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Subcellular Location‐Dependent Activation and Signaling of the Delta‐Opioid Receptor

G protein‐coupled receptor (GPCR) signaling from intracellular compartments is an emerging idea in the field. Classically, GPCRs have been thought to signal mainly from the plasma membrane. However, GPCRs localized to endosomes and the Golgi are a critical component of receptor signaling. GPCR location affects signaling at multiple levels, from generation of second messengers to transcriptional responses, and even physiological responses. One physiologically relevant receptor that shows location‐dependent signaling is the delta‐opioid receptor (DOR), an attractive alternative target for pain management. DOR is localized primarily to intracellular compartments, including the Golgi, in neuronal cells. Relocation of these receptors to the cell surface increases the ability of DOR agonists to relieve pain, suggesting that the subcellular location and signaling of this receptor are closely linked and important for receptor pharmacology. However, the mechanisms by which DOR relocation to the plasma membrane from Golgi membranes influences receptor pharmacology are poorly understood. Live cell imaging with nanobody and mini‐G protein biosensors indicates receptor localization influences ligand‐induced recruitment of active‐conformation biosensors. Additionally, we used cAMP and calcium sensors to study how DOR localization influences receptor signaling. Together, our data support a model in which DOR activation and signaling are spatially regulated. This spatial regulation may underlie the complexity of physiological effects associated with DOR activation and provide new ways to modulate receptor signaling.