TY - JOUR T1 - Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 888 LP - 898 DO - 10.1124/mol.105.015222 VL - 69 IS - 3 AU - Carlos P. Fitzsimons AU - Ursula A. Gompels AU - Dennis Verzijl AU - Henry F. Vischer AU - Claire Mattick AU - Rob Leurs AU - Martine J. Smit Y1 - 2006/03/01 UR - http://molpharm.aspetjournals.org/content/69/3/888.abstract N2 - 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 Gq/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 Gi/o proteins. For each of the tested chemokines, coexpression of U51 with a variety of Gα 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. ER -