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Distinct G protein–coupled receptor recycling pathways allow spatial control of downstream G protein signaling

Bowman, Shanna Lynn, Shiwarski, Daniel John, Puthenveedu, Manojkumar A.·2016·Journal of Cell Biology
DOI 10.1083/jcb.201512068PMC PMC5037407
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Abstract

G protein–coupled receptors (GPCRs) are recycled via a sequence-dependent pathway that is spatially and biochemically distinct from bulk recycling. Why there are two distinct recycling pathways from the endosome is a fundamental question in cell biology. In this study, we show that the separation of these two pathways is essential for normal spatial encoding of GPCR signaling. The prototypical β-2 adrenergic receptor (B2AR) activates Gα stimulatory protein (Gαs) on the endosome exclusively in sequence-dependent recycling tubules marked by actin/sorting nexin/retromer tubular (ASRT) microdomains. B2AR was detected in an active conformation in bulk recycling tubules, but was unable to activate Gαs. Protein kinase A phosphorylation of B2AR increases the fraction of receptors localized to ASRT domains and biases the downstream transcriptional effects of B2AR to genes controlled by endosomal signals. Our results identify the physiological relevance of separating GPCR recycling from bulk recycling and suggest a mechanism to tune downstream responses of GPCR signaling by manipulating the spatial origin of G protein signaling.

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  • These foci represent previously described retrieval sub-domains from where cargo-enriched transport carriers exit the endosome.

    “These foci therefore represent the previously described retrieval sub-domains from where cargo-enriched transport carriers exit the endosome for transport to their destination9,34,35,39,41,49.”

    From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [39]

    The Introduction and Results and discussion (page unavailable) describe endosomal microdomains that sort B2AR into tubular domains for recycling to the cell surface. They do not establish that the citing paper’s foci are those domains or show cargo-enriched transport carriers exiting from them. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Specific endosomal membrane sub-domains are enriched for either degradative components such as ESCRT or recycling machinery including Retromer, Retriever, the CCC complex, and WASH-dependent actin patches.

    “A number of studies have shown that specific endosomal membrane sub-domains are enriched for either degradative components such as ESCRT or recycling machinery including Retromer, Retriever, the CCC complex, and WASH-dependent actin patches9,34–44”

    From Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway (2024) · cites this paper as [39]

    The Introduction describes actin/sorting nexin/retromer tubular endosomal microdomains and distinguishes specialized recycling domains from bulk-recycling domains. The cited paper therefore supports the retromer- and actin-associated recycling portion, but the passages do not establish enrichment of ESCRT, Retriever, the CCC complex, or WASH-dependent actin patches in the sub-domains described. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Core retrieval and recycling complexes localise to specific retrieval sub-domains that are physically distinct from ESCRT-demarcated degradative sub-domains on the same endosome.

    “On the limiting membrane of endosomes, electron and light microscopy has established that core retrieval and recycling complexes localise to specific retrieval sub-domains that, while present on the same endosome, are physically distinct from ESCRT-demarcated degradative sub-domains19,32–37.”

    From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [35]

    The Introduction (page not available in our copy) describes GPCR recycling microdomains as spatially distinct from bulk-recycling domains on the same endosome. It does not identify those other domains as ESCRT-demarcated degradative domains or establish the claimed physical separation from them. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

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Metadata

Authors
Bowman, S. L., Shiwarski, D. J., & Puthenveedu, M. A.
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2016-09-19
Volume
214
Issue
7
Pages
797-806
ISSN
  • 0021-9525
  • 1540-8140
DOI
10.1083/jcb.201512068
PMC
PMC5037407
Cited by
83
References
1
Language
en
Funders
  • National Institute of Neurological Disorders and Stroke (NS007433)
  • National Science Foundation (1517776)
  • National Institutes of Health (GM117425)

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