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

beta(1)-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 beta(1)-adrenergic receptor carboxyl terminus as bait, we identified the novel beta(1)-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 beta(1)-adrenergic receptor in COS-7 cells. Essential for this interaction is the Ser residue of the beta(1)-adrenergic receptor carboxyl-terminal ESKV motif. Our data also demonstrate that beta(1)-adrenergic receptor stimulation activates the mitogen-activated protein kinase, ERK1/2. beta(1)-adrenergic receptor-mediated ERK1/2 activation was inhibited by pertussis toxin, implicating G(i), and was substantially decreased by the expression of GIPC. Expression of GIPC had no observable effect on beta(1)-adrenergic receptor sequestration or receptor-mediated cAMP accumulation. This GIPC effect was specific for the beta(1)-adrenergic receptor and was dependent on an intact PDZ binding motif. These data suggest that GIPC can regulate beta(1)-adrenergic receptor-stimulated, G(i)-mediated, ERK activation while having no effect on receptor internalization or G(s)-mediated cAMP signaling.