TY - JOUR TI - Compartment-specific opioid receptor signaling is selectively modulated by different dynorphin peptides AU - Kunselman, Jennifer M AU - Gupta, Achla AU - Gomes, Ivone AU - Devi, Lakshmi A AU - Puthenveedu, Manojkumar A A2 - Pfeffer, Suzanne R A2 - Evans, Christopher VL - 10 PY - 2021 DA - 2021/04/28 SP - e60270 C1 - eLife 2021;10:e60270 DO - 10.7554/eLife.60270 UR - https://doi.org/10.7554/eLife.60270 AB - Many signal transduction systems have an apparent redundancy built into them, where multiple physiological agonists activate the same receptors. Whether this is true redundancy, or whether this provides an as-yet unrecognized specificity in downstream signaling, is not well understood. We address this question using the kappa opioid receptor (KOR), a physiologically relevant G protein-coupled receptor (GPCR) that is activated by multiple members of the Dynorphin family of opioid peptides. We show that two related peptides, Dynorphin A and Dynorphin B, bind and activate KOR to similar extents in mammalian neuroendocrine cells and rat striatal neurons, but localize KOR to distinct intracellular compartments and drive different post-endocytic fates of the receptor. Strikingly, localization of KOR to the degradative pathway by Dynorphin A induces sustained KOR signaling from these compartments. Our results suggest that seemingly redundant endogenous peptides can fine-tune signaling by regulating the spatiotemporal profile of KOR signaling. KW - GPCR trafficking KW - endogenous opioid KW - endosomal signaling JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -