Cannabinoids Receptors

Author: Francesco Licciardi
Date: 18/03/2009


Receptors description


When in 1940s the cannabinoids were discovered it was argued that the apparently low stereoselectivity of cannabinoids, coupled with their high lipid solubility, made it unlikely that they were acting through a receptor but rather they were changing the properties of lipid membranes while they interacted with them.
Doubts emerged when it was discovered that cannabinoids inhibited activation of adenylyl cyclase in a neuroblastoma cell line.
Soon afterwards in 1990 was discovered a receptor CB1 who was most dense in the basal ganglia, the hippocampus, other forebrain areas and cerebellum suggesting roles for cannabinoids in cognition and movement. A second receptor, the CB2 receptor, with 48% homology with the CB1 receptor, was cloned in 1993. Thus far these are the only two cannabinoid subtypes recognised, apart from a splice variant of the CB1 receptor termed the CB1a receptor.

The distribution of the CB1 receptor outside the brain includes the nerves of the sensory and sympathetic nervous systems as well as the testis and some elements of the immune system in humans, such as the tonsils, though CB2 receptors predominate on immune cells reported as being detectable in rat spleen, testis, thymus and lung but not in rat brain, heart, kidney or liver.

CB1 expression aerea

However there is evidence that other receptor subtypes may exist and that the endogenous ligands for cannabinoid receptors may act through non-receptor pathways.

Pagina di Protein su CB1 umana
Pagina di Protein su CB2 umana

Signaling pathway

Both the CB1 and CB2 receptors are G-protein-coupled receptors of the rhodopsin superfamily.

Responses are sensitive to pertussis toxin which suggests that they exert their actions through activating Gi/o and further studies showed that cannabinoid receptor stimulation in cell membranes produced activation of four Ga subunits:

  • Gia2,
  • Gia3,
  • Goa1,
  • Goa2.

Both are therefore able to inhibit the activity of membrane-bound adenylyl cyclase.
For example neuroblastoma cells contain CB1 receptors, and adenylyl cyclase activity in membranes derived from these cells can be inhibited by the endocannabinoid anandamide.
Anandamide was a functional antagonist at CB2 receptors in mast cells and this suggests that endogenous cannabinoids might have the ability to give fine control of inflammatory actions through regulation of CB2 receptors.

After Gi/o has been inhibited by pertussis toxin, then cyclic AMP accumulation can be stimulated by CB1 receptors. This might be related to the type of adenylyl cyclase present.
In the case of the CB1 receptor, the inhibitory action on adenylyl cyclase inhibits D-type, and enhances A-type, K+ channel activity.

CB1 receptors also inhibit neuronal P/Q and N-type, but not L-type, Ca2+ channel activity.
However, anandamide and WIN55,212-2 inhibit L-type Ca2+ currents in cat cerebral artery vascular smooth muscle cells and correlates with relaxation of cat cerebral arterial rings.

CB2 receptor signalling has not been reported to affect ion channel activity, but both it and the CB1 receptor exert effects through mitogen-activated protein (MAP) kinases and can modulate cell death.
Anandamide both induces and inhibits apoptosis in human neuroblastoma and lymphoma cells.
It induced apoptosis by stimulating vanilloid receptors and inhibited apoptosis by stimulating a cannabinoid receptor sensitive to both the CB1 receptor-selective antagonist, SR141716A, and the CB2 selective antagonist, SR144528.
One pathway that has been implicated in the inhibition of apoptosis is activation of phosphoinositide 3k-kinase (PI3K) and protein kinase B (Akt) which mediates inhibition of ischaemia/reperfusion-induced cardiac apoptosis.
As CB1 receptors are coupled to PI3K and Akt activation , it is possible that CB1 receptors may limit apoptosis via this pathway.

In contrast, longer (5 day) exposure to cannabinoids results in apoptosis, mediated by either CB1 or CB2 receptor activation. A potential role of cannabinoids in the regulation of cellular migration and proliferation has been identified with the discovery that activation of CB1 receptors can activate MAP kinase, p38 kinase and c-Jun kinase.
It appears that the ceramide pathway may be the link between cannabinoid receptors and the extracellular signal-regulated kinase (ERK) cascade.
Per maggiori informazioni Wikipedia


The two antagonists most commonly used to define the subtype of cannabinoid receptor mediating a response, SR141716A ( CB1 receptor-selective ) and SR144528 ( CB2 receptor-selective ), are diarylpyrazoles and are shown.

Both can act as inverse agonists, that is they can exert opposite biological effects to the agonists in the absence of cannabinoid receptor stimulation suggesting that the receptors may show tonic activation of intracellular signalling processes in the absence of an agonist.
Other antagonists include the close relatives of SR141716A, AM251 and AM281; they selectively block CB1 receptors and AM281 shows inverse agonist activity.
At CB2 receptors, AM630 (6-iodopravolidine) has been introduced as a selective antagonist with inverse agonist action.
Per maggiori informazioni Wikipedia

Per informazioni sui ligandi endogeni
Per informazioni sui esocannabinoidi


C.ROBIN HILEY and WILLIAM R.FORD (2004) Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling
Biol.Rev., 79 pp 187-205

Pharmacology & therapeutics 95 pp 175-184

Francesco Licciardi e Matteo Manfredi

2009-03-19T08:52:00 - Gianpiero Pescarmona

GPR55: a new member of the cannabinoid receptor clan?

Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis, 2021

  • The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO
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