scholarly journals Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Deng ◽  
Guorui Deng ◽  
Justin L. Grobe ◽  
Huxing Cui
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Cardiovascular Function ◽  
Metabolic Homeostasis ◽  
Downstream Signaling ◽  
Relative Contribution ◽  
Hypothalamic Nuclei ◽  
Central Origin ◽  
Sympathetic Overdrive ◽  
G Protein Coupled

Obesity is commonly associated with sympathetic overdrive, which is one of the major risk factors for the development of cardiovascular diseases, such as hypertension and heart failure. Over the past few decades, there has been a growing understanding of molecular mechanisms underlying obesity development with central origin; however, the relative contribution of these molecular changes to the regulation of cardiovascular function remains vague. A variety of G-protein coupled receptors (GPCRs) and their downstream signaling pathways activated in distinct hypothalamic neurons by different metabolic hormones, neuropeptides and monoamine neurotransmitters are crucial not only for the regulation of appetite and metabolic homeostasis but also for the sympathetic control of cardiovascular function. In this review, we will highlight the main GPCRs and associated hypothalamic nuclei that are important for both metabolic homeostasis and cardiovascular function. The potential downstream molecular mediators of these GPCRs will also be discussed.

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 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.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

scholarly journals GPRC5A: An Emerging Biomarker in Human Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaoxia Jiang ◽  
Xin Xu ◽  
Mengjie Wu ◽  
Zhonghai Guan ◽  
Xingyun Su ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Lung Tumor ◽  
Human Cancer ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Aberrant Expression ◽  
Human Cancers ◽  
G Protein Coupled

Aberrant expression of G protein-coupled receptors (GPCRs) is frequently associated with tumorigenesis. G Protein-coupled receptor class C group 5 member A (GPRC5A) is a member of the GPCR superfamily, is expressed preferentially in lung tissues, and is regulated by various entities at multiple levels. GPRC5A exerts a tumor suppressive role in lung cancer and GPRC5A deletion promotes lung tumor initiation and progression. Recent advances have highlighted that GPRC5A dysregulation is found in various human cancers and is related to many tumor-associated signaling pathways, including the cyclic adenosine monophosphate (cAMP), nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT) 3, and focal adhesion kinase (FAK)/Src signaling. This review aimed to summarize our updated view on the biology and regulation of GPRC5A, its expression in human cancers, and the linked signaling pathways. A better comprehension of the underlying cellular and molecular mechanisms of GPRC5A will provide novel insights into its potential diagnostic and therapeutic value.

G protein-coupled receptor kinase 2 (GRK2) as an integrative signalling node in the regulation of cardiovascular function and metabolic homeostasis

2018 ◽  
Vol 41 ◽  
pp. 25-32 ◽  
Author(s):  
Federico Mayor ◽  
Marta Cruces-Sande ◽  
Alba C. Arcones ◽  
Rocío Vila-Bedmar ◽  
Ana M. Briones ◽  
...  
Keyword(s):  
G Protein ◽  
Cardiovascular Function ◽  
Receptor Kinase ◽  
Metabolic Homeostasis ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Utilization of Biased G Protein-Coupled Receptor Signaling towards Development of Safer and Personalized Therapeutics

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2052 ◽  
Author(s):  
Metehan Ilter ◽  
Samman Mansoor ◽  
Ozge Sensoy
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Genetic Background ◽  
Patient Specific ◽  
Downstream Signaling ◽  
Physiological Processes ◽  
Holistic Understanding ◽  
Dynamics Simulations ◽  
And Function ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are involved in a wide variety of physiological processes. Therefore, approximately 40% of currently prescribed drugs have targeted this receptor family. Discovery of β -arrestin mediated signaling and also separability of G protein and β -arrestin signaling pathways have switched the research focus in the GPCR field towards development of biased ligands, which provide engagement of the receptor with a certain effector, thus enriching a specific signaling pathway. In this review, we summarize possible factors that impact signaling profiles of GPCRs such as oligomerization, drug treatment, disease conditions, genetic background, etc. along with relevant molecules that can be used to modulate signaling properties of GPCRs such as allosteric or bitopic ligands, ions, aptamers and pepducins. Moreover, we also discuss the importance of inclusion of pharmacogenomics and molecular dynamics simulations to achieve a holistic understanding of the relation between genetic background and structure and function of GPCRs and GPCR-related proteins. Consequently, specific downstream signaling pathways can be enriched while those that bring unwanted side effects can be prevented on a patient-specific basis. This will improve studies that centered on development of safer and personalized therapeutics, thus alleviating the burden on economy and public health.

scholarly journals Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

2020 ◽  
Vol 21 (5) ◽  
pp. 1845 ◽  
Author(s):  
Qian Zhao ◽  
Hong-Ping Zhu ◽  
Xin Xie ◽  
Qing Mao ◽  
Yan-Qing Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Dual Inhibitor ◽  
Downstream Signaling ◽  
Cycle Arrest ◽  
Through Flow ◽  
Melanoma Xenograft

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

scholarly journals The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunlu Jiang ◽  
Maocai Yan ◽  
Chunmei Wang ◽  
Qinqin Wang ◽  
Xiaoyu Chen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
G Protein ◽  
Peptide Ligands ◽  
Erk Activation ◽  
Downstream Signaling ◽  
Apelin Receptor ◽  
Clathrin Adaptor ◽  
And Function ◽  
G Protein Coupled

Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu1-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca2+ mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu1-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

2020 ◽  
Vol 134 (5) ◽  
pp. 473-512 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Sheila Collins
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Signaling Pathways ◽  
G Protein ◽  
Uncoupling Protein ◽  
Beige Adipocytes ◽  
Nucleotide Regulation ◽  
Ucp1 Expression ◽  
Thermogenic Adipocytes ◽  
G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

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