Cannabinoid CB2 receptor: a new target for controlling neural cell survival?

doi:10.1016/j.tips.2006.11.001

Trends in Pharmacological Sciences

Volume 28, Issue 1, January 2007, Pages 39-45

https://doi.org/10.1016/j.tips.2006.11.001 Get rights and content

Two types of cannabinoid receptor have been cloned and characterized. Whereas CB₁ receptors are ubiquitously expressed in neurons of the CNS, CB₂ receptors have been thought to be absent from the CNS. Recent data now question this notion and support the expression of CB₂ receptors in microglial cells, astrocytes and even some neuron subpopulations. This discrete distribution makes CB₂ receptors interesting targets for treating neurological disorders because CB₂-selective agonists lack psychoactivity. Here, we review evidence supporting the idea that CB₂ receptors are implicated in the control of fundamental neural cell processes, such as proliferation and survival, and that their pharmacological manipulation might be useful for both delaying the progression of neurodegenerative disorders and inhibiting the growth of glial tumors.

Section snippets

Introduction: the cannabinoid signaling system

The great increase in cannabinoid research in recent years has been a direct consequence of the discovery of the ‘endogenous cannabinoid system’ – a new intercellular communication network [1]. The endogenous cannabinoid system comprises at least two types of G protein-coupled receptor, called the cannabinoid CB₁ and CB₂ receptors, that are activated by a family of endogenous arachidonic acid derivatives, the endocannabinoids, and by Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the principal active

Biochemistry, pharmacology and distribution of the CB₂ receptor

The gene encoding the human cannabinoid CB₂ receptor was cloned in 1993 (recently reviewed in Ref. [8]). It is located in chromosome 1p36 and encodes a protein of 360 amino acids with an overall homology to CB₁ receptors of 44%, although this homology rises to 68% when only the transmembrane regions are compared. It belongs to the seven-transmembrane-domain, G-protein-coupled receptor class [9], and can modulate various signal transduction pathways involved in controlling cell proliferation,

The CB₂ receptor and the cell death or survival decision

The CB₂ receptor has been implicated in controlling the proliferation, differentiation and survival of both neural and non-neural cells. For example, activation of CB₂ receptors in rat RTMGL1 microglial cells [11] and mouse neural progenitors [12] promotes cell proliferation. Moreover, an inverse relation between expression of the CB₂ receptor and the stage of cell differentiation is evident in neural cells (from neural progenitors to mature neurons and neuroglial cells [12]) and in B cells

Concluding remarks and future perspectives

Recent data support the concept that brain CB₂ receptors have important functions in attenuating neuroinflammatory processes and in inhibiting the survival of transformed neural cells. These receptors are upregulated in pathological conditions, presumably as part of an endogenous mechanism of defense against various brain-damaging insults; however, further work is required to obtain full characterization of the possible roles that these receptors have in those processes.

Essential issues to be

Acknowledgements

We thank our laboratory colleagues for continuous support. Work in our laboratories is funded by grants from the Ministerio de Educación y Ciencia (SAF2006–11333 to J.F-R., SAF2004–00237 to J.R., SAF2006–00918 to M.G.), Fundación Científica de la Asociación Española Contra el Cáncer (to M.G.), Universidad Complutense-Comunidad de Madrid (950344 to M.G. and J.F-R.) and Fundación Mapfre Medicina (to J.R.).

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Trends in Pharmacological Sciences

ReviewCannabinoid CB2 receptor: a new target for controlling neural cell survival?

Section snippets

Introduction: the cannabinoid signaling system

Biochemistry, pharmacology and distribution of the CB2 receptor

The CB2 receptor and the cell death or survival decision

Concluding remarks and future perspectives

Acknowledgements

Pharmacol. Ther.

Pharmacol. Ther.

FEBS Lett.

FEBS Lett.

Cancer Cell

Prog. Lipid Res.

Chem. Phys. Lipids

Neuron

Neuropharmacology

J. Dermatol. Sci.

Neuroscience

Blood

Blood

Trends Mol. Med.

Neurobiol. Dis.

Eur. J. Pharmacol.

Neuropharmacology

The molecular logic of endocannabinoid signalling

Nat. Rev. Neurosci.

Cannabinoid receptors as therapeutic targets

Annu. Rev. Pharmacol. Toxicol.

Cannabinoids: potential anticancer agents

Nat. Rev. Cancer

Pharmacological actions of cannabinoids

Handb. Exp. Pharmacol.

Cannabinoids in neurodegeneration and neuroprotection

Targeting the cannabinoid CB2 receptor: mutations, modeling and development of CB2 selective ligands

Curr. Med. Chem.

International Union of Pharmacology. XXVII. Classification of cannabinoid receptors

Pharmacol. Rev.

Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression

Eur. J. Biochem.

Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism

Mol. Pharmacol.

Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation

FASEB J.

Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol 3-kinase/Akt signaling

J. Neurosci.

Differential roles of CB1 and CB2 cannabinoid receptors in mast cells

J. Immunol.

Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor

Cancer Res.

Review
Cannabinoid CB₂ receptor: a new target for controlling neural cell survival?

Biochemistry, pharmacology and distribution of the CB₂ receptor

The CB₂ receptor and the cell death or survival decision

Targeting the cannabinoid CB₂ receptor: mutations, modeling and development of CB₂ selective ligands

Signaling pathway associated with stimulation of CB₂ peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression

Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB₂ receptor-dependent mechanism

Non-psychoactive CB₂ cannabinoid agonists stimulate neural progenitor proliferation

Differential roles of CB₁ and CB₂ cannabinoid receptors in mast cells

Inhibition of glioma growth in vivo by selective activation of the CB₂ cannabinoid receptor