HEP (2005) 168:81–115
©cSpringer-Verlag 2005
Molecular Biology of Cannabinoid Receptors
M.E. Abood
Forbes Norris MDA/ALS Research, California Pacific Medical Center, 2351 Clay St 416,
San Francisco CA, 94115, USA
[email protected]
1Introduction.................................... 82
2 General Structure and Distribution ....................... 84
3 Gene Structure and Species Diversity ...................... 87
4LigandRecognitionattheCB 1 Receptor..................... 89
4.1 The Aminoalklylindole/SR141716A Binding Region............... 89
4.2 The Classical/Non-Classical/Endogenous CB Binding Region ......... 90
5LigandRecognitionattheCB 2 Receptor..................... 91
5.1 Identification of Amino Acids Which Discriminate CB 1 and CB 2
ReceptorSubtypes................................. 91
5.2 The SR14428 Binding Site. ............................ 94
6ReceptorConformation.............................. 94
7CB 1 Receptor Activation ............................. 95
7.1 ConstitutiveActivity................................ 95
7.2 Residues Involved in Activation of CB 1 ...................... 97
8CB 2 Receptor Activation and Constitutive Activity ............... 98
8.1 ConstitutiveActivity................................ 98
8.2 CB 2 ReceptorActivation.............................. 98
9CB 1 Receptor Polymorphisms in Addiction and Disease ............ 99
10 TheRoleofReceptorRegulationintheDevelopment
of Cannabinoid Tolerance............................. 101
11 Physiological Receptor Regulation and Disease................. 103
12 Evidence for Additional Cannabinoid Receptor Subtypes ........... 104
13 Conclusion..................................... 105
References ........................................ 106
AbstractTo date, two cannabinoid receptors have been isolated by molecular
cloning. The CB 1 and CB 2 cannabinoid receptors are members of the G protein-
coupled receptor family. There is also evidence for additional cannabinoid recep-
tor subtypes. The CB 1 and CB 2 receptors recognize endogenous and exogenous
cannabinoid compounds, which fall into five structurally diverse classes. Muta-
genesis and molecular modeling studies have identified several key amino acid