Abstract
Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gαi-GDP free of Gβγ. We previously demonstrated that the AGS4-Gαi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gαi module to the receptor analogous to canonical Gαβγ heterotrimer. We have demonstrated that the AGS4-Gαi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gαi module in the regulation of leukocyte function.
Footnotes
- Received October 23, 2016.
- Accepted December 28, 2016.
↵1 Current affiliation: University of Texas Health Science Center, Houston, Houston, Texas.
↵2 Current affiliation: Department of Biology, Charleston Southern University.
↵3 Current affiliation: Department of Pharmacology, Wayne State University, Detroit, Michigan.
This work was supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences [Grant R01-GM086510 to J.B.B.], National Institute of General Medical Sciences South Carolina Institutional Development Awards Networks of Biomedical Research Excellence [Grant P20-GM103499 to M.B.O.], National Cancer Institute [Grant T32-CA119945 to M.B.O.), MUSC institutional funds (to J.B.B.), and the intramural research program of the National Institute of Allergy and Infectious Diseases (to J.H.K.). This work was also enabled by support from the National Institutes of Health National Institute on Neurologic Diseases and Stroke [Grant R01-NS24821] and National Institute on Drug Abuse [Grant R01-DA025896], both to Dr. Stephen M. Lanier (Wayne State University). The research presented in this article was supported in part by the Flow Cytometry and Cell Sorting Shared Resource, funded by a Cancer Center Support grant from the National Cancer Institute [Grant P30 CA138313 to the Hollings Cancer Center at the Medical University of South Carolina] and in part by the National Center for Research Resources and the Office of the Director of the National Institutes of Health [Grant C06 RR015455 to the Hollings Cancer Center at the Medical University of South Carolina].
- U.S. Government work not protected by U.S. copyright
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