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Linking Cannabinoid Receptor Type II (CB2) Biology to Function


Cannabinoids, the primary bioactive components in marijuana, bind and signal through endogenous cannabinoid receptors. mRNA encoding for the cannabinoid receptor type II (CB2) predominates in human leukocytes. CB2 is a G protein-coupled receptor (GPCR) and traditionally thought to be expressed on the cell surface. However, as reliable methods for imaging CB2 were lacking, we hypothesized that a monoclonal antibody raised against the N-terminus of CB2 could be combined with conventional and imaging flow cytometry to study CB2 protein expression. Detection was validated using gene-modified cell lines and isotype control antibodies. When applied to peripheral blood cells, no CB2 was detected on T cells, monocytes, and dendritic cells, but it was detected on the surface of B cells. However, following membrane permeabilization, a high concentration of intracellular CB2 was detected. When B cells were exposed to cannabinoids, surface CB2 internalized but not in the pattern of pre-existing intracellular CB2. The expression of GPCRs at different cellular locations can promote functional heterogeneity with respect to downstream signaling and function. As such, we hypothesized that this differential expression of CB2 by leukocytes is likely a highly-regulated event and plays an important role in cannabinoid function. In order to further assess, we studied the expression on human B cells from different tissue sources and identified that surface CB2 was present in naïve and memory B cells but lacking on the surface of activated B cells. Furthermore, B cell lymphomas with an activated phenotype exhibited the same pattern. Naïve cord blood B cells were therefore activated in vitro, allowing us to directly link the acquisition of an activated phenotype to the loss of surface CB2. Findings were confirmed with confocal microscopy and demonstrated a diffuse but punctate intracellular distribution of CB2 that did not overlap with either lysosomal or mitochondrial staining. Our findings document a novel and dynamic multi-compartment expression pattern for CB2 in B cells that is specifically modulated during B cell activation. The intracellular location of CB2 and the specific role of different receptors on biologic function remains to be determined but will likely be very informative in understanding cannabinoid biology.

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