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Review
. 2019 Apr:57:83-89.
doi: 10.1016/j.ceb.2018.12.006. Epub 2019 Jan 29.

Spatial encoding of GPCR signaling in the nervous system

Zara Y Weinberg  1 , Stephanie E Crilly  2 , Manojkumar A Puthenveedu  3
Affiliations
Review

Spatial encoding of GPCR signaling in the nervous system

Zara Y Weinberg et al. Curr Opin Cell Biol. 2019 Apr.

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 the spatial segregation of signaling from the cell surface, endosomes, and the Golgi by receptors relevant to the nervous system.

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Conflict of interest statement

Disclosure:

The authors declare no conflicts of interest.

Figures

None
Diversity in GPCR signaling from subcellular locations.
At the plasma membrane GPCRs can signal through both G proteins and arrestins. Receptors like NK1R and B2AR can couple to different G proteins depending on the circumstances, although how this selectivity is regulated is not well understood. Most GPCRs change their diffusion, clustering, and localization to endocytic domains in response to agonist. The rates of these changes are different between different agonists, which could in turn dictate effector coupling and signaling as has been described for μOR. Many GPCRs also signal from endosomes once internalized. Some receptors like NK1R could couple directly to different effectors in endosomes compared to the plasma membrane to cause different physiological effects. B2AR couples to Gs in both locations but cause divergent transcriptional outputs depending on where it is activated. GPCR signaling from the Golgi has recently been described for B1AR and δOR, two GPCRs with steady-state Golgi localization. The physiological consequences and in vivo relevance of receptors signaling at the Golgi are still being explored. Exciting future work on the mechanisms and signaling of receptors at different sites in their trafficking itinerary may allow us to develop therapeutic strategies that spatially restrict receptor activation in subcellular locations and therefore fine-tune the consequences of receptor signaling.
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