Table Of ContentGasotransmitters: 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
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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
