Non-canonical G protein signaling

Nürnberg, Bernd; Beer-Hammer, Sandra; Reisinger, Ellen; Leiss, Veronika

doi:10.1016/j.pharmthera.2024.108589

Cited by 4 publications

(4 citation statements)

References 318 publications

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“…We used a functional active polyclonal peptide antibody that binds to the extreme C-terminus of Gα i2 in a selective and specific manner [55]. The antibody is not only directed to a region that is important for receptor-G protein interaction but also for effector regulation by steric hindrance [2,37,72]. Indeed, our data show that it is a functionally active antibody that is effective in vivo.…”

Section: Discussionmentioning

confidence: 91%

“…Further support for this assumption is coming from studies targeting phosphodiesterase-4 subtype B (PDE4B) for cardioprotection in acute MI via neutrophils and microcirculation [99]. Despite uncertainty about the mode of action of metoprolol or PDE4B inhibition on neutrophils and other target cells that protect them from mIRI, alternative pathways involving biased signaling are conceivable [72].…”

Section: Discussionmentioning

confidence: 99%

“…While Gα i1 is found primarily in the brain, Gα i2 and Gα i3 are abundantly expressed in the heart, the endothelium, and the immune system [20]. Many biologic functions of leukocytes, including adhesion and chemotaxis, occur through Gα i -mediated signaling [12,43,72,94]. For neutrophilic granulocytes, Gα i2 has been shown to be indispensable for their accumulation at different sites of inflammation and for chemokine-induced intravascular arrest [57,100,103].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury

Köhler,

Leiss,

Beichert

et al. 2024

Basic Res Cardiol

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Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gαi proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gαi2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gαi2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2−/− → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gαi2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2−/−vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gαi2 for mIRI. Here, we show that infarct size was substantially reduced when Gαi2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2fl/fl LysM-Cre+/tg vs 42.0% Gnai2fl/fl; p < 0.01) or selectively blocked with specific antibodies directed against Gαi2 (AAR: 19.0% (anti-Gαi2) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2fl/fl; LysM-Cre+/tg) vs 31 (Gnai2fl/fl); p < 0.001) and in anti-Gαi2 antibody-treated (PNCs: 9 (anti-Gαi2) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gαi2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gαi2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gαi2) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gαi2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury

Köhler,

Leiss,

Beichert

et al. 2024

Basic Res Cardiol

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“…Current models of GPCR signaling have evolved beyond a single GPCR activating a specific heterotrimeric G protein pathway at the cell surface to encompass dynamic multidimensional signaling hubs 4 . These include the ability of GPCRs to activate multiple G proteins, associate with an array of adaptor proteins 5 and form oligomeric complexes 6,7 . Furthermore, GPCRs assemble distinct signaling hubs in varied subcellular compartments in addition to the plasma membrane, including endosomes 8 , the nucleus 9 , Golgi and mitochondria 4,10 .…”

Section: Introductionmentioning

confidence: 99%

A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

Shchepinova,

Richardson,

Houghton

et al. 2024

Preprint

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SummaryCellular signaling by membrane G protein-coupled receptors (GPCRs) is orchestrated by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome as it evolves over time and space in response to an agonist can offer a unique window on pleiotropic signaling decoding and functional selectivity at a cellular level. In this study, we employed proximity-based APEX2 proteomics to interrogate the interaction network of the GPCR for luteinizing hormone (LHR) on a sub-minute timescale. We developed an analytical approach integrating quantitative multiplexed proteomics and temporal reference profiles, providing a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is exquisitely regulated at a spatial level, leading to identification of novel interactors including the Ras-related GTPase RAP2B that modulate both receptor signaling and post-endocytic trafficking, and providing a resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments.

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Neutrophil diversity and function in health and disease

Zhang,

Xia,

et al. 2024

Sig Transduct Target Ther

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Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.

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Non-canonical G protein signaling

Cited by 4 publications

References 318 publications

Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury

Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury

A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

Neutrophil diversity and function in health and disease

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