Trafficking and compartmentalized signaling of the delta-opioid receptor

Opioid receptors are class A G protein coupled receptors (GPCRs). The delta-opioid receptor (DOPr) in particular is a key therapeutic target for chronic pain and gastrointestinal disorders. Like other opioid receptors, drugs targeting DOPr are effective analgesics but their use is limited due to their addictive liabilities they possess. Recent studies suggest that DOPr internalization may contribute towards the development of tolerance and analgesia. Once considered merely as cell surface sensors, more recent studies have revealed the importance of GPCR signaling from within endosomes. Moreover, the temporal and spatial segregation of signals generated by agonist stimulated GPCR trafficking can give rise to a range of discrete cellular responses following activation of the same second messenger systems. This is referred to as compartmentalized signaling. The study of how differential receptor trafficking in response to various ligands underlies potential differences in compartmentalized signaling profiles may therefore be key to selectively promote physiologically beneficial signaling without the deleterious side effects. This thesis reveals that DOPr endocytosis is critically important for opioid signaling in subcellular compartments, which may account for the differential effects of DOPr agonists on analgesia and tolerance. Our findings reveal differences in the recruitment of regulatory proteins to DOPr following stimulation with agonists that induce varying degrees of DOPr internalization, which dictates the pathway through which DOPr traffics. This thesis also illustrates distinct signaling responses as a consequence of differential agonist stimulated DOPr trafficking thus highlighting the importance of DOPr internalization for the activation and inhibition of specific signaling cascades. Collectively, the present findings demonstrate a link between DOPr trafficking and compartmentalized signaling which may underlie the beneficial therapeutic effects of weakly internalizing DOPr agonists.