Functional selectivity of GPCR-directed drug action through location bias

Nat Chem Biol. 2017 Jul;13(7):799-806. doi: 10.1038/nchembio.2389. Epub 2017 May 29.


G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β2-adrenergic GPCR can activate Gs-linked cyclic AMP (Gs-cAMP) signaling from endosomes. We show here that the homologous human β1-adrenergic receptor initiates an internal Gs-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.

MeSH terms

  • Adrenergic beta-Antagonists / chemistry
  • Adrenergic beta-Antagonists / pharmacology*
  • Dobutamine / chemistry
  • Dobutamine / pharmacology*
  • Epinephrine / chemistry
  • Epinephrine / pharmacology*
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / metabolism
  • HeLa Cells
  • Humans
  • Ligands
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Structure-Activity Relationship


  • Adrenergic beta-Antagonists
  • Ligands
  • Receptors, Adrenergic, beta-1
  • Dobutamine
  • Epinephrine