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G protein ?q exerts expression level-dependent distinct signaling paradigms.

ABSTRACT: G protein ?q-coupled receptors (Gq-GPCRs) primarily signal through G?qGTP mediated phospholipase C? (PLC?) stimulation and the subsequent hydrolysis of phosphatidylinositol 4, 5 bisphosphate (PIP2). Though Gq-heterotrimer activation results in both G?qGTP and G??, unlike Gi/o-receptors, it is unclear if Gq-coupled receptors employ G?? as a major signal transducer. Compared to Gi/o- and Gs-coupled receptors, we observed that most cell types exhibit a limited free G?? generation upon Gq-pathway and G?q/11 heterotrimer activation. We show that cells transfected with G?q or endogenously expressing more than average-levels of G?q/11 compared to G?s and G?i exhibit a distinct signaling regime primarily characterized by recovery-resistant PIP2 hydrolysis. Interestingly, the elevated Gq-expression is also associated with enhanced free G?? generation and signaling. Furthermore, the gene GNAQ, which encodes for G?q, has recently been identified as a cancer driver gene. We also show that GNAQ is overexpressed in tumor samples of patients with Kidney Chromophobe (KICH) and Kidney renal papillary (KIRP) cell carcinomas in a matched tumor-normal sample analysis, which demonstrates the clinical significance of G?q expression. Overall, our data indicates that cells usually express low G?q levels, likely safeguarding cells from excessive calcium as wells as from G?? signaling.

SUBMITTER: Kankanamge D

PROVIDER: S-EPMC6534355 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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G protein αq exerts expression level-dependent distinct signaling paradigms.

Kankanamge Dinesh D Tennakoon Mithila M Weerasinghe Amila A Cedeno-Rosario Luis L Chadee Deborah N DN Karunarathne Ajith A

Cellular signalling 20190305

G protein αq-coupled receptors (Gq-GPCRs) primarily signal through GαqGTP mediated phospholipase Cβ (PLCβ) stimulation and the subsequent hydrolysis of phosphatidylinositol 4, 5 bisphosphate (PIP2). Though Gq-heterotrimer activation results in both GαqGTP and Gβγ, unlike Gi/o-receptors, it is unclear if Gq-coupled receptors employ Gβγ as a major signal transducer. Compared to Gi/o- and Gs-coupled receptors, we observed that most cell types exhibit a limited free Gβγ generation upon Gq-pathway an ...[more]

PMID: 30849518

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Project description:BackgroundWNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia.MethodsMouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [γ-(35)S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways.ResultsAstrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric G(i/o) proteins to reduce cyclic AMP levels and to activate a G(i/o) protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2) axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation.ConclusionsThus, WNT-5A-induced and G protein-dependent signaling to ERK1/2 is important for the regulation of proinflammatory responses in mouse primary microglia cells. We show for the first time that WNT-5A/G protein signaling mediates physiologically important processes in primary mammalian cells with natural receptor and G protein stochiometry. Consequently, WNT-5A emerges as an important means of astrocyte-microglia communication and we, therefore, suggest WNT-5A as a new player in neuroinflammatory conditions, such as neurodegenerative disease, hypoxia, stroke, injury and infection.

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G protein ?q exerts expression level-dependent distinct signaling paradigms.

Publications

G protein αq exerts expression level-dependent distinct signaling paradigms.

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