892:Camphanes; D007211:Indoles; D008024:Ligands; D009025:Morpholines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C088155:methanandamide; D005576:Colforsin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; C109925:AM 281; C402944:JHW 015