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Review
. 2008 Jan 16;82(3-4):125-34.
doi: 10.1016/j.lfs.2007.10.024. Epub 2007 Nov 13.

Desensitization of herpesvirus-encoded G protein-coupled receptors

Joseph D Sherrill  1 , William E Miller
Affiliations
Review

Desensitization of herpesvirus-encoded G protein-coupled receptors

Joseph D Sherrill et al. Life Sci. .

Abstract

Members of the herpesvirus family, including human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), encode G protein-coupled receptor (GPCR) homologs, which strongly activate classical G protein signal transduction networks within the cell. In animal models of herpesvirus infection, the viral GPCRs appear to play physiologically important roles by enabling viral replication within tropic tissues and by promoting reactivation from latency. While a number of studies have defined intracellular signaling pathways activated by herpesviral GPCRs, it remains unclear if their physiological function is subjected to the process of desensitization as observed for cellular GPCRs. G protein-coupled receptor kinases (GRK) and arrestin proteins have been recently implicated in regulating viral GPCR signaling; however, the role that these desensitization proteins play in viral GPCR function in vivo remains unknown. Here, we review what is currently known regarding viral GPCR desensitization and discuss potential biological ramifications of viral GPCR regulation by the host cell desensitization machinery.

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Figures

Figure 1
Figure 1. Typical model of GPCR activation and desensitization
(Left) Agonist-bound GPCRs activate heterotrimeric G proteins through catalyzing GDP to GTP exchange on the Gα subunit. (Right) Following agonist binding, activated receptors are phosphorylated by GRKs, allowing for the binding of arrestin proteins to block further G protein signaling activity and facilitate receptor internalization. Arrestins also serve as scaffolding proteins to recruit various signaling molecules to activate non-traditional signaling pathways.
Figure 2
Figure 2. The carboxy terminal tails of viral GPCRs regulated by cellular kinases
The carboxy terminal tails of US28, M33, and ORF74 contain a number of Ser and Thr residues (bolded), which may serve as phosphorylation sites for cellular kinases previously shown to facilitate viral GPCR desensitization (Bais et al., 1998; Geras-Raaka et al., 1998; Miller et al., 2003; Mokros et al., 2002; Sherrill and Miller, 2006). Also shown for comparison is the carboxy terminal tail of the human CC-chemokine receptor 5 (CCR5) and its Ser residues (bolded) previously shown to be phosphorylated by GRKs and PKC (Aramori et al., 1997; Oppermann et al., 1999).
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