scholarly journals Anaphylactic shock depends on endothelial Gq/G11

2009 ◽  
Vol 206 (2) ◽  
pp. 411-420 ◽  
Author(s):  
Hanna Korhonen ◽  
Beate Fisslthaler ◽  
Alexandra Moers ◽  
Angela Wirth ◽  
Daniel Habermehl ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Anaphylactic Shock ◽  
Platelet Activating Factor ◽  
Severe Allergic Reaction ◽  
Downstream Signaling ◽  
Systemic Anaphylaxis ◽  
Multiple Organs ◽  
Nitric Oxide Formation ◽  
G Protein Coupled

Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein–coupled receptors, which are linked to the heterotrimeric G proteins Gq/G11, G12/G13, and Gi. The role of downstream signaling pathways activated by anaphylactic mediators in defined organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of Gq/G11- and G12/G13-mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq/G11-mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various inflammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial Gαq/Gα11 deficiency. Mice with endothelium-specific Gαq/Gα11 deficiency, but not with Gα12/Gα13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11-mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.

scholarly journals Trafficking to the primary cilium membrane

2017 ◽  
Vol 28 (2) ◽  
pp. 233-239 ◽  
Author(s):  
Saikat Mukhopadhyay ◽  
Hemant B. Badgandi ◽  
Sun-hee Hwang ◽  
Bandarigoda Somatilaka ◽  
Issei S. Shimada ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Signaling Pathways ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Diffusion Barriers ◽  
Disease Pathogenesis ◽  
Ciliary Membrane ◽  
Multiple Organs ◽  
Sensory Reception

The primary cilium has been found to be associated with a number of cellular signaling pathways, such as vertebrate hedgehog signaling, and implicated in the pathogenesis of diseases affecting multiple organs, including the neural tube, kidney, and brain. The primary cilium is the site where a subset of the cell's membrane proteins is enriched. However, pathways that target and concentrate membrane proteins in cilia are not well understood. Processes determining the level of proteins in the ciliary membrane include entry into the compartment, removal, and retention by diffusion barriers such as the transition zone. Proteins that are concentrated in the ciliary membrane are also localized to other cellular sites. Thus it is critical to determine the particular role for ciliary compartmentalization in sensory reception and signaling pathways. Here we provide a brief overview of our current understanding of compartmentalization of proteins in the ciliary membrane and the dynamics of trafficking into and out of the cilium. We also discuss major unanswered questions regarding the role that defects in ciliary compartmentalization might play in disease pathogenesis. Understanding the trafficking mechanisms that underlie the role of ciliary compartmentalization in signaling might provide unique approaches for intervention in progressive ciliopathies.

scholarly journals LncRNAs Regulatory Networks in Cellular Senescence

2019 ◽  
Vol 20 (11) ◽  
pp. 2615 ◽  
Author(s):  
Pavan Kumar Puvvula
Keyword(s):  
Signaling Pathways ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Translation Regulation ◽  
Reading Frame ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Fate Decision ◽  
Functional Mechanisms

Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with no open reading frame. They play a key role in the regulation of cellular processes such as genome integrity, chromatin organization, gene expression, translation regulation, and signal transduction. Recent studies indicated that lncRNAs are not only dysregulated in different types of diseases but also function as direct effectors or mediators for many pathological symptoms. This review focuses on the current findings of the lncRNAs and their dysregulated signaling pathways in senescence. Different functional mechanisms of lncRNAs and their downstream signaling pathways are integrated to provide a bird’s-eye view of lncRNA networks in senescence. This review not only highlights the role of lncRNAs in cell fate decision but also discusses how several feedback loops are interconnected to execute persistent senescence response. Finally, the significance of lncRNAs in senescence-associated diseases and their therapeutic and diagnostic potentials are highlighted.

scholarly journals Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders

2019 ◽  
Vol 20 (13) ◽  
pp. 3207 ◽  
Author(s):  
Hidetoshi Komatsu ◽  
Mamoru Fukuchi ◽  
Yugo Habata
Keyword(s):  
Psychiatric Disorders ◽  
Signaling Pathways ◽  
Brain Function ◽  
Marked Reduction ◽  
G Protein Coupled Receptors ◽  
Detailed Understanding ◽  
Gpcr Signaling ◽  
Downstream Signaling ◽  
Multiple Signaling ◽  
G Protein Coupled

Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor’s downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders.

Multiple Signaling Pathways for Platelet-Activating Factor Receptor

Physiology ◽  
1992 ◽  
Vol 7 (2) ◽  
pp. 72-75
Author(s):  
SD Shukla
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
G Protein ◽  
Platelet Activating Factor ◽  
G Protein Coupled Receptors ◽  
Kinase C ◽  
Paf Receptor ◽  
Multiple Signaling ◽  
G Protein Coupled

Platelet-activating factor (PAF) receptor is coupled to multiple signaling pathways, including phospholipid turnover via phospholipases C, D, A2;Ca2+ mobilization;and activation of protein kinase C and tyrosine kinase. The cloned receptor shows homology to G protein-coupled receptors. These developments highlight receptor functions of this novel phospholipid agonist.

scholarly journals Targeting GPCRs & their Signaling as a Therapeutic Option in Melanoma

2022 ◽  
Author(s):  
Jeremy H Raymond ◽  
Zackie Aktary ◽  
Lionel Larue ◽  
Véronique Delmas
Keyword(s):  
Therapeutic Option ◽  
Treatment Options ◽  
Paracrine Factors ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Activating Mutations ◽  
New Therapeutic Approaches ◽  
And Migration ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G proteins, which induce cellular signaling through various pathways. Such signaling modulates essential cellular processes of melanomagenesis, such as proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden treatment options in melanoma in the future.

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