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J. Biol. Chem., Vol. 278, Issue 28, 26295-26301, July 11, 2003

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GIPC Interacts with the ₁-Adrenergic Receptor and Regulates ₁-Adrenergic Receptor-mediated ERK Activation^*

Liaoyuan A. Hu , Wei Chen, Negin P. Martin, Erin J. Whalen, Richard T. Premont and Robert J. Lefkowitz, An investigator of the Howard Hughes Medical Institute. 

From the Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

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 ₁-adrenergic receptor carboxyl terminus as bait, we identified the novel 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 ₁-adrenergic receptor in COS-7 cells. Essential for this interaction is the Ser residue of the ₁-adrenergic receptor carboxyl-terminal ESKV motif. Our data also demonstrate that ₁-adrenergic receptor stimulation activates the mitogen-activated protein kinase, ERK1/2. 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 ₁-adrenergic receptor sequestration or receptor-mediated cAMP accumulation. This GIPC effect was specific for the ₁-adrenergic receptor and was dependent on an intact PDZ binding motif. These data suggest that GIPC can regulate ₁-adrenergic receptor-stimulated, G_i-mediated, ERK activation while having no effect on receptor internalization or G_s-mediated cAMP signaling.

Received for publication, December 4, 2002 , and in revised form, April 23, 2003.

^* This work was supported in part by National Institutes of Health Grant HL16037 (to R. J. L). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from the American Heart Association.

To whom correspondence should be addressed: Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, NC, 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.

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