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Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51

Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Faculty of Sciences, Vrije Universiteit Amsterdam, Faculty of Sciences, Amsterdam, The Netherlands (C.P.F., D.V., H.F.V., R.L., M.J.S.); and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom (U.A.G., C.M.)

The human herpes virus 6 (HHV-6)-encoded chemokine receptor U51 constitutively activates phospholipase C (PLC) and inhibits cAMP-responsive element (CRE)-mediated gene transcription via the activation of G_q/11 proteins. Yet, chemokines known to bind U51 differentially regulate U51 coupling to G proteins. CCL5/RANTES induced pertussis toxin (PTX)-insensitive increases in PLC activity and changes in intracellular free calcium concentration ([Ca²⁺]_i), whereas both CCL2/MCP-1 and CCL11/eotaxin failed to stimulate PLC activity or increase [Ca²⁺]_i. In contrast, all three chemokines counteracted the effects of U51 on CRE activity via the activation of PTX-sensitive G_i/o proteins. For each of the tested chemokines, coexpression of U51 with a variety of G subunits, however, revealed a distinct profile for preferred G-protein coupling, which could be shifted by modulation of the relative expression of G proteins. These findings are consistent with a chemokine-selective trafficking of receptor stimulus to distinct G proteins and suggest that the constitutive activity of U51 and the chemokine-induced signaling involve different active states of the receptor. By virtue of its ability to constitutively activate signaling pathways, its G-protein promiscuity, and the chemokine-directed trafficking of receptor stimulus, U51 can be considered a sensitive and versatile virally encoded signaling device, potentially of importance in HHV-6-related pathologies.

Address correspondence to: Dr. Martine J. Smit, Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, The Netherlands. E-mail: smit{at}few.vu.nl

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