DOCSLIB.ORG

Metabolic Phenotyping of Murine Hearts Overexpressing Constitutively Active Soluble Guanylate Cyclase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Metabolic Phenotyping of Murine Hearts Overexpressing Constitutively Active Soluble Guanylate Cyclase METABOLIC PHENOTYPING OF MURINE HEARTS OVEREXPRESSING CONSTITUTIVELY ACTIVE SOLUBLE GUANYLATE CYCLASE Ramzi Khairallah Department of Experimental Medicine Faculty of Medicine McGill University, Montreal Quebec, Canada A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master’s in Science August 2007 ©Ramzi Khairallah, 2007 1 Table of Contents Table of Contents .......................................................................................................................................... 2 Abstract ......................................................................................................................................................... 5 Résumé ......................................................................................................................................................... 6 Acknowledgments ......................................................................................................................................... 7 Chapter I ‐ Introduction ................................................................................................................................ 8 Cardiac hypertrophy and its progression to failure .................................................................................. 8 Molecular pathways leading to cardiomyocyte hypertrophy ............................................................. 11 Calcineurin‐ Nuclear Factor of Activated T‐cells (NFAT) signaling .................................................. 11 PI3K/Akt/GSK‐3‐dependent signaling ............................................................................................. 12 GPCR signaling ................................................................................................................................. 14 MAPK Pathways .............................................................................................................................. 16 Antihypertrophic pathways ................................................................................................................ 17 The Nitric Oxide (NO) signaling pathway ........................................................................................ 18 The natriuretic peptide signaling pathway ..................................................................................... 19 The cGMP signaling pathway .......................................................................................................... 19 Cardiac energy metabolism .................................................................................................................... 20 Cardiac energy substrate utilization pathways and its acute regulation ............................................ 20 General overview ............................................................................................................................ 20 Carbohydrate metabolism .............................................................................................................. 21 Fatty acid metabolism ..................................................................................................................... 25 The citric acid cycle ......................................................................................................................... 27 Control of cardiac metabolic phenotype through signaling pathways ........................................... 27 Metabolic remodeling in the healthy and diseased heart .................................................................. 28 The normal metabolic switch from fetal to adult state .................................................................. 28 2 Metabolic remodeling in disease .................................................................................................... 28 Role of the NO/cGMP pathway in metabolic remodeling .................................................................. 30 Chapter II ‐ Manuscript ............................................................................................................................... 32 Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation ........................................................................................................................................... 33 Abstract ............................................................................................................................................... 34 Introduction ........................................................................................................................................ 35 Experimental Procedures .................................................................................................................... 36 Materials and animal model ........................................................................................................... 36 Working mouse heart perfusion ..................................................................................................... 36 Tissue processing ............................................................................................................................ 37 Levels and activity of factors involved in triglyceride hydrolysis .................................................... 38 Statistical Analysis ........................................................................................................................... 39 Results ................................................................................................................................................. 40 Perfused GC+/0 hearts show decreased contribution of exogenous oleate to acetyl‐CoA and enhanced glycolysis ........................................................................................................................ 40 Lack of alteration in mechanisms regulating β‐oxidation for perfused GC+/0 hearts ...................... 40 Perfused GC+/0 hearts shuttle more exogenous 13C‐labeled oleate into triglycerides .................... 41 GC+/0 hearts exhibit alterations in factors influencing triglyceride lipolysis ................................... 41 GC+/0hearts are resistant to fasting‐induced triglyceride accumulation ......................................... 41 Discussion............................................................................................................................................ 43 Acknowledgements ............................................................................................................................. 46 Figure Legends .................................................................................................................................... 50 References .......................................................................................................................................... 52 Methodological Considerations .............................................................................................................. 62 Working heart perfusion system ........................................................................................................ 62 3 Measurements of myocardial triglyceride turnover and lipolysis ...................................................... 64 Conceptual considerations ..................................................................................................................... 65 The mitochondrial permeability transition pore (MPTP) and PKCε .................................................... 66 Other mechanisms ‐ potential involvement of calcium, calcineurin‐NFAT, lipotoxicity and MAPK signalling ............................................................................................................................................. 67 Broader relevance of this study and clinical perspectives ...................................................................... 69 Conclusion and future perspectives ........................................................................................................... 71 Reference .................................................................................................................................................... 72 4 Abstract Although enhanced cGMP signaling can prevent hypertrophy, mechanisms underlying this cardioprotective effect are not well understood. In this study, we assessed the potential involvement of alterations in myocardial energy substrate metabolism, a parameter known to be determinant in the development of hypertrophy. We used mice overexpressing a constitutively active soluble guanylate cyclase in a cardiomyocyte‐specific manner (GC+/0) and ex vivo heart perfusion at physiological workload with 13C‐labeled substrates. Compared to controls, hearts from GC+/0 mice displayed a 38±9% lower contribution of exogenous fatty acids to acetyl‐CoA formation, while that of carbohydrates remained unchanged despite a two‐fold increase in glycolysis. The lower contribution of exogenous fatty acids to energy production was not associated with changes in energy demand or supply (contractile function, oxygen consumption, tissue acetyl‐CoA or CoA levels, citric acid cycle flux rate) or the regulation of β‐ oxidation (acetyl‐CoA carboxylase activity, tissue malonyl‐CoA levels). However, GC+/0 hearts showed a two‐fold increase in the incorporation of exogenous oleate into triglycerides. Furthermore, a concomitant increase in triglyceride hydrolysis
Load more

Recommended publications
  • Identi®Cation and Role of Adenylyl Cyclase in Auxin Signalling in Higher
    letters to nature + + + P.P. thank the Academy of Finland and the Deutsche Forschungsgemeinschaft, respectively, for ®nancial CO , 53), 77 (C6H5 , 60), 73 (TMSi , 84); 6-methyl-4-hydroxy-2-pyrone: RRt 0.35, 198 (M+, 18), 183 ([M-Me]+, 16), 170 ([M-CO]+, 54), 155 ([M-CO-Me]+, support. + + Correspondence and requests for materials should be addressed to J.S. (e-mail: [email protected] 15), 139 ([M-Me-CO2] , 10), 127 ([M-Me-2CO] , 13), 99 (12), 84 (13), 73 + + freiburg.de). (TMSi , 100), 43 (CH3CO , 55). The numbers show m/z values, and the key fragments and their relative intensities are indicated in parentheses. Received 4 August; accepted 14 October 1998. erratum 1. Helariutta, Y. et al. Chalcone synthase-like genes active during corolla development are differentially expressed and encode enzymes with different catalytic properties in Gerbera hybrida (Asteraceae). Plant Mol. Biol. 28, 47±60 (1995). 2. Helariutta, Y. et al. Duplication and functional divergence in the chalcone synthase gene family of 8 Asteraceae: evolution with substrate change and catalytic simpli®cation. Proc. Natl Acad. Sci. USA 93, Crystal structure of the complex 9033±9038 (1996). 3. Thaisrivongs, S. et al. Structure-based design of HIV protease inhibitors: 5,6-dihydro-4-hydroxy-2- of the cyclin D-dependent pyrones as effective, nonpeptidic inhibitors. J. Med. Chem. 39, 4630±4642 (1996). 4. Hagen, S. E. et al. Synthesis of 5,6-dihydro-4-hydroxy-2-pyrones as HIV-1 protease inhibitors: the kinase Cdk6 bound to the profound effect of polarity on antiviral activity. J. Med. Chem.
    [Show full text]
  • Soluble Guanylate Cyclase and Cgmp-Dependent Protein Kinase I Expression in the Human Corpus Cavernosum
    International Journal of Impotence Research (2000) 12, 157±164 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum T Klotz1*, W Bloch2, J Zimmermann1, P Ruth3, U Engelmann1 and K Addicks2 1Department of Urology, University of Cologne; 2Institute I of Anatomy, University of Cologne; and 3Institute of Pharmacology, TU University of Munich, Germany Nitric oxide (NO) as a mediator in smooth muscle cells causes rapid and robust increases in cGMP levels. The cGMP-dependent protein kinase I has emerged as an important signal transduction mediator for smooth muscle relaxation. The purpose of this study was to examine the existence and distribution of two key enzymes of the NO=cGMP pathway, the cGMP-dependent kinase I (cGK I) and the soluble guanylate cyclase (sGC) in human cavernosal tissue. The expression of the enzymes were examined in corpus cavernosum specimens of 23 patients. Eleven potent patients suffered from penile deviations and were treated via Nesbit's surgical method. Nine long-term impotent patients underwent implantation of ¯exible hydraulic prothesis. Three potent patients underwent trans-sexual operations. Expression of the sGC and cGK I were examined immunohistochemically using speci®c antibodies. In all specimens of cavernosal tissue a distinct immunoreactivity was observed in different parts and structures. We found a high expression of sGC and cGK I in smooth muscle cells of vessels and in the ®bromuscular stroma. The endothelium of the cavernosal sinus, of the cavernosal arteries, and the cavernosal nerve ®bers showed an immunoreactivity against sGC.
    [Show full text]
  • Soluble Guanylate Cyclase B1-Subunit Expression Is Increased in Mononuclear Cells from Patients with Erectile Dysfunction
    International Journal of Impotence Research (2006) 18, 432–437 & 2006 Nature Publishing Group All rights reserved 0955-9930/06 $30.00 www.nature.com/ijir ORIGINAL ARTICLE Soluble guanylate cyclase b1-subunit expression is increased in mononuclear cells from patients with erectile dysfunction PJ Mateos-Ca´ceres1, J Garcia-Cardoso2, L Lapuente1, JJ Zamorano-Leo´n1, D Sacrista´n1, TP de Prada1, J Calahorra2, C Macaya1, R Vela-Navarrete2 and AJ Lo´pez-Farre´1 1Cardiovascular Research Unit, Cardiovascular Institute, Hospital Clı´nico San Carlos, Madrid, Spain and 2Urology Department, Fundacio´n Jime´nez Diaz, Madrid, Spain The aim was to determine in circulating mononuclear cells from patients with erectile dysfunction (ED), the level of expression of endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC) b1-subunit and phosphodiesterase type-V (PDE-V). Peripheral mononuclear cells from nine patients with ED of vascular origin and nine patients with ED of neurological origin were obtained. Fourteen age-matched volunteers with normal erectile function were used as control. Reduction in eNOS protein was observed in the mononuclear cells from patients with ED of vascular origin but not in those from neurological origin. Although sGC b1-subunit expression was increased in mononuclear cells from patients with ED, the sGC activity was reduced. However, only the patients with ED of vascular origin showed an increased expression of PDE-V. This work shows for the first time that, independently of the aetiology of ED, the expression of sGC b1-subunit was increased in circulating mononuclear cells; however, the expression of both eNOS and PDE-V was only modified in the circulating mononuclear cells from patients with ED of vascular origin.
    [Show full text]
  • Looking for New Classes of Bronchodilators
    REVIEW BRONCHODILATORS The future of bronchodilation: looking for new classes of bronchodilators Mario Cazzola1, Paola Rogliani 1 and Maria Gabriella Matera2 Affiliations: 1Dept of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. 2Dept of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy. Correspondence: Mario Cazzola, Dept of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy. E-mail: [email protected] @ERSpublications There is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39 Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators. Eur Respir Rev 2019; 28: 190095 [https://doi.org/10.1183/16000617.0095-2019]. ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.
    [Show full text]
  • Nitric Oxide Activates Guanylate Cyclase and Increases Guanosine 3':5'
    Proc. Natl. Acad. Sci. USA Vol. 74, No. 8, pp. 3203-3207, August 1977 Biochemistry Nitric oxide activates guanylate cyclase and increases guanosine 3':5'-cyclic monophosphate levels in various tissue preparations (nitro compounds/adenosine 3':5'-cyclic monophosphate/sodium nitroprusside/sodium azide/nitrogen oxides) WILLIAM P. ARNOLD, CHANDRA K. MITTAL, SHOJI KATSUKI, AND FERID MURAD Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, and Anesthesiology, University of Virginia, Charlottesville, Virginia 22903 Communicated by Alfred Gilman, May 16, 1977 ABSTRACT Nitric oxide gas (NO) increased guanylate cy- tigation of this activation. NO activated all crude and partially clase [GTP pyrophosphate-yase (cyclizing), EC 4.6.1.21 activity purified guanylate cyclase preparations examined. It also in- in soluble and particulate preparations from various tissues. The effect was dose-dependent and was observed with all tissue creased cyclic GMP but not adenosine 3':5'-cyclic monophos- preparations examined. The extent of activation was variable phate (cyclic AMP) levels in incubations of minces from various among different tissue preparations and was greatest (19- to rat tissues. 33-fold) with supernatant fractions of homogenates from liver, lung, tracheal smooth muscle, heart, kidney, cerebral cortex, and MATERIALS AND METHODS cerebellum. Smaller effects (5- to 14-fold) were observed with supernatant fractions from skeletal muscle, spleen, intestinal Male Sprague-Dawley rats weighing 150-250 g were decapi- muscle, adrenal, and epididymal fat. Activation was also ob- tated. Tissues were rapidly removed, placed in cold 0.-25 M served with partially purified preparations of guanylate cyclase. sucrose/10 mM Tris-HCl buffer (pH 7.6), and homogenized Activation of rat liver supernatant preparations was augmented in nine volumes of this solution by using a glass homogenizer slightly with reducing agents, decreased with some oxidizing and Teflon pestle at 2-4°.
    [Show full text]
  • A Nitric Oxide/Cysteine Interaction Mediates the Activation of Soluble Guanylate Cyclase
    A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase Nathaniel B. Fernhoffa,1, Emily R. Derbyshirea,1,2, and Michael A. Marlettaa,b,c,3 Departments of aMolecular and Cell Biology and bChemistry, University of California, Berkeley, CA 94720; and cCalifornia Institute for Quantitative Biosciences and Division of Physical Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Contributed by Michael A. Marletta, October 1, 2009 (sent for review August 22, 2009) Nitric oxide (NO) regulates a number of essential physiological pro- high activity of the xsNO state rapidly reverts to the low activity of cesses by activating soluble guanylate cyclase (sGC) to produce the the 1-NO state. Thus, all three sGC states (basal, 1-NO, and xsNO) second messenger cGMP. The mechanism of NO sensing was previ- can be prepared and studied in vitro (7, 8). Importantly, these ously thought to result exclusively from NO binding to the sGC heme; results define two different states of purified sGC with heme bound however, recent studies indicate that heme-bound NO only partially NO (7, 8), one with a high activity and one with a low activity. activates sGC and additional NO is involved in the mechanism of Further evidence for a non-heme NO binding site was obtained maximal NO activation. Furthermore, thiol oxidation of sGC cysteines by blocking the heme site with the tight-binding ligand butyl results in the loss of enzyme activity. Herein the role of cysteines in isocyanide, and then showing that NO still activated the enzyme NO-stimulated sGC activity investigated. We find that the thiol mod- (14).
    [Show full text]
  • Biosignaling-2014.Pdf
    Biosignaling Principals of Biochemistry, Lehninger, Chap 12 CBIO7100 Su Dharmawardhane [email protected] Lecture Outline } Introduction: Importance of cell signaling to periodontal disease } Principals of signal transduction, adaptors } G protein coupled receptors, Chemokine receptors } Receptor tyrosine kinases } Inflammatory signaling: Toll like receptor signaling and the role of NfκB in periodontitis } Receptor guanylyl kinases } Hormone receptors INTRODUCTION } Why do I have to learn about signaling? I am going to be a dentist Signaling is central to teeth development and decay. Signaling is important in periodontal disease. Periodontal Disease (Gum Disease) } Periodontal disease is inflammation and infection that destroys the tissues that support the teeth, including the gums, the periodontal ligaments, and the tooth sockets (alveolar bone). } Gingivitis: inflammation of the gums due to bacteria. Signaling molecules produced by bacteria activate receptors on periodontal cells to ultimately destroy periodontal tissue. } Although periodontal disease is initiated by bacteria that colonize the tooth surface and ginigva, the host signaling response is essential for breakdown of bone and connective tissue: Osteoclastogenesis and bone resorption. } Periodontal infection requires expression of a number of signaling molecules: proinflammatory and antiinflammatory cytokines, growth factors, etc. Cell signaling in periodontal disease u de Souza, et al. 2012. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease. Appl. Oral Sci. 20:128-138. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage periodontal disease. u Kirkwood, et al., Novel host response therapeutic approaches to treat periodontal diseases. Periodontol 2000. 2007 ; 43: 294–315. Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens.
    [Show full text]
  • New Insights Into the Role of Soluble Guanylate Cyclase in Blood Pressure Regulation
    New insights into the role of soluble guanylate cyclase in blood pressure regulation The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Buys, Emmanuel, and Patrick Sips. 2014. New Insights into the Role of Soluble Guanylate Cyclase in Blood Pressure Regulation. Current Opinion in Nephrology and Hypertension 23, no. 2: 135–142. doi:10.1097/01.mnh.0000441048.91041.3a. Published Version doi:10.1097/01.mnh.0000441048.91041.3a Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:29731915 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA NIH Public Access Author Manuscript Curr Opin Nephrol Hypertens. Author manuscript; available in PMC 2015 March 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Curr Opin Nephrol Hypertens. 2014 March ; 23(2): 135–142. doi:10.1097/01.mnh.0000441048.91041.3a. New Insights into the Role of Soluble Guanylate Cyclase in Blood Pressure Regulation Emmanuel Buys1 and Patrick Sips2 1Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Abstract Purpose of review—Nitric oxide (NO) – soluble guanylate cyclase (sGC)-dependent signaling mechanisms have a profound effect on the regulation of blood pressure.
    [Show full text]
  • Non-Canonical Chemical Feedback Self-Limits Nitric Oxide-Cyclic GMP Signaling in Health and Disease Vu Thao-Vi Dao1,2,9, Mahmoud H
    www.nature.com/scientificreports OPEN Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease Vu Thao-Vi Dao1,2,9, Mahmoud H. Elbatreek1,3,9 ✉ , Martin Deile4, Pavel I. Nedvetsky5, Andreas Güldner6, César Ibarra-Alvarado7, Axel Gödecke8 & Harald H. H. W. Schmidt1 ✉ Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This efect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP- dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in- vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation. Te nitric oxide (NO)-cGMP signaling pathway plays several essential roles in physiology, including cardio- pulmonary homeostasis1,2.
    [Show full text]
  • Identification of the Molecular Basis of Anti-Fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast
    https://www.scientificarchives.com/journal/archives-of-proteomics-and-bioinformatics Archives of Proteomics and Bioinformatics Research Article Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast Sunhwa Kim1*, Ashmita Saigal1, Weilong Zhao2, Peyvand Amini1, Alex M. Tamburino3, Subharekha Raghavan4, Maarten Hoek5# 1Cardiometabolic Disease Biology-Discovery, Merck & Co., Inc., South San Francisco, CA, USA 2Scientific informatics, Merck & Co., Inc., South San Francisco, CA, USA 3Discovery pGx, Merck & Co., Inc., West Point, PA, USA 4Chemistry Capabilities Accelerate Therapeutics, Merck & Co., Inc., Kenilworth, NJ, USA 5Cardiovascular, Metabolic, Renal, Ophthalmology Biology-Discovery, Merck & Co., Inc., South San Francisco, CA, USA #Present Address: Maze Therapeutics, South San Francisco, CA USA *Correspondence should be addressed to Sunhwa Kim; [email protected] Received date: September 09, 2020, Accepted date: November 11, 2020 Copyright: © 2020 Kim S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fibrotic lung disease. Advanced IPF patients often demonstrate pulmonary hypertension, which severely impairs patients’ quality of life. The critical physiological roles of soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway have been well characterized in vasodilation and the corresponding therapies and pathway agonists have shown clinical benefits in treating hypertension. In recent years, many preclinical studies have demonstrated anti-fibrotic efficacy of sGC-cGMP activation in various experimental fibrosis models but the molecular basis of the efficacy in these models are not well understood.
    [Show full text]
  • Receptor Guanylyl Cyclases
    Receptor guanylyl cyclases. S K Wong, D L Garbers J Clin Invest. 1992;90(2):299-305. https://doi.org/10.1172/JCI115862. Research Article Three different guanylyl cyclase cell receptors are known, but others will likely be discovered within the next few years. The general function of these receptors appear to relate to the regulation of fluid volume or fluid movement. New receptors, or possibly the currently known receptors, therefore, may be discovered in areas of the body where fluid volume regulation is important. Such fluids whose volume or composition might be regulated by guanylyl cyclase receptors include synovial fluid, uterine/oviductal luminal fluid, follicular fluid, aqueous humor, cerebral spinal fluid, seminiferous tubule luminal fluid, epididymal luminal fluid, seminal plasma, and airway luminal fluid. The function of the heterodimeric forms of guanylyl cyclase appear to relate to a primary regulation of nitric oxide (or similar molecules) concentrations, which are in turn regulated by a Ca2+/calmodulin-sensitive nitric oxide synthase. Find the latest version: https://jci.me/115862/pdf Perspectives Receptor Guanylyl Cyclases Stephen K.-F. Wong and David L. Garbers Department ofPharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235 Introduction it therefore remains possible that these forms will closely resem- Cyclic GMP is an intracellular signaling molecule that regu- ble known plasma membrane receptor forms. lates ion channels, cyclic AMP concentrations by virtue of its The second major group of guanylyl cyclases appears to effects on selective phosphodiesterases, and protein kinases to exist as heterodimers containing heme as a prosthetic group alter cellular processes and behavior.
    [Show full text]
  • Moonlighting Proteins Shine New Light on Molecular Signaling Niches
    International Journal of Molecular Sciences Review Moonlighting Proteins Shine New Light on Molecular Signaling Niches Ilona Turek and Helen Irving * Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; [email protected] * Correspondence: [email protected] Abstract: Plants as sessile organisms face daily environmental challenges and have developed highly nuanced signaling systems to enable suitable growth, development, defense, or stalling responses. Moonlighting proteins have multiple tasks and contribute to cellular signaling cascades where they produce additional variables adding to the complexity or fuzziness of biological systems. Here we examine roles of moonlighting kinases that also generate 30,50-cyclic guanosine monophosphate (cGMP) in plants. These proteins include receptor like kinases and lipid kinases. Their guanylate cyclase activity potentiates the development of localized cGMP-enriched nanodomains or niches surrounding the kinase and its interactome. These nanodomains contribute to allosteric regulation of kinase and other molecules in the immediate complex directly or indirectly modulating signal cas- cades. Effects include downregulation of kinase activity, modulation of other members of the protein complexes such as cyclic nucleotide gated channels and potential triggering of cGMP-dependent degradation cascades terminating signaling. The additional layers of information provided by the moonlighting kinases are discussed in terms of how they may be used to provide a layer of fuzziness to effectively modulate cellular signaling cascades. Keywords: guanylate cyclase; receptor like kinase; brassinosteroid insensitive 1 (BRI1); phytosul- Citation: Turek, I.; Irving, H. fokine receptor 1 (PSKR1); danger associated peptide receptor (PEPR1 and PEPR2); wall associated Moonlighting Proteins Shine New kinase like 10 (WAKL10); nanodomains; moonlighting proteins; cryptic enzyme; 30,50-cyclic guano- Light on Molecular Signaling Niches.
    [Show full text]