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Spatiotemporal Control of ERK Activity by b 2 ‐adrenergic Signaling
Author(s) -
Kwon Yonghoon,
Clark Mary J.,
Keyes Jeremiah,
Walters Geneva,
Sunahara Roger K.,
Zhang Jin
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07537
Subject(s) - mapk/erk pathway , endosome , microbiology and biotechnology , g protein coupled receptor , signal transduction , receptor , chemistry , biology , intracellular , biochemistry
G‐protein coupled receptors (GPCRs) play vital roles in regulating physiological functions, such as sympathetic nervous regulation, and senses of vision and olfaction. Signaling of the β2‐adrenergic receptor (β2‐AR), which is a prototypical class A GPCR, has been proposed to control activation of ERK, subsequently regulating different processes including gene expression. However, the molecular mechanism of ERK activation downstream of β2AR signaling is not clearly understood. Here we investigate the molecular mechanism of β2‐AR mediated ERK activation using improved version of FRET‐based ERK biosensors targeted to various subcellular regions which enable us to visualize spatial and temporal regulation of ERK activity in living cells. Epinephrine stimulation leads to increases of ERK activity at the endosome and in the nucleus but not at the plasma membrane. An Nb37 nanobody that stables the active Gα s conformation enhances and prolongs the endosomal and nuclear ERK activity. We propose a new model that an endosome‐localized active β2AR recruits critical signaling components to facilitate ERK activation on the endosome. These findings provide a molecular basis for location selective activation of ERK by β2‐AR signaling. Support or Funding Information This work was supported by the National Institutes of Health (R01 DK073368 to J.Z.)