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J. Biol. Chem., Vol. 281, Issue 19, 13199-13208, May 12, 2006

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Molecular Pharmacological Phenotyping of EBI2

AN ORPHAN SEVEN-TRANSMEMBRANE RECEPTOR WITH CONSTITUTIVE ACTIVITY^*

Mette M. Rosenkilde¹, Tau Benned-Jensen, Helene Andersen, Peter J. Holst^¶, Thomas N. Kledal, Hans R. Lüttichau^||, Jørgen K. Larsen^**, Jan P. Christensen^¶, and Thue W. Schwartz

From the Laboratory for Molecular Pharmacology, Department of Pharmacology, University of Copenhagen, and the ^¶Institute for Medical Microbiology and Immunology, The Panum Institute, Building 18.6, Blegdamsvej 3, 2200 Copenhagen N, Copenhagen, the Clinical Research Unit, Copenhagen University Hospital, 2650 Hvidovre, and the ^||Department for Infectious Diseases, ^**Finsen Laboratory, The Finsen Center, Copenhagen University Hospital, 2200 Copenhagen, Denmark

Epstein-Barr virus (EBV)-induced receptor 2 (EBI2) is an orphan seven-transmembrane (7TM) receptor originally identified as the most up-regulated gene (>200-fold) in EBV-infected cells. Here we show that EBI2 signals with constitutive activity through G_i as determined by a receptor-mediated inhibition of forskolin-induced cAMP production and an induction of the serum response element-driven transcriptional activity in a pertussis toxin-sensitive manner. G_s and G_q were not activated constitutively as determined by the lack of cAMP production, the lack of inositol phosphate turnover, and the lack of activities of the transcription factors: cAMP response element-binding protein and nuclear factor-B. Immunohistochemistry and confocal microscopy of FLAG- and green fluorescent protein-tagged EBI2 revealed cell-surface expression. A putative N-terminal truncated version of EBI2, 4-EBI2, showed similar expression and signaling through G_i as full-length EBI2. By using a ³²P-labeled EBI2 probe we found a very high expression in lymphoid tissue (spleen and lymph node) and peripheral blood mononuclear cells and a high expression in lung tissue. Real-time PCR of EBV-infected cells showed high expression of EBI2 during latent and lytic infection, in contrast to the EBV-encoded 7TM receptor BILF1, which was induced during lytic infection. EBI2 clustered with the orphan GPR18 by alignment analysis as well as by close proximity in the chromosomal region 13q32.3. Based on the constitutive signaling and cellular expression pattern of EBI2, it is suggested that it may function in conjunction with BILF1 in the reprogramming of the cell during EBV infection.

Received for publication, March 9, 2006 , and in revised form, March 14, 2006.

^* The work was supported by the Danish Medical Council, the NovoNordisk Foundation, the Carlsberg Foundation, and the Aase and Ejnar Danielsen Foundation. 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.: 45-3532-7608; Fax: 45-3532-7610; E-mail: rosenkilde{at}molpharm.dk.

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				T. Benned-Jensen and M. M. Rosenkilde Structural Motifs of Importance for the Constitutive Activity of the Orphan 7TM Receptor EBI2: Analysis of Receptor Activation in the Absence of an Agonist Mol. Pharmacol., October 1, 2008; 74(4): 1008 - 1021. [Abstract] [Full Text] [PDF]