Dual agonist occupancy of at 1 -R-α 2C -AR heterodimers results in atypical G s -PKA signaling

Academic Article


  • Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT 1 receptor (AT1-R) and NE α 2C -adrenergic receptor (α 2C -AR) could underlie their functional cross-talk to control NE secretion. Multiple bioluminescence resonance energy transfer and protein complementation assays allowed us to accurately probe the structures and functions of the α 2C -AR-AT1-R dimer promoted by ligand binding to individual protomers. We found that dual agonist occupancy resulted in a conformation of the heterodimer different from that induced by active individual protomers and triggered atypical G s -cAMP-PKA signaling. This specific pharmacological signaling unit was identified in vivo to promote not only NE hypersecretion in sympathetic neurons but also sympathetic hyperactivity in mice. Thus, we uncovered a new process by which GPCR heterodimerization creates an original functional pharmacological entity and that could constitute a promising new target in cardiovascular therapeutics.
  • Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 20971650
  • Author List

  • Bellot M; Galandrin S; Boularan C; Matthies HJ; Despas F; Denis C; Javitch J; Mazères S; Sanni SJ; Pons V
  • Start Page

  • 271
  • End Page

  • 279
  • Volume

  • 11
  • Issue

  • 4