Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor.
The chemokine receptor, CCR-5, a G protein-coupled receptor (GPCR) which mediates chemotactic responses of certain leukocytes, has been shown to serve as the primary co-receptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1). Here we describe functional coupling of CCR-5 to inhibition of forskolin-stimulated cAMP formation via a pertussis toxin-sensitive G(i) protein mechanism in transfected HEK 293 cells. In response to chemokines, CCR-5 was desensitized, phosphorylated and sequestered like a prototypic GPCR only following overexpression of G protein-coupled receptor kinases (GRKs) and beta-arrestins in HEK 293 cells. The lack of CCR-5 desensitization in HEK 293 cells in the absence of GRK overexpression suggests that differences in cellular complements of GRK and/or beta-arrestin proteins could represent an important mechanism determining cellular responsiveness. When tested, the activity of CCR-5 as an HIV-1 co-receptor was dependent neither upon its ability to signal nor its ability to be desensitized and internalized following agonist stimulation. Thus, while chemokine-promoted cellular signaling, phosphorylation and internalization of CCR-5 may play an important role in regulation of chemotactic responses in leukocytes, these functions are dissociable from its HIV-1 co-receptor function.
Aramori
I
I
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Ferguson
S S
SS
Bieniasz
P D
PD
Zhang
J
J
Cullen
B
B
Cullen
M G
MG
D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism; D015658:HIV Infections / Q000209:etiology / Q000378:metabolism; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007700:Kinetics; D009154:Mutation; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection; D000071557:beta-Arrestins
D019390:Arrestins; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D000071557:beta-Arrestins; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins