Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators

  1. Mikel Garcia-Marcos  Is a corresponding author
  1. Boston University School of Medicine, United States

Abstract

It has become evident that activation of heterotrimeric G-proteins by cytoplasmic proteins that are not GPCRs plays a role in physiology and disease. Despite sharing the same biochemical Guanine-nucleotide Exchange Factor (GEF) activity as GPCRs in vitro, the mechanisms by which these cytoplasmic proteins trigger G-protein-dependent signaling in cells have not been elucidated. Heterotrimeric G-proteins can give rise to two active signaling species, Gα-GTP and dissociated Gβγ, with different downstream effectors, but how non-receptor GEFs affect the levels of these two species in cells is not known. Here, a systematic comparison of GPCRs and three unrelated non-receptor proteins with GEF activity in vitro (GIV/Girdin, AGS1, and Ric-8A) revealed high divergence in their contribution to generating Gα-GTP and free Gβγ in cells directly measured with live-cell biosensors. These findings demonstrate fundamental differences in how receptor and non-receptor G-protein activators promote signaling in cells despite sharing similar biochemical activities in vitro.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. Mikel Garcia-Marcos

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    For correspondence
    mgm1@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9513-4826

Funding

National Institute of General Medical Sciences (R01GM136132)

  • Mikel Garcia-Marcos

National Institute of Neurological Disorders and Stroke (R01NS117101)

  • Mikel Garcia-Marcos

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Garcia-Marcos

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Mikel Garcia-Marcos
(2021)
Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators
eLife 10:e65620.
https://doi.org/10.7554/eLife.65620

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https://doi.org/10.7554/eLife.65620