Spatial encoding of GPCR signaling in the nervous system

Abstract

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.

Homologous Regulation of Mu Opioid Receptor Recycling by Gβγ, Protein Kinase C, and Receptor Phosphorylation

“…However, recent evidence shows that many GPCRs can signal from intracellular sites, and that intracellular signaling can have distinct downstream effects compared with signaling from the surface (Irannejad et al, 2013;Vilardaga et al, 2014;Thomsen et al, 2018). Intracellular signaling from endosomal microdomains might be a general characteristic of GPCRs, as the list of GPCRs that can signal from intracellular compartments is still growing (Caengprasath and Hanyaloglu, 2019;Weinberg et al, 2019). This supports the emerging idea that an equally important role of trafficking is to transfer receptors between distinct signaling environments within a cell.…”

Compartment-specific opioid receptor signaling is selectively modulated by Dynorphin subtypes

“…Considering the emerging importance of spatial encoding in diversifying the outcomes of GPCR signaling (7,(11)(12), we next asked whether DynA or DynB generated distinctive intracellular localization patterns of KOR. PC12 cells stably expressing SpH-KOR were treated with DynA or DynB for 20 min.…”

“…It is possible that different Dynorphins could cause agonist-specific post-translational modifications, which is a general emerging theme for opioid receptors (21)(22). To the best of our knowledge, however, this is the first example of different physiological agonists driving spatial localization and trafficking of a GPCR -a process that has been studied largely using receptor mutants or by depleting key components of the trafficking machinery so far (9,11,23).…”

“…While this is still an emerging field, a growing body of evidence suggests that GPCRs are active in endosomes and other intracellular compartments, and that receptors in endosomes can cause distinct signaling consequences compared to receptors on the cell surface (8)(9)(10). Receptors rapidly and dynamically move between intracellular compartments and the surface by trafficking, and trafficking could therefore act as a master regulator of GPCR signaling by selectively amplifying signals from specific locations (11)(12). Whether physiological systems take advantage of trafficking to localize receptors to different compartments and dictate location-biased signaling, however, is still not known.…”

“…Quantitation, across multiple cells, of the percentage of KOR endosomes that colocalize with each the endosomal markers noted. KOR primarily localizes in Rab7 and Lamp1 positive late endosomes after DynA (n= 8,10,9,11,20, and 17 cells respectively). C) A similar quantitation of immunofluorescence images after DynB shows that KOR localizes less with late endosomes, and more with markers of early/recycling endosomes (n=18,16,15,18,23, and 29 cells respectively).…”