GIPC interacts with the β1-adrenergic receptor and regulates β1-adrenergic receptor-mediated ERK activation

Abstract

β1-adrenergic receptors, expressed at high levels in the human heart, have a carboxyl-terminal ESKV motif that can directly interact with PDZ domain-containing proteins. Using the β1-adrenergic receptor carboxyl terminus as bait, we identified the novel β1-adrenergic receptor-binding partner GIPC in a yeast two-hybrid screen of a human heart cDNA library. Here we demonstrate that the PDZ domain-containing protein, GIPC, co-immunoprecipitates with the β1-adrenergic receptor in COS-7 cells. Essential for this interaction is the Ser residue of the β1-adrenergic receptor carboxyl-terminal ESKV motif. Our data also demonstrate that β1-adrenergic receptor stimulation activates the mitogen-activated protein kinase, ERK1/2. β1-adrenergic receptor-mediated ERK1/2 activation was inhibited by pertussis toxin, implicating Gi, and was substantially decreased by the expression of GIPC. Expression of GIPC had no observable effect on β1-adrenergic receptor sequestration or receptor-mediated cAMP accumulation. This GIPC effect was specific for the β1-adrenergic receptor and was dependent on an intact PDZ binding motif. These data suggest that GIPC can regulate β1-adrenergic receptor-stimulated, Gi-mediated, ERK activation while having no effect on receptor internalization or Gs-mediated cAMP signaling.