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Signaling and crosstalk of the angiotensin AT2-receptor and the receptor MAS

ABSTRACT: The AT2-receptor (AT2R) and the receptor MAS are GPCRs within the renin-angiotensin-system mediating protective actions. Their unconventional signaling mechanisms are still not well characterized, but those known display a high degree of similarity. The proposed project is part of a large-scale collaboration with the group of Robson Santos, a leader in Ang1-7/MAS research, aiming at a better characterization of AT2R-MAS signaling and crosstalk. Building up on our finding that the AT2R and MAS heterodimerise and on the mapping of the entire Ang-(1−7)/MAS signaling network by the Santos group, the proposed studies will look at AT2R-MAS signaling in two ways: mapping the AT2R signaling network by quantitative phosphoproteomics and compare it with the MAS network.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Aortic Endothelial Cell

SUBMITTER: Stefan J. Kempf

LAB HEAD: Martin R. Larsen

PROVIDER: PXD005802 | Pride | 2022-11-18

REPOSITORIES: pride

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Project description:Neuroinflammation is a hallmark of various neurological diseases such as Alzheimer’s disease. The aim of the study was to elucidate the dose-dependent in vitro molecular mechanism of TNFα in neurons related to neuroprotection and -degeneration. We performed a quantitative proteomics and phospho-proteomics study in HT22 neuronal cells as well as differentiated human neurons to elucidate alterations in TNFα dose-dependent (0.1 – 100.0 ng/ml) signaling pathways. We report here that 10.0 ng/ml TNFα reduces mitochondrial signaling and inhibits protein translation signaling related to mTOR but leads also at the same time to induction of neuroprotective MAPK-CREB signaling after 24 hours in HT22 cells. Stimulation of TNFα (1.0 ng/ml, 24 hours) in human neurons reveals similar cellular mechanisms on protein translation signaling related to mTOR as seen in HT22 cells at 10.0 ng/ml dose whereas mitochondrial membrane potential and reactive oxygen species level were not changed. SiRNA-mediated knockdown of CREB in human neurons prior to TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasures the reduced CREB signaling. In vivo data of TNFα knock-out transgenic mice showed that learning ability does not depend on TNFα during normal aging but that TNFα preserves the learning and memory ability during episodes of systemic inflammation resembling the persistent neuroinflammation status as seen in Alzheimer´s disease. This may be based on modulation of CREB as revealed by our in vitro studies. Our data indicate that several molecular targets and signaling pathways induced by TNFα in neurons resemble those of Alzheimer´s pathology. It may suggest that TNFα functions as a contributing factor to this neurodegenerative disease but has also at the same time neuroprotective properties regulating learning and memory formation under neuroinflammatory status.

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Signaling and crosstalk of the angiotensin AT2-receptor and the receptor MAS

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