Novel biased G-protein coupled receptor-signalling paradigm regulating growth factor and pathogen-sensing receptors

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Rationale: The gaps in our knowledge regarding how µ-opioid and cannabinoids (CB) are implicated in host metabolism via their G protein-coupled receptors (GPCR) reinforces the importance of research needed to understand the mechanistic action of these molecules. The specific mechanisms and details of the effects of µ-opioid and cannabinoid (CB) on host metabolism and energy homeostasis remain to be elucidated. This topic is highly relevant as µ-opioid and CB are used by Canadians; yet, they have been associated with increased risk factors for drug side effects and inflammatory provenances. My NSERC funded research to date has uncovered a molecular link connecting growth factor-binding receptor activation and immune-mediated inflammation to a novel biased G protein-coupled receptor (GPCR)-signaling platform. GPCRs are critical conduits that sense and communicate extracellular stimuli. Their diversity and physiological importance thus make them superb multifunctional receptors. They can participate in alternate signaling pathways, and this property led to the concept of biased GPCR agonism. Can this G-protein signalling platform pre-associate with growth factor receptor tyrosine kinases (RTKs), pathogen-sensing Toll-like receptors (TLRs) and µ-opioid and CB GPCRs? Also, can this biased µ-opioid and CB GPCR signaling platform potentiate neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk in regulating RTKs and TLRs, all of which share common metabolic, pain and inflammatory provenances? Central hypothesis: µ-opioid and CB biased agonists-induced insulin receptor IRß subunit, and TLR transactivation is mediated by neuromedin B (NMBR)-Neu1-MMP9 crosstalk on the cell surface in the modification of receptor glycosylation. The research questions (Q) are four-fold. Q#1: Can GPCR-specific µ-opioid and CB agonists mediate Neu1-MMP9 crosstalk to induce IRß and TLR receptors? Q#2: Is there a common GPCR variant linked to MMP9 required for receptor ligand and GPCR µ-opioid and CB agonists-induced Neu1 activity? Q#3: Is there a unique connector(s) such as syndecans (Syn-1-4), lipid-linked glypican (Gpc-1-4) or galectin-3 keeping GPCR µ-opioid- and CB-MMP9-Neu1 in complex with insulin IRß, and TLR receptors. Q#4: Is GPCR µ-opioid- and CB-Neu1-MMP-9 in complex with insulin IRß, and TLR receptors on the cell surface, essential for the expression of these receptors?  Impact and Significance: An innovative and promising new signaling paradigm is proposed for opioids and CB receptors as a potential signal-transducing mechanism for insulin and TLR receptors. The significance of these findings would provide support for an exciting new emerging mechanism(s) for the control of receptor signaling. We will be the first to explore this new idea about how these receptors interact and explain how, otherwise, healthy Canadians develop debilitating drug side effects. HQP Training: Excellent environment for HQP training successful completion.