HEP (2005) 168:53–79
©cSpringer-Verlag 2005
Cannabinoid Receptor Signaling
A.C. Howlett
Neuroscience/Drug Abuse Research Program, 208 JLC-BBRI, North Carolina Central
University, 700 George Street, Durham NC, 27707, USA
[email protected]
1Introduction.................................... 54
2 The Cyclic AMP and Protein Kinase A Signal Transduction Pathway ..... 56
2.1 CannabinoidReceptor-MediatedInhibitionofCyclicAMPProduction .... 56
2.2 Cannabinoid Receptor-Mediated Stimulation of Cyclic AMP Production... 57
3 Cannabinoid Receptor-Mediated Ca2+Fluxes and Phospholipases C and A .58
4 Cannabinoid Receptor-Mediated Regulation of Ion Channels ......... 59
4.1 Voltage-Gated Ca2+-Channels .......................... 59
4.2 G Protein-Coupled Inwardly-Rectifying K+Channels ............. 60
4.3 Depolarization-InducedSuppressionofInhibitionandExcitation....... 60
5 Cannabinoid Receptor-Mediated Signal Transduction to the Nucleus..... 61
5.1 p42/p44 Mitogen-Activated Protein Kinases
(ExtracellularSignal-RegulatedKinase1and2)................. 61
5.2 p38MAPKandJunN-TerminalKinases ..................... 63
6 Cannabinoid Receptor-Mediated Nitric Oxide Production........... 63
7 Mechanisms by Which the CB 1 Receptor Signals Through G Proteins..... 65
8 Cellular Changes in Signal Transduction upon Chronic Exposure to Agonists 67
8.1 Phosphorylation of the Cannabinoid Receptors as a Mechanism for Desensiti-
zation........................................ 68
9 Summary and Predictions ............................ 68
References ........................................ 69
AbstractThe cannabinoid receptor family currently includes two types: CB 1 ,char-
acterized in neuronal cells and brain, and CB 2 , characterized in immune cells
and tissues. CB 1 and CB 2 receptors are members of the superfamily of seven-
transmembrane-spanning (7-TM) receptors, having a protein structure defined
by an array of seven membrane-spanning helices with intervening intracellular
loops and a C-terminal domain that can associate with G proteins. Cannabinoid
receptors are associated with G proteins of the Gi/o family (Gi1,2 and 3, and Go1
and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and
cells, although signaling via Gs stimulates adenylyl cyclase in some experimen-
tal models. Evidence exists for cannabinoid receptor-mediated Ca2+fluxes and
stimulation of phospholipases A and C. Stimulation of CB 1 and CB 2 cannabinoid