Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 20, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2025846118
Keywords
GPCR; endosomal signaling; Gq; 11; arrestin
Categories
Funding
- Swedish Society for Medical Research [P18-0098]
- FAPESP [2016/24120-3]
- Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR)
- NIH [GM130142]
- CIHR [FDN-148431]
- Canada Research Chair in Signal Transduction and Molecular Pharmacology
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This study uses bioluminescence resonance energy transfer (BRET) to investigate the translocation and activity of Gq in endosomes, revealing different mechanisms underlying Gq activity at the plasma membrane and endosomes.
G protein-coupled receptors (GPCRs) are gatekeepers of cellular homeostasis and the targets of a large proportion of drugs. In addition to their signaling activity at the plasma membrane, it has been proposed that their actions may result from translocation and activation of G proteins at endomembranes-namely endosomes. This could have a significant impact on our understanding of how signals from GPCR-targeting drugs are propagated within the cell. However, little is known about the mechanisms that drive G protein movement and activation in subcellular compartments. Using bioluminescence resonance energy transfer (BRET)-based effector membrane translocation assays, we dissected the mechanisms underlying endosomal Gq trafficking and activity following activation of Gq-coupled receptors, including the angiotensin II type 1, bradykinin B2, oxytocin, thromboxane A2 alpha isoform, and muscarinic acetylcholine M3 receptors. Our data reveal that GPCR-promoted activation of Gq at the plasma membrane induces its translocation to endosomes independently of beta-arrestin engagement and receptor endocytosis. In contrast, Gq activity at endosomes was found to rely on both receptor endocytosisdependent and -independent mechanisms. In addition to shedding light on the molecular processes controlling subcellular Gq signaling, our study provides a set of tools that will be generally applicable to the study of G protein translocation and activation at endosomes and other subcellular organelles, as well as the contribution of signal propagation to drug action.
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