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J. Biol. Chem., Vol. 277, Issue 20, 17916-17927, May 17, 2002

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Aspartic Acid 564 in the Third Cytoplasmic Loop of the Luteinizing Hormone/Choriogonadotropin Receptor Is Crucial for Phosphorylation-independent Interaction with Arrestin2^*

Sutapa Mukherjee, Vsevolod V. Gurevich^§, Anita Preninger^¶, Heidi E. Hamm^¶, Marie-France Bader^**, Asgerally T. Fazleabas, Lutz Birnbaumer^§§, and Mary Hunzicker-Dunn^¶¶

From the Departments of  Cell and Molecular Biology and ^¶ Molecular Pharmacology and Biological Chemistry and the Neuroscience Institute, Northwestern University Medical School, Chicago, Illinois 60611, the ^§ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, ^** CNRS UPR-2356, Neurotransmission et Sécrétion Neuroendocrine, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France, and the  Department of Obstetrics and Gynecology, University of Illinois College of Medicine, Chicago, Illinois 60612, and the ^§§ Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Arrestin2 binding to the active but unphosphorylated luteinizing hormone/choriogonadotropin receptor (LH/CG R) in ovarian follicles is triggered by activation of ADP-ribosylation factor 6 (ARF6) and leads to uncoupling of this receptor from cAMP signaling. We sought to determine how arrestin2 binds to LH/CG R, if binding is of high affinity, and if the receptor also binds arrestin3. Desensitization of intact LH/CG R was equally sensitive to ectopic constructs of arrestin2 that bind other G protein-coupled receptors (GPCRs) either in a phosphorylation-independent or -dependent manner. Intact LH/CG R was not desensitized by ectopic arrestin3 constructs. Surface plasmon resonance studies showed that arrestin2 bound a synthetic third intracellular (3i) LH/CG R loop peptide with picomolar affinity; arrestin3 bound with millimolar affinity. To determine whether Asp-564 in the 3i loop mimicked the phosphorylated residue of other GPCRs, human embryonic kidney (HEK) cells were transfected with wild-type (WT) and D564G LH/CG R. An agonist-stimulated ARF6-dependent arrestin2 undocking pathway to drive desensitization of WT receptor was recapitulated in HEK cell membranes, and ectopic arrestin2 promoted desensitization of WT LH/CG R. However, D564G LH/CG R in HEK cells was not desensitized, and synthetic 3i D564G peptide did not bind arrestin2. Synthetic 3i loop peptides containing D564E, D564V, or D564N also did not bind arrestin2. We conclude that the ARF6-mediated mechanism to release a pool of membrane-delimited arrestin to bind GPCRs may be a widespread mechanism to deliver arrestin to GPCRs for receptor desensitization. Unlike other GPCRs that additionally require receptor phosphorylation, LH/CG R activation is sufficient to expose a conformation in which Asp-564 in the 3i loop confers high affinity binding selectively to arrestin2.

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