cannabinoid receptors. It was hypothesized that the receptors of cannabinoids may

be intracellular due to their lipophilic nature. Later in 1988, cannabinoid receptor

was found to be on the plasma membrane of the neuronal tissue in the brain (Devane

et al. 1988). In 1990, cannabinoid receptor 1 (CB1) was cloned by Matsuda. After

3 years, in 1993 another receptor CB2 was identified by Munro (Matsuda et al. 1990;

Munro et al. 1993). Further research revealed that both the cannabinoid receptors

belong to the G-protein-coupled receptor (GPCR) superfamily.

12.3

Distribution of the Receptors

12.3.1 Cannabinoid Receptor 1 (CB1)

CB1 receptors are found primarily in the central nervous system (CNS). However,

these receptors are not exclusive to CNS and also expressed in immune cells,

pituitary gland, blood vessels, lung, bladder, adrenal gland, liver, adipose tissue,

and reproductive and gastrointestinal tissues (Cacciola et al. 2010).

12.3.2 Cannabinoid Receptor 2 (CB2)

CB2 receptors are located predominantly in immune cells (B and natural killer cells)

and also in the spleen, thymus, tonsils, splenic macrophage-monocyte preparations,

peripheral blood leukocytes, and mast cells. Activated receptors can regulate

immune cell migration as well as cytokine release in the brain. Later, its expression

was also reported in neuronal microglia cells, cerebellum, brain stem cells,

mid-brain, striatum, and hippocampus (Cacciola et al. 2010).

CB1 and CB2 receptors share 44% overall identity with each other. They are

distinct in their distribution across the tissue and their sensitivity toward various

agonists and antagonists.

12.3.3 GPR55 Receptors

GPR55 (ligand-gated ion channel) receptors are non-CB1/CB2 G-protein-coupled

receptor protein which interacts with cannabinoid receptor ligands. In 1999, GPR55

was first identified via in silico studies and subsequently cloned (Sawzdargo et al.

1999). GPR55 receptors are distributed both in CNS and in periphery. Ryberg et al.

found out that endocannabinoids can activate these receptors by using [³⁵S] GTPγS

assay in HEK293 cell line (Ryberg et al. 2007).

Over the years, the role of GPR55 has been extensively studied by the researchers

in various pathological conditions. From those studies, it becomes evident that these

receptors play pivotal roles in cancer (breast and brain) (Andradas et al. 2011)

immune regulation (Balenga et al. 2011), pain modulation (Schuelert and

McDougall

2011),

diabetes,

obesity

(Moreno-Navarrete

et

al.

2012),

and

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Emerging Role of Cannabinoid System Modulators in Treatment of Cancer

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