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

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.