“ Atypical” Cannabinoid Receptors In most articles on the endocannabinoid system, the story stops there. However, let’ s get to the exciting new research from the last two decades that is rarely talked about!
We have known for some time that the CB1 and CB2 receptors do not mediate all the actions of cannabinoids. How could we know this? Mice with genetically-deleted CB1 and CB2 receptors were crossbred to create mice that had neither receptor. If no other receptors were activated by cannabinoids, then there should be no effect of THC or anandamide in these mice.
However, starting with the first report in 1999, we have observed many different effects of cannabinoids in these double knockout mice. For example, cannabinoids were still able to affect blood pressure, pain, inflammation, and gastric motility in the absence of CB1 and CB2 receptors.
At this point, the hunt was on to find new cannabinoid receptors! Since then, we have discovered that endocannabinoids bind to many receptors that were not considered part of the endocannabinoid system.
GPR18 This receptor was discovered in 1997, but for several years it was an“ orphan receptor”, meaning that they did not know what its ligand was. In 2006, a surprising discovery was made – this receptor could be activated by endocannabinoids!
GPR18 can be activated by anandamide, but it’ s main endocannabinoid ligand appears to be N-arachidonoyl glycine( NAGly), which is a metabolite of anandamide.
The GPR18 receptor is expressed highly in the spinal cord, small intestine, immune cells, spleen, bone marrow, thymus, lungs, testis and cerebellum.
GPR18 activation can lower blood pressure. It also has significant functions in immune cells. It acts as a powerful chemoattractant – meaning it induces migration of immune cells.
GPR55 This receptor has a similar story to GPR18. It was an orphan receptor for many years until its ligands were discovered. GPR55 is activated by the endocannabinoids 2-AG and anandamide, but its main ligand appears to be another putative endocannabinoid called glycophosphatidylinositol( GLPI)
This receptor is expressed at high levels in the central nervous system, as well as adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder and kidneys. It’ s wide tissue distribution gives it roles in a variety of body systems.
GPR55 activation causes hypotension( lowers blood pressure), is anti-inflammatory, and is in some cases anti-nociceptive( pain blocking). GPR55 regulates energy intake and expenditure, which could impact diseases such as obesity and diabetes. It is also expressed in bone cells with a possible role in osteoporosis. GPR55 is neuroprotective and decreased neurodegeneration in models of multiple sclerosis.
GPR119 GPR119 expression is restricted to a limited number of tissues. It is primarily found in the pancreas and gastrointestinal tract – hinting that its role is the regulation of energy and metabolism.
GPR119 is activated primarily by the endocannabinoid OEA, with minimal activation by other endocannabinoids such as anandamide and 2-AG.
Activation reduces food intake, improves handling of blood sugar, and decreases body weight. These effects appear to be mediated through regulation of hormones such as insulin and GLP-1.