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J. Biol. Chem., Vol. 281, Issue 5, 2701-2710, February 3, 2006

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Arrestin-mediated ERK Activation by Gonadotropin-releasing Hormone Receptors

RECEPTOR-SPECIFIC ACTIVATION MECHANISMS AND COMPARTMENTALIZATION^*

Christopher J. Caunt, Ann R. Finch, Kathleen R. Sedgley, Lisa Oakley, Louis M. Luttrell^¶, and Craig A. McArdle¹

From the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom, the Departments of Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and the ^¶Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401

Activation of seven-transmembrane region receptors typically causes their phosphorylation with consequent arrestin binding and desensitization. Arrestins also act as scaffolds, mediating signaling to Raf and ERK and, for some receptors, inhibiting nuclear translocation of ERK. GnRH receptors (GnRHRs) act via G_q/11 to stimulate the phospholipase C/Ca²⁺/protein kinase C (PKC) cascade and the Raf/MEK/ERK cassette. Uniquely, type I mammalian GnRHRs lack the C-tails that are found in other seven-transmembrane region receptors (including nonmammalian GnRHRs) and are implicated in arrestin binding. Here we have compared ERK signaling by human GnRHRs (hGnRHRs) and Xenopus GnRHRs (XGnRHRs). In HeLa cells, XGnRHRs underwent rapid and arrestin-dependent internalization and caused arrestin/green fluorescent protein (GFP) translocation to the membrane and endosomes, whereas hGnRHRs did not. Internalized XGnRHRs were co-localized with arrestin-GFP, whereas hGnRHRs were not. Both receptors mediated transient ERK phosphorylation and nuclear translocation (revealed by immunohistochemistry or by imaging of co-transfected ERK2-GFP), and for both, ERK phosphorylation was reduced by PKC inhibition but not by inhibiting epidermal growth factor receptor autophosphorylation. In the presence of PKC inhibitor, arrestin-(319-418) blocked XGnRHR-mediated, but not hGnRHR-mediated, ERK phosphorylation. When receptor number was varied, hGnRHRs activated phospholipase C and ERK more efficiently than XGnRHRs but were less efficient at causing ERK2-GFP translocation. At high receptor number, XGnRHRs and hGnRHRs both caused ERK2-GFP translocation to the nucleus, but at low receptor number, XGnRHRs caused ERK2-GFP translocation, whereas hGnRHRs did not. Thus, experiments with XGnRHRs have revealed the first direct evidence of arrestin-mediated (probably G protein-independent) GnRHR signaling, whereas those with hGnRHRs imply that scaffolds other than arrestins can determine GnRHR effects on ERK compartmentalization.

Received for publication, July 5, 2005 , and in revised form, September 26, 2005.

^* This work was supported by a Wellcome Trust project grant (to C. A. M.). 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.

¹ To whom correspondence should be addressed. Tel.: 0117-331-3077; Fax: 0117-331-3035; E-mail: craig.mcardle{at}bris.ac.uk.

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