The trafficking of G protein coupled‐receptors (GPCRs) is one of the most exciting areas in cell biology because of recent advances demonstrating that GPCR signaling is spatially encoded. GPCRs, acting in a diverse array of physiological systems, can have differential signaling consequences depending on their subcellular localization. At the plasma membrane, GPCR organization could fine‐tune the initial stages of receptor signaling by determining the magnitude of signaling and the type of effectors to which receptors can couple. This organization is mediated by the lipid composition of the plasma membrane, receptor‐receptor interactions, and receptor interactions with intracellular scaffolding proteins. GPCR organization is subsequently changed by ligand binding and the regulated endocytosis of these receptors. Activated GPCRs can modulate the dynamics of their own endocytosis through changing clathrin‐coated pit dynamics, and through the scaffolding adaptor protein β‐arrestin. This endocytic regulation has signaling consequences, predominantly through modulation of the MAPK cascade. This review explores what is known about receptor sorting at the plasma membrane, protein partners that control receptor endocytosis, and the ways in which receptor sorting at the plasma membrane regulates downstream trafficking and signaling.

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Several GPCRs, including receptors previously thought to signal primarily from the cell surface, have been recently shown to signal from many intracellular compartments. This raises the idea that signaling by any given receptor is spatially encoded in the cell, with distinct sites of signal origin dictating distinct downstream consequences. We will discuss recent developments that address this novel facet of GPCR physiology, focusing on spatial segregation of signaling from the cell surface, endosomes, and the Golgi by receptors relevant to the nervous system.

Background and Purpose: The δ-opioid receptor is an emerging target for the management of chronic pain and depression. Biased signalling, the preferential activation of one signalling pathway over another downstream of δ-receptors, may generate better therapeutic profiles. BMS 986187 is a positive allosteric modulator of δ-receptors. Here, we ask if BMS 986187 can directly activate the receptor from an allosteric site, without an orthosteric ligand, and if a signalling bias is generated. Experimental Approach: We used several clonal cell lines expressing δ-receptors, to assess effects of BMS 986187 on events downstream of δ-receptors by measuring G-protein activation, β-arrestin 2 recruitment, receptor phosphorylation, loss of surface receptor expression, ERK1/ERK2 phosphorylation, and receptor desensitization. Key Results: BMS 986187 is a G protein biased allosteric agonist, relative to βarrestin 2 recruitment. Despite showing direct and potent G protein activation, BMS 986187 has a low potency to recruit β-arrestin 2. This appears to reflect the inability of BMS 986187 to elicit any significant receptor phosphorylation, consistent with low receptor internalization and a slower onset of desensitization, compared with the full agonist SNC80. Conclusions and Implications: This is the first evidence of biased agonism mediated through direct binding to an allosteric site on an opioid receptor, without a ligand at the orthosteric site. Our data suggest that agonists targeting δ-receptors, or indeed any GPCR, through allosteric sites may be a novel way to promote signalling bias and thereby potentially produce a more specific pharmacology than can be observed by activation via the orthosteric site. 1 | INTRODUCTION Chronic pain and depression are two of the most common medical ailments experienced worldwide and are often co-morbid. For example, an estimated 25% of the United States population (75 million people) experience moderate-to-severe chronic pain (Reinke, 2014), whereas an estimated 15-20% experience depression (Kessler & Bromet, 2013). Opioid analgesics that target the μ-opioid receptor are the most widely prescribed drugs for both chronic and acute pain but suffer from serious side effects including respiratory depression and abuse liability (McNicol et al., 2017; Przewłocki & Przewłocka, 2001). Treatments for depression are varied, but under the best circumstances, only an estimated 50% of patients show full remission (Rush et al., 2006). Mounting evidence suggests that agonists targeting the δ-opioid receptor, a GPCR, are effective in preclinical models of chronic pain and depression and could provide for new therapies