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Mechanisms Of G Protein Regulation By Rgs Proteins And Small Molecule Inhibitors
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Book Synopsis Mechanisms of G Protein Regulation by RGS Proteins and Small Molecule Inhibitors by : Stanley Michinobu Kanai
Download or read book Mechanisms of G Protein Regulation by RGS Proteins and Small Molecule Inhibitors written by Stanley Michinobu Kanai and published by . This book was released on 2017 with total page 114 pages. Available in PDF, EPUB and Kindle. Book excerpt: G protein coupled receptors transduce diverse extracellular signals like hormones, neurotransmitters, and photons to specific cellular responses through heterotrimeric G proteins. G proteins activate numerous effectors and signal transduction pathways, and therefore the regulation of G proteins is crucial for faithful propagation of specific cellular and physiological responses. A better understanding of the mechanisms that regulate G proteins should provide new insight into signaling pathways that govern healthy and disease states, and also provide opportunities for discovery of novel therapeutic targets.Regulator of G protein signaling (RGS) proteins are crucial regulators of G proteins, for they control amplitude and duration of G protein signaling responses. RGS2 is particularly important because it is associated with many physiological and disease processes. A key concept that has emerged is that physiological and disease processes are extremely sensitive to even modest changes in RGS2 expression levels. The goals of this dissertation were to investigate the mechanism that controls RGS2 levels and to determine how dynamic RGS2 levels affect GPCR signaling. The particular focus was on the ubiquitin proteasome pathway (UPP), which is one of the key mechanisms that control RGS2 expression levels. Rather than looking for components of the UPP that recognize and degrade RGS2, a comprehensive analysis was performed on the RGS2 N-terminal domain to identify signals required for degradation. This analysis revealed a novel bipartite hydrophobic motif that is required for degradation. Intriguingly, deletion of these hydrophobic motifs did not abrogate binding with E3 ligases associated with RGS2 degradation, suggesting additional mechanisms are involved. The effect of UPP mediated degradation of RGS2 on regulation of GPCR signaling was also explored. Using a cell based, kinetically resolved, GPCR reporter assay, it was demonstrated that proteasome degradation of RGS2 dynamically regulates GPCR signaling, influencing both agonist efficacy and the rate of receptor resensitization.G protein signaling pathways also can be modulated by small molecule inhibitors. YM-254890 and FR900359 are a class of small molecule inhibitors for G proteins that are selective and cell permeable. They are promising research tools and leads for therapeutic agents, but the exact molecular mechanism of action of these inhibitors is not known. The second part of the dissertation describes early stages of a study that aims to elucidate the mechanism of action of YM and FR. Preliminary results that support an allosteric model of inhibition are reported, followed by a discussion of future work that will further test this model.
Book Synopsis Understanding Specificity of Small Molecule Inhibitors of Regulators of G-protein Signaling (rgs) Proteins by : Vincent Shaw
Download or read book Understanding Specificity of Small Molecule Inhibitors of Regulators of G-protein Signaling (rgs) Proteins written by Vincent Shaw and published by . This book was released on 2019 with total page 201 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Mechanism and Specificity of G Protein Regulation by RGS Proteins by : Keng-Li Lan
Download or read book Mechanism and Specificity of G Protein Regulation by RGS Proteins written by Keng-Li Lan and published by . This book was released on 1999 with total page 442 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Biology of RGS Proteins by :
Download or read book Molecular Biology of RGS Proteins written by and published by Academic Press. This book was released on 2009-07-21 with total page 389 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Biology of RGS Proteins, a volume of Progress in Molecular Biology and Translational Science, will include historical discussion of RGS proteins, the role of RGS proteins in addiction, depression and Parkinson's disease and the biology and functional regulation of RGS9 isoforms. This publication further discusses RGS proteins in cellular signaling, protein control in lymphocyte function, and alternative splicing of RGS transcripts and nuclear RGS proteins, offering the latest in research of RGS proteins.
Book Synopsis Pharmacology of G Protein Coupled Receptors by : Richard R. Neubig
Download or read book Pharmacology of G Protein Coupled Receptors written by Richard R. Neubig and published by Academic Press. This book was released on 2011-09-19 with total page 408 pages. Available in PDF, EPUB and Kindle. Book excerpt: G protein coupled receptors remain the most important class of therapeutic targets in medicine. In the last 5 years, tremendous advances have been made in our understanding of the structure and mechanism of this critical family of drug targets. The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors. It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones. In addition, emerging drug targets such as receptor families for fatty acids, carboxylic acids, lipid mediators, etc. are included. Final chapters cover novel mechanisms of signal regulation through PDZ domains and RGS proteins. This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists. The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists
Book Synopsis G Protein Signaling by : Alan V. Smrcka
Download or read book G Protein Signaling written by Alan V. Smrcka and published by Humana Press. This book was released on 2003-09-15 with total page 250 pages. Available in PDF, EPUB and Kindle. Book excerpt: A collection of cutting-edge methods for investigating G protein signaling from a variety of perspectives ranging from in vitro biochemistry to whole animal studies. Among the readily reproducible techniques presented are those for the purification of G proteins and effectors enzymes, assays of these purified G proteins and effector enzymes, and for the study of G proteins interactions with effectors in intact cells. Additional methods are provided for assaying G protein coupled receptor structure, function, and localization; for studying the physiological roles for endogenous G proteins; and for examining lipid and phosphate modifications of RGS proteins.
Download or read book Molecular Biology of the Cell written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Mechanisms and Pathways of Heterotrimeric G Protein Signaling by : Stephen Sprang
Download or read book Mechanisms and Pathways of Heterotrimeric G Protein Signaling written by Stephen Sprang and published by Academic Press. This book was released on 2007-10-01 with total page 262 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume in the Advances in Protein Chemistry series features cutting-edge articles on topics in protein chemistry. This volume includes chapters on the structural basis of effector regulation and signal termination in heterotrimeric Gƒуnƒnproteins; How do receptors activate G proteins; Some mechanistic insights into GPCR activation from detergent solubilized ternary complexes on beads; Activation of G protein coupled receptors; Kinetic analysis of g-protein-coupled receptor signaling using fluorescence resonance energy transfer in living cells; Regulation of Rho Guanine Nucleotide Exchange Factors (RhoGEFs) by G proteins.
Book Synopsis Regulators of G Protein Signaling, Part A by :
Download or read book Regulators of G Protein Signaling, Part A written by and published by Elsevier. This book was released on 2004-11-25 with total page 475 pages. Available in PDF, EPUB and Kindle. Book excerpt: Regulators of G Protein Signaling, Part A is an in-depth treatment of G-Protein Signaling, and will cover general methods of analysis of RGS protein analysis, including Expression and post-translational modification, Assays of GAP activity and allosteric control, Electrophysiological methods and RGS-insensitive Ga subunits, Mouse models of RGS protein action, Methods of RGS protein inhibition, and G-protein regulators of model organisms. - Table of Contents - Expression and post-translational modification - Assays of GAP activity and allosteric control - Electrophysiological methods and RGS-insenstitive Ga subunits - Mouse Models of RGS protein action - Methods of RGS protein inhibition - G-protein regulators of model organisms
Book Synopsis G Protein Pathways, Part C: Effector Mechanisms by :
Download or read book G Protein Pathways, Part C: Effector Mechanisms written by and published by Elsevier. This book was released on 2001-10-15 with total page 695 pages. Available in PDF, EPUB and Kindle. Book excerpt: This third volume in the trio covering G proteins, features integrated approaches to studying G proteins. Methods pertaining to signaling mechanisms are presented, including theoretical and modeling approaches, biochemistry and molecular biology, and cell biology and physiology. The techniques for studying the structure and function of G proteins are important not only to those with specific research interests in them, but also endocrinologists and pharmacologists conducting research on signaling mechanisms that are increasingly understood to interact with G proteins.
Book Synopsis Molecular Mechanisms Regulating G Protein Signaling in Brain and Heart by : Ekaterina N. Posokhova
Download or read book Molecular Mechanisms Regulating G Protein Signaling in Brain and Heart written by Ekaterina N. Posokhova and published by . This book was released on 2012 with total page 100 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis G Protein Signaling by : Gerd Steding
Download or read book G Protein Signaling written by Gerd Steding and published by . This book was released on 2009-02-16 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: It has been almost four decades since the discovery of signal transduction by G proteins. Much progress has been made in unraveling their roles in metabolism, cell growth, differentiation and apoptosis. G protein-coupled receptors (GPCRs) now represent a class of important therapeutic targets for drug discovery, and are involved in many different areas including CNS disorders, cardiovascular disease, inflammatory disease, tumor and metabolic disease. This collection of reviews presents the latest findings and perspectives of G protein signaling systems. The focus is placed on the discussion of the regulation and functions of various G protein subunits. New insights into interactions between G proteins and other key players of physiological processes are also put forward to inspire further studies. Researchers in the fields of neuroscience, molecular biology and pharmacology should find this publication useful as it provides an overview of the recent progress in understanding molecular mechanisms of G protein signaling.
Book Synopsis Regulation of G Protein Signaling by GoLoco Motif Containing Proteins by : Peishen Zhao
Download or read book Regulation of G Protein Signaling by GoLoco Motif Containing Proteins written by Peishen Zhao and published by . This book was released on 2011 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: Signal transduction via heterotrimeric G proteins in response to transmembrane G protein-coupled receptors plays a central aspect in how cells integrate extracellular stimuli and produce biological responses. In addition to receptor-mediated activation of heterotrimeric G proteins, during the last few decades, accessory proteins have been found to regulate G protein activity via different mechanisms. Several proteins have been identified that contain multiple G protein regulatory domains. Using various molecular and biochemical approaches, we have characterized the effects of two such proteins, G18 and RGS14, on G protein activity. Both proteins contain a second G protein binding domain in addition to the GoLoco domain, which primarily acts as a guanine nucleotide dissociation inhibitor (GDI) on Gi/o proteins. Our results identified that the N-terminal region of G18 is a novel G protein-interacting domain, which may have distinct regulatory effects within the Gi/o subfamily and could potentially play a role in differentiating signals between these related G proteins. In addition, we characterized the tissue and cellular distribution of G18. We found that G18 is expressed in primary isolated rat aortic smooth muscle cells and endothelial cells. A protein-protein interaction assay indicated that G18 is able to directly interact with RGS5, an RGS protein that is also highly expressed in vascular tissue. This interaction results in an increase in RGS5 GTPase accelerating protein (GAP) activity with little or no effect on G18 activity. In Chapter 4 of the thesis, we identified a novel GAP enhancing domain located at the Rasbinding (RB) region of RGS14. This enhancement may be due to the intramolecular interaction between the RB domain and the RGS domain. Furthermore, this interaction may also result in an inhibitory effect on the GDI activity of the RGS14 GoLoco motif. Overall, my work suggests that GoLoco motif containing proteins G18 and RGS14 are organizers of G protein signaling that also modulate RGS protein function.
Book Synopsis Neuromorphic Olfaction by : Krishna C. Persaud
Download or read book Neuromorphic Olfaction written by Krishna C. Persaud and published by CRC Press. This book was released on 2016-04-19 with total page 237 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many advances have been made in the last decade in the understanding of the computational principles underlying olfactory system functioning. Neuromorphic Olfaction is a collaboration among European researchers who, through NEUROCHEM (Fp7-Grant Agreement Number 216916)-a challenging and innovative European-funded project-introduce novel computing p
Book Synopsis Allosteric Modulation of G Protein-Coupled Receptors by : Robert Laprairie
Download or read book Allosteric Modulation of G Protein-Coupled Receptors written by Robert Laprairie and published by Elsevier. This book was released on 2022-02-10 with total page 212 pages. Available in PDF, EPUB and Kindle. Book excerpt: Allosteric Modulation of G Protein-Coupled Receptors reviews fundamental information on G protein-coupled receptors (GPCRs) and allosteric modulation, presenting original research in the area and collectively providing a comprehensive description of key issues in GPCR allosteric modulation. The book provides background on core concepts of molecular pharmacology while also introducing the most important advances and studies in the area. It also discusses key methodologies. This is an essential book for researchers and advanced students engaged in pharmacology, toxicology and pharmaceutical sciences training and research. Many of the GPCR-targeted drugs released in the past decade have specifically worked via allosteric mechanisms. Unlike direct orthosteric-acting compounds that occupy a similar receptor site to that of endogenous ligands, allosteric modulators alter GPCR-dependent signaling at a site apart from the endogenous ligand. Recent methodological and analytical advances have greatly improved our ability to understand the signaling mechanisms of GPCRs. We now know that allostery is a common regulatory mechanism for all GPCRs and not - as we once believed - unique to a few receptor subfamilies. Introduces background on core concepts of molecular pharmacology, including statistical analyses, non-linear regression, complex models and GPCR-dependent signal transduction as they relate to allosteric modulation Discusses critical advances and landmark studies, including discoveries in the area of GPCR allosteric modulation, which are reviewed for their importance in positive and negative regulation, protein-protein interactions, and small molecule drug discovery Includes key methodologies used to study allosteric modulation at the in silico, in vitro, and in vivo levels of drug discovery and characterization
Book Synopsis Encyclopedia of Signaling Molecules by : Sangdun Choi
Download or read book Encyclopedia of Signaling Molecules written by Sangdun Choi and published by Springer. This book was released on 2017-12-15 with total page 6330 pages. Available in PDF, EPUB and Kindle. Book excerpt: The second edition of this encyclopedia presents over 400 biologically important signaling molecules and the content is built on the core concepts of their functions along with early findings written by some of the world’s foremost experts. The molecules are described by recognized leaders in each molecule. The interactions of these single molecules in signal transduction networks will also be explored. This encyclopedia marks a new era in overview of current cellular signaling molecules for the specialist and the interested non-specialist alike. Currently, there are more than 30,000 genes in human genome. However, not all the proteins encoded by these genes work equally in order to maintain homeostasis. Understanding the important signaling molecules as completely as possible will significantly improve our research-based teaching and scientific capabilities.
Book Synopsis The Functional Characterization of Two Regulators of G-protein Signaling Proteins Abundantly Expressed in Vascular Smooth Muscle Cells by : Steven Gu
Download or read book The Functional Characterization of Two Regulators of G-protein Signaling Proteins Abundantly Expressed in Vascular Smooth Muscle Cells written by Steven Gu and published by . This book was released on 2009 with total page 452 pages. Available in PDF, EPUB and Kindle. Book excerpt: Precise regulation of heterotrimeric G-protein signaling is important for maintaining proper cardiovascular system function. Indeed, G-protein signaling is frequently upregulated during cardiovascular disease suggesting that identifying mechanisms for inhibiting G-protein signaling may be an effective therapeutic strategy for the treatment and prevention of disease. The work presented in this thesis is directed at two RGS proteins, RGS2 and RGS5, the two highest expressing RGS proteins in VSMCs. Despite the large number of studies published on them, there is still much to be learned about the specific G-protein pathways that each RGS protein controls. Using genetic and molecular models, we set out to identify novel regulatory pathways controlling RGS2 and RGS5 function. We hypothesize that characterizing the determinants and regulation of RGS protein function will provide a better understanding of the signaling that occurs within VSMCs under both physiologic and pathophysiologic conditions.Finally, our last study focuses on the function and regulation of RGS5, the single highest expressing RGS protein in VSMCs. We show that the regulation of RGS5 is dependent, similar to other VSMC-specific genes, on the activity of SRF and myocardin. However, interestingly, RGS5 expression is further controlled by the extent of DNA methylation that occurs in its proximal promoter. We show that this is an important regulator of RGS5 expression both in development as well as during disease, specifically in-stent restenosis.Our work presented in the first three studies of this thesis, describes novel regulatory pathways that are involved in regulating RGS2 protein function. We describe the production of RGS2 protein isoforms that are the result of alternative translational start site usage. Interestingly, the expression pattern of these proteins is controlled by the signaling status of the cell. In the second two studies, we identify a functional consequence of RGS2-interaction with the plasma membrane. We show that this is dependent on the interaction between the amphipathic alpha-helix and anionic phospholipids present in the plasma membrane. We further show that disruptions in this interaction, as occurs in the human population, can lead to reduced RGS2 function and thus potentially hypertension.
