Research Article
No access
Published Online: 1 May 2018

Genetic Variant Q63R of Cannabinoid Receptor 2 Causes Differential ERK Phosphorylation in Human Immune Cells

Publication: Genetic Testing and Molecular Biomarkers
Volume 22, Issue Number 5

Abstract

Background: The cannabinoid receptor 2 (CB2R) is primarily expressed in immune tissues and implicated in immune regulation. In models of inflammatory diseases, modulation of CB2R alters function of immune cells and affects the progression of disease. We therefore believe that CB2R modulation could be a promising therapy for inflammatory diseases. In humans, the nonsynonymous mutation Q63R, the most common variant of the CB2 receptor, has been found to be associated with multiple diseases, including idiopathic arthritis, obesity, and celiac diseases. However, it is not clear whether the Q63R variant indeed alters signaling of CB2R and whether the change in a specific signaling pathway contributes to the pathogenesis of inflammatory diseases. Better understanding of the signaling downstream of CB2R in immune cells may provide a molecular base for better usage of CB2R modulators.
Methods: We studied the signaling caused by CB2R activation in cell lines and primary immune cells possessing Q63R variant.
Results: We found that activation of CB2R in immune cells by either an endogenous (2-AG) or a synthetic (CP5,940) ligand causes transient phosphorylation of extracellular signal-regulated kinases (ERK). Phosphorylation of ERK in immune cells due to activation of CB2R is coupled to Gi protein. In human peripheral blood mononuclear cells, phosphorylation of ERK caused by CB2R activation is especially intense in B cells and T cells.
Conclusions: Activation of both CB2R variants 63Q and 63R causes phosphorylation of ERK. However, the signal intensity caused by 63R activation is relatively weaker than that caused by 63Q activation.

Get full access to this article

View all available purchase options and get full access to this article.

References

Bellini G, Grandone A, Torella M, et al. (2015a) The cannabinoid receptor 2 Q63R variant modulates the relationship between childhood obesity and age at menarche. PLoS One 10:e0140142.
Bellini G, Olivieri AN, Grandone A, et al. (2015b) Association between cannabinoid receptor type 2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis. Scand J Rheumatol 44:284–287.
Cencioni MT, Chiurchiu V, Catanzaro G, et al. (2010) Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One 5:e8688.
Cota D. (2007) CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab Res Rev 23:507–517.
Horvath B, Magid L, Mukhopadhyay P, et al. (2012) A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. Br J Pharmacol 165:2462–2478.
Kinsey SG, Mahadevan A, Zhao B, et al. (2011) The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects. Neuropharmacology 60:244–251.
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685.
Murineddu G, Deligia F, Dore A, et al. (2013) Different classes of CB2 ligands potentially useful in the treatment of pain. Recent Pat CNS Drug Discov 8:42–69.
Ninfa A, Ballou D, Benore M (2008) Fundamental Laboratory Approaches for Biochemistry and Biotechnology. New Jersey: Wiley. p 113.
Rossi F, Bellini G, Tolone C, et al. (2012) The cannabinoid receptor type 2 Q63R variant increases the risk of celiac disease: implication for a novel molecular biomarker and future therapeutic intervention. Pharmacol Res 66:88–94.
Rossi F, Mancusi S, Bellini G, et al. (2011) CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 96:1883–1885.
Turcotte C, Blanchet MR, Laviolette M, Flamand N (2016) The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci 73:4449–4470.

Information & Authors

Information

Published In

cover image Genetic Testing and Molecular Biomarkers
Genetic Testing and Molecular Biomarkers
Volume 22Issue Number 5May 2018
Pages: 320 - 326
PubMed: 29694791

History

Published in print: May 2018
Published online: 1 May 2018
Published ahead of print: 25 April 2018

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Jingru Wang
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Juehua Xu
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Jie Liu
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Huang Zhu
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Yanyan Peng
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Zhi-Ming Ding
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.
Haiqing Hua
Lilly China Research and Development Center (LCRDC), Eli Lilly & Company, Shanghai, China.

Notes

Address correspondence to:Haiqing Hua, PhDLilly China Research and Development Center (LCRDC)Eli Lilly & CompanyShanghai 201203China
E-mail: [email protected]

Author Disclosure Statement

All authors are employees and may hold stocks of Eli Lilly & Co. Eli Lilly & Co. provided support in the form of salaries for authors and funding for research materials, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the article. All relevant data are within the article.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top