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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
Author(s) -
Aramori Ichiro,
Zhang Jie,
Ferguson Stephen S.G.,
Bieniasz Paul D.,
Cullen Bryan R.,
Caron Marc G.
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.15.4606
Subject(s) - biology , internalization , chemokine receptor , desensitization (medicine) , c c chemokine receptor type 6 , receptor , ccr1 , c c chemokine receptor type 7 , homologous desensitization , microbiology and biotechnology , mechanism (biology) , chemokine receptor ccr5 , signal transduction , g protein coupled receptor , co receptor , chemokine , genetics , philosophy , epistemology
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 β‐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 β‐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.