Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Targeting CB₂-GPR55 receptor heteromers modulates cancer cell signaling

The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology

Biomedical nanoparticles modulate specific CD4(+) T cell stimulation by inhibition of antigen processing in dendritic cells

Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications. To investigate nanoparticle-dependent outcomes on immune responses, dendritic cells (DCs) were treated with model biomedical poly(vinylalcohol)-coated super-paramagnetic iron oxide nanoparticles (PVA-SPIONs). PVA-SPIONs uptake by human monocyte-derived DCs (MDDCs) was analyzed by flow cytometry (FACS) and advanced imaging techniques. Viability, activation, function, and stimulatory capacity of MDDCs were assessed by FACS and an in vitro CD4(+) T cell assay. PVA-SPION uptake was dose-dependent, decreased by lipopolysaccharide (LPS)-induced MDDC maturation at higher particle concentrations, and was inhibited by cytochalasin D pre-treatment. PVA-SPIONs did not alter surface marker expression (CD80, CD83, CD86, myeloid/plasmacytoid DC markers) or antigen-uptake, but decreased the capacity of MDDCs to process antigen, stimulate CD4(+) T cells, and induce cytokines. The decreased antigen processing and CD4(+) T cell stimulation capability of MDDCs following PVA-SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure

The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management and metabolic diseases. However, around 2007 the tide began to turn when several cannabinoid receptor type 1 (CB1) antagonists/inverse agonists failed as therapeutics against overweight and its complications. More recently, the development of FAAH (Fatty Acid Amide Hydrolase) inhibitors against pain has also faced serious setbacks. In retrospect the much greater complexity of the ECS than originally assumed has played a fundamental role in these difficulties. Although there is no doubt that endocannabinoids and their receptors are of great (patho-)physiological relevance, it has become clear that the ECS is intimately intertwined with other biological systems. Endocannabinoids exist in equilibrium with fatty acids and their metabolic derivatives, including eicosanoids and prostamides. Furthermore, there are several biologically active analogues of endocannabinoids, in particular fatty acid amides, with metabolic pathways overlapping those of the ECS. Finally, endocannabinoids per se and their congeners show “promiscuous” behaviour going beyond interactions with CB1 and CB2 receptors. It has become clear that the complexity of what may be called the “endocannabinoidome” demands for pharmacological approaches that take into account these dynamics. Targeting the “endocannabinoidome” continues to offer opportunities for prevention and therapy, in particular for chronic diseases. However, chances for success are more likely to come from “multiple-target” than from “single-target” approaches

Adhesion G protein-coupled receptors: opportunities for drug discovery

The seminal discovery of the novel activation mechanism of Adhesion GPCRs (aGPCRs)1,2, together with their strong and growing links to disease from human genetics and pre-clinical research, has prompted a rapid reconsideration of this unique family of receptors for classical drug discovery. However, while acknowledged as a sub-family of GPCRs by the IUPHAR3, these receptors are anything but classical with their complex gene structures, large multi-domain N-termini, autocatalytic cleavage and tethered ligands. Initially thought to have a purely structural role, the increasing functional complexity of this GPCR sub-family and the many, potentially unique mechanisms of modulation challenges the way we have perceived this protein class until now. Significantly, if 50% of non-sensory GPCRs are unexploited as drug targets4, this figure reaches 100% for aGPCRs so the potential to develop novel therapies could be substantial5. Here, we discuss the unique opportunities and challenges brought by aGPCRs in the context of drug discovery programs naturally starting with target identification then extending to target validation, assay building and safety considerations