Received for publication May 27, 2005.
Revised November 30, 2005.
Accepted for publication December 5, 2005.

Chemokine-directed trafficking of receptor stimulus to different Gproteins: selective inducible and constitutive signaling by human herpesvirus 6-encoded chemokine receptor U51

Abstract

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 PTX-insensitive increases in PLC activity and changes in [Ca²⁺]_i, while 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, co-expression 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.

Key words: Chemotactic peptides, Gi family, Gq/11 family, IP3/DAG, Calcium (G Protein Coupled Signals), Receptor synthesis/trafficking, CREB, Receptor binding studies

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