Document Type
Article
Publication Date
7-1-2017
Abstract
G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β 2 -adrenergic GPCR can activate G s -linked cyclic AMP (G s -cAMP) signaling from endosomes. We show here that the homologous human β 1 -adrenergic receptor initiates an internal G s -cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that β-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose 'location bias' as a new principle for achieving functional selectivity of GPCR-directed drug action.
Recommended Citation
Irannejad, Roshanak; Pessino, Veronica; Mika, Delphine; Huang, Bo; Wedegaertner, Philip B.; Conti, Marco; and von Zastrow, Mark, "Functional selectivity of GPCR-directed drug action through location bias." (2017). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 141.
https://jdc.jefferson.edu/bmpfp/141
PubMed ID
28553949
Language
English
Comments
This article has been peer reviewed. It is the authors' final version prior to publication in Nature Chemical Biology, Volume 13, Issue 7, July 2017, Pages 799-806.
The published version is available at https://doi.org/10.1038/nchembio.2389. Copyright © Springer