Selective G Protein Coupling by C-C Chemokine Receptors (*)
- From the (1)Departments of Pharmacology and Physiology,
- (2)Biochemistry, and
- (3)Oncology, University of Rochester, Rochester, New York 14642
- § To whom correspondence should be addressed. Tel.: 716-275-2029; Fax: 716-244-9283.
Abstract
The C-C chemokines are major mediators of chemotaxis of monocytes and some T cells in inflammatory reactions. The pathways
by which the C-C chemokine receptors activate phospholipase C (PLC) were investigated in cotransfected COS-7 cells. The C-C
chemokine receptor-1 (CKR-1), the MCP-1 receptor-A (MCP-1Ra), and MCP-1Rb can reconstitute ligand-induced accumulation of
inositol phosphates with PLC β2 in a pertussis toxin-sensitive manner, presumably through Gβ
released from the G
proteins. However, these three receptors demonstrated different specificity in coupling to the α subunits of the G
class. While none of the receptors can couple to Gαq/11, MCP-1Rb can couple to both Gα14 and Gα16, but its splicing variant,
MCP-1Rb, cannot. Since MCP-1Ra and -b differ only in their C-terminal intracellular domains, the C-terminal ends of MCP-1Rs
determine G protein coupling specificity. CKR-1 can couple to Gα14 but not to Gα16, suggesting some of the C-C chemokine receptors,
unlike the C-X-C chemokine receptors, discriminate against Gα16, a hematopoietic-specific Gα subunit. The intriguing specificity
in coupling of the G
class of G proteins implies that the chemokines may be involved in some distinct functions in vivo. The commonality of the chemokine receptors in coupling to the G
-Gβ
-PLC β2 pathway provides a potential target for developing broad spectrum anti-inflammatory drugs.
Footnotes
-
↵* This work was supported by the Pharmaceutical Research and Manufacturers Foundation of America, Inc. and a National Institutes of Health Grant GM53162R29 (to D. W.), by the Leukemia Society of America, and by Grant IRG-18 from the American Cancer Society (to H. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- IL
-
interleukin
- MCP
-
macrophage chemotactic protein
- RANTES
-
regulated upon activation, normal T cell expressed and secreted
- MIP
-
macrophage inflammatory protein
- PLC
-
phospholipase C
- IP
-
inositol phosphate
- PTX
-
pertussis toxin.
-
- Received September 18, 1995.
- Revision received December 27, 1995.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
