Gasotransmitters: Physiology and Pathophysiology Anton Hermann Guzel F. Sitdikova • Thomas M. Weiger Editors Gasotransmitters: Physiology and Pathophysiology 123 Editors Prof.Dr. AntonHermann A.o.Prof. Dr.ThomasM. Weiger Department of Cell Biology Department of Cell Biology Division ofCellular and Molecular Division ofCellular and Molecular Neurobiology Neurobiology Universityof Salzburg Universityof Salzburg Salzburg Salzburg Austria Austria Prof.Dr. GuzelF. Sitdikova Department of Humanand Animal Physiology Kazan Federal University Kazan Russia ISBN 978-3-642-30337-1 ISBN 978-3-642-30338-8 (eBook) DOI 10.1007/978-3-642-30338-8 SpringerHeidelbergNewYorkDordrechtLondon LibraryofCongressControlNumber:2012941637 (cid:2)Springer-VerlagBerlinHeidelberg2012 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionor informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purposeofbeingenteredandexecutedonacomputersystem,forexclusiveusebythepurchaserofthe work. 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Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Preface FromancientGreekphilosopherstheideaevolvedthatan‘‘animalicspirit’’called ‘‘pneuma’’pervades throughourbodyacting primarilyatthebrain,theheart,and theliver.Asavitalforceitallowedthevariouspartsofthebodytocommunicate with each other. This idea survived several 100 years—longer than most of our present hypothesis. It came as a great surprise to the scientific community when researchers discovered that poisonous gases, endogenously produced by a great variety of living organisms from bacteria to men, exert important intra- and intercellular tasks—kind of reviving the pneuma idea. Since the epochal discovery of the radical nitric oxide (NO) as gaseous signaling molecule two other gases—carbon monoxide(CO)andhydrogensulfide(H S)—havebeenfoundtobealsoinvolved 2 inaplethora ofphysiologicalandpathophysiological functions.Thegases,now a family of at least three, have been termed ‘‘gasotransmitters’’. A definition of moleculestobeclassifiedasgasotransmittersisgivenbyUntereineretal.intheir chapter. The mostprominent features that characterize the gases and discriminate them from classical transmitters are their amphiphilicchemical nature that allows them to diffuse in the cytosol as well as through lipid membranes which prevents them from being stored in vesicles. The gases, because of their small size and hencehighdiffusionratecan,immediatelyaftertheyarereleased,actinautocrine orparacrinefashionandincontrasttotheclassicaltransmittersarenotlocalizedto specific synaptic sites. Since the gases may affect many cells in their vicinity this function has been called ‘‘volumesignalling’’.Of course, thiskind ofsignaling is not as punctual in targeting postsynaptic cells as it is the case with classical synaptic transmission and its action is highly dependent on the concentration gradientwithinthetissue.Volumesignalingisparticularlyinterestinginthebrain wherethousandsormillionsofsynapticcontactsmaybeaffected.Theimplication of such signals on nervous function and information processing in the central nervous system, however, remains to be investigated in detail. In experiments using knockout animals it could be shown for all gasotrans- mitters that after elimination of appropriate enzymes the gases are no longer produced and the expected pathophysiological modifications developed, v vi Preface i.e., metabolic or erectile dysfunctions, or high blood pressure. Since the book on ‘‘SignalTransductionandtheGasotransmitters:NO,CO,andH SinBiologyand 2 Medicine‘‘,hasbeenissuedbyRuiWang(2004)animpressiveamountofdatahas been collected and a great wealth of further information is distributed in the literature. We have asked distinguished colleagues in the field to summarize and review important biological, pharmacological, and medical functions on gaso- transmitters and their implications. The authors were asked in particular to criti- cally review the literature from their point of view and to ask questions and even speculate on new vistas. Ulrich Förstermann and Huige Li in their chapter ‘‘Nitric Oxide: Biological Synthesis and Functions’’ summarize principles of NO biosynthesis, regulatory mechanisms, and a large array of physiological and pathophysiological functions. NO, due to its highly reactive chemical nature, is also capable of destroying parasites andtumor cells; however,inhigh concentrations itexhibits aJanus face contributing to processes such as neurodegeneration, inflammation, and tissue damage. Ashley Untereiner et al. describe in their chapter ‘‘The role of CO as a gaso- transmitter in cardiovascular and metabolic regulation’’ the production, physio- logical functions, such as in proliferation and apoptosis, pathophysiological actions of CO, as in diabetes, vascular diseases, hypertension, atherosclerosis, or myocardial infarction. In their final sections they summarize cellular and molec- ular mechanisms of CO effects including ion channel and receptor signaling and discuss the interaction of CO with other gases. Hideo Kimura in his chapter on ‘‘Physiological and pathophysiological func- tions of hydrogen sulfide’’, after introducing some basic properties and the amphipathic chemistry of H S, its free and bound conditions, describes some 2 detection methods and the endogenous enzymatic production of the gas. Furthermore,physiologicalfunctions,suchassynapticmodulationinthebrainand in the retina, in smooth muscle relaxation, its cytoprotective and pathophysio- logicalrolesinparticularinethylmalonicencephalopathy,inDown’ssyndromeor in vascular dysfunctions, and some therapeutic implications are covered. In the chapter by Hanjing Peng et al. on ‘‘Methods for detection of gaso- transmitters’’ a great deal of chemical and technical details are summarized. Various new techniques and chemoprobes for measuring all three gases, their applicability to biological systems, and their advantages and limitations are discussed. Electrochemical measurements appear most sensitive and allow for determination of temporal concentration changes, whereas fluorescent probes are favorable for spatial monitoring in living cells. Guzel Sitdikova and Andrey Zefirov specialized in their chapter ‘‘Gasotrans- mitters on the regulation of neuromuscular transmission’’. All three gases are produced in the central nervous system in response to neural excitation and modulate neurotransmitter release and are involved in the regulation of synaptic plasticityaffectingpre-orpostsynapticsitesbydifferentmechanisms.Theauthors summarize the literature and present own data concerning the effects and Preface vii mechanismsofthetransmittergasesintheperipheralnervoussystemfocusingon neuromuscular synapses. Finally,AntonHermannetal.focuson‘‘Ca2+activatedBKchannelmodulation by gasotransmitters’’. These ion channels, which are present in a large variety of cellsandorgans,areprominenttargetsofthegases.Thestructureandfunctionsof these channels and their pharmacology and posttranslational modifications are described. BK channel modulation through gasotransmitters and their implication for physiology and pathophysiology are highlighted. The advent of gasotransmitters has profoundly changed our way of thinking about biosynthesis, liberation, storage, and action mechanisms by cellular signaling. The gases will certainly play an increasingly important role to under- standhowcellularsignalingismodulatedandfine-tuned,particularlyinthebrain. TheinvestigationoftheinteractionofNO,CO,andH Sisstillatitsinfancy!More 2 knowledge is needed concerning the metabolic products of gasotransmitters, in particular of NO and H S, and the functions of some related molecules, such as 2 nitrosoniumcation(NO+),whichisisoelectronicwithCOorthehyponitriteanion (NO-). Future studies will have to probe into further details of their physiology, pathophysiology, and pharmacology. The development of drugs containing specific active ingredients with little or no side effects to manipulate the ana-/ metabolism of gasotransmitters or their targets could be of an interesting and probably fruitful pharmacological task. Anton Hermann Guzel Sitdikova Thomas Weiger Contents 1 Nitric Oxide: Biological Synthesis and Functions. . . . . . . . . . . . . . 1 Ulrich Förstermann and Huige Li 2 The Role of Carbon Monoxide as a Gasotransmitter in Cardiovascular and Metabolic Regulation. . . . . . . . . . . . . . . . . 37 Ashley A. Untereiner, Lingyun Wu and Rui Wang 3 Physiological and Pathophysiological Functions of Hydrogen Sulfide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Hideo Kimura 4 Methods for the Detection of Gasotransmitters . . . . . . . . . . . . . . . 99 Hanjing Peng, Weixuan Chen and Binghe Wang 5 Gasotransmitters in Regulation of Neuromuscular Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Guzel F. Sitdikova and Andrey L. Zefirov 6 Modulated by Gasotransmitters: BK Channels . . . . . . . . . . . . . . . 163 Anton Hermann, Guzel F. Sitdikova and Thomas M. Weiger Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 ix Chapter 1 Nitric Oxide: Biological Synthesis and Functions Ulrich Förstermann and Huige Li Abstract Thepluripotentgaseousmessengermoleculenitricoxide(NO)controls vital functions such as neurotransmission or vascular tone (via activation of sol- ubleguanylylcyclase),genetranscription,mRNAtranslation(viairon-responsive elements),andpost-translationalmodificationsofproteins(viaADP-ribosylation). Inhigherconcentrations,NOiscapableofdestroyingparasitesandtumorcellsby inhibiting iron-containing enzymes or directly interacting with the DNA of these cells.InviewofthismultitudeoffunctionsofNO,itisimportanttounderstandthe mechanisms by which cells accomplish and regulate the production of this molecule. In mammals, three isozymes of NO synthase (NOS; L-arginine, NADPH:oxygenoxidoreductases,nitric oxideforming;EC1.14.13.39)havebeen identified. These isoforms are referred to as neuronal ‘‘n’’NOS (or NOS I), inducible ‘‘i’’NOS (or NOS II), and endothelial ‘‘e’’NOS (or NOS III). In patho- physiology, massive amounts of NO produced by hyperactive nNOS or highly expressed iNOS can contribute to processes such as neurodegeneration, inflam- mation, and tissue damage. This chapter will describe principles of NO biosyn- thesis,regulatorymechanismscontrollingtheproductionofthismolecule,andthe largearrayof(physiologicandpathophysiologic)functionsthatMotherNaturehas assigned to this small messenger molecule. Keywords (6R)-5,6,7,8-tetrahydrobiopterin(cid:2)Glutathione(cid:2)L-arginine(cid:2)Asymmetric dimethyl-L-arginine(cid:2)NADPHoxidase(cid:2)Peroxynitrite U.Förstermann(&)(cid:2)H.Li DepartmentofPharmacology,JohannesGutenbergUniversityMedicalCenter, ObereZahlbacherStrasse67,55101Mainz,Germany e-mail:[email protected] A.Hermannetal.(eds.),Gasotransmitters:PhysiologyandPathophysiology, 1 DOI:10.1007/978-3-642-30338-8_1,(cid:2)Springer-VerlagBerlinHeidelberg2012 2 U.FörstermannandH.Li Abbreviations AMP Adenosine monophosphate ADMA Asymmetric dimethyl-L-arginine ADP Adenosine diphosphate Ala Alanine Akt Serine/threonine kinase (= protein kinase B) AMPK AMP-activated protein kinase Asp Aspartate AVE9488 4-fluoro-N-indan-2-yl-benzamide (eNOS expression enhancer) BH Quinonoid 6,7-[8H]-H -biopterin 2 2 BH . Trihydrobiopterin radical 3 BH .H+ Trihydropterin radical cation protonated at N5 3 BH (6R)-5,6,7,8-tetrahydro-L-biopterin 4 CAPON Carboxy-terminal PDZ ligand of nNOS CaM Calmodulin CaMK Ca2+/Calmodulin-dependent protein kinase cyclic GMP Cyclic guanosine monophosphate DDAH Dimethylarginine dimethylaminohydrolase Dexras1 A small monomeric G protein found predominantly in brain eNOS Endothelial nitric oxide synthase FAD Flavin adenine dinucleotide FMN Flavin mononucleotide GLGF Glycine, leucine, glycine, phenylalanine motif H O Hydrogen peroxide 2 2 hsp90 Heat shock protein 90 hsp70 Heat shock protein 70 iNOS Inducible nitric oxide synthase LLC-PK Porcine kidney tubular epithelial cells 1 L-NMMA NG-monomethyl-L-arginine LPS Bacterial lipopolysaccharide mRNA Messenger ribonucleic acid NAP110 NOS-associated protein 110 kDa NADPH Reduced nicotinamide adenine dinucleotide phosphate NMDA N-methyl-D-aspartate nNOS Neuronal nitric oxide synthase NO Nitric oxide NOS Nitric oxide synthase NOSIP Nitric oxide synthase interacting protein O-. Superoxide anion 2 ONOO- Peroxynitrite PARP Poly(ADP-ribose)polymerase PDZ Postsynapticdensityprotein95/discslarge/ZO-1homologydomain PIN Protein inhibitor of nNOS PFK-M Phosphofructokinase (muscle type) 1 NitricOxide:BiologicalSynthesisandFunctions 3 PKA Protein kinase A PKC Protein kinase C PRMT Protein arginine N-methyltransferase Ser Serine SMTC S-methyl-L-thiocitrulline (inhibitor of nNOS) ROS Reactive oxygen species Thr Threonine Tyr Tyrosine VEGF Vascular endothelial growth factor 1.1 Introduction Nitric oxide (NO) is a gaseous messenger molecule, that controls servoregulatory functionssuchasneurotransmission(O’Delletal.1991;SchumanandMadison1991)or vasculartone(Rapoportetal.1983;Förstermannetal.1986)(bystimulatingNOsensitive guanylylcyclase),regulatesgenetranscription(Khanetal.1996;Gudietal.1999)and mRNAtranslation(forexamplebybindingtoiron-responsiveelements)(Pantopoulos and Hentze 1995; Liu et al. 2002), and produces post-translational modifications of proteins(forexamplebyADP-ribosylation)(Pozdnyakovetal.1993;Bruneetal.1994). AnimportantmodeofinactivationofNOisitsreactionwithsuperoxideanion(O-.)to 2 form the potent oxidant peroxynitrite (ONOO-). This compound can cause oxidative damage, nitration, and S-nitrosylation of biomolecules including proteins, lipids, and DNA(MikkelsenandWardman2003;Leeetal.2003).NitrosativestressbyONOO-has been implicated in DNA single strand breakage, followed by poly(ADP-ribose) polymerase(PARP)activation(Ridnouretal.2004).NOsynthases(NOS;L-arginine, NADPH: oxygen oxidoreductases, nitric oxide forming; EC 1.14.13.39) are phyloge- neticallyoldenzymesandexistinorganismsaslowasnematodes,protozoa,andevenin plants.Threedifferentmammalianisoformsoftheenzymehavebeenidentified:neuronal ‘‘n’’NOS(orNOS I),inducible‘‘i’’NOS(orNOS II),andendothelial‘‘e’’NOS(orNOS III)(Förstermannetal.1994;FörstermannandSessa2011;Fig. 1.1). 1.2 Three Mammalian Isoforms of NOS 1.2.1 Basic Characteristics of the Three Isozymes nNOSisalowoutputenzyme thatisconstitutively expressedinneuronsandsome othercelltypes.iNOSisahighoutputenzymewhoseexpressioncanbeinducedby cytokinesandotheragentsinalmostanycelltype.ItsactivityislargelyCa2+-inde- pendent. eNOS is also a low output enzyme that is constitutively expressed in