Article ; Online: RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms.
The Journal of biological chemistry
2024 Volume 300, Issue 4, Page(s) 107127
Abstract: Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent ... ...
| Abstract | Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner. |
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| MeSH term(s) | Animals ; Humans ; Mice ; Asthma/metabolism ; Asthma/genetics ; Asthma/pathology ; Bronchoconstriction/genetics ; Dinoprostone/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; Mice, Knockout ; Phosphatidylinositol 3-Kinases/metabolism ; Respiratory Hypersensitivity/metabolism ; Respiratory Hypersensitivity/genetics ; Respiratory Hypersensitivity/pathology ; RGS Proteins/metabolism ; RGS Proteins/genetics ; Cell Line | |||||
| Chemical Substances | Dinoprostone (K7Q1JQR04M) ; GTPase-Activating Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; RGS Proteins ; RGS4 protein (175335-35-0) | |||||
| Language | English | |||||
| Publishing date | 2024-03-02 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2997-x | |||||
| ISSN | 1083-351X ; 0021-9258 | |||||
| ISSN (online) | 1083-351X | |||||
| ISSN | 0021-9258 | |||||
| DOI | 10.1016/j.jbc.2024.107127 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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