Adenosine Receptors in Neurology and Psychiatry,

503 Pages·2014·5.956 MB·English

by  Mori, Akihisa

INTERNATIONAL
REVIEW OF
NEUROBIOLOGY
VOLUME119
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King's College, London, UK
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CONTRIBUTORS
Jiang-FanChen
DepartmentofNeurology,BostonUniversitySchoolofMedicine,Boston,Massachusetts,
USA,andTheMolecularMedicineInstitute,WenzhouMedicalUniversity,Wenzhou,
Zhejiang,PRChina
YijuangChern
DivisionofNeuroscience,InstituteofBiomedicalSciences,AcademiaSinica,Taipei,
Taiwan
RodrigoA.Cunha
CNC-CenterforNeuroscienceandCellBiology,andFacultyofMedicine,Universityof
Coimbra,Coimbra,Portugal
The´re`seDiPaolo
NeuroscienceResearchUnit,CentrederechercheduCHUdeQue´bec,andFacultyof
Pharmacy,LavalUniversity,Quebec,Quebec,Canada
Zhi-LiHuang
DepartmentofPharmacology,StateKeyLaboratoryofMedicalNeurobiology,Instituteof
BrainScience,ShanghaiMedicalCollegeofFudanUniversity,Shanghai,China
KiichIshiwata
ResearchTeamforNeuroimaging,TokyoMetropolitanInstituteofGerontology,Tokyo,
Japan
PeterJenner
NeurodegenerativeDiseasesResearchGroup,InstituteofPharmaceuticalSciences,School
ofBiomedicalSciences,King’sCollege,London,UnitedKingdom
TakakoKadowaki-Horita
CentralNervousSystemResearchLaboratories,Research&DevelopmentDivision,Kyowa
HakkoKirinCo.,Ltd.,Sunto-gun,Shizuoka,Japan
TomoyukiKanda
CentralNervousSystemResearchLaboratories,Research&DevelopmentDivision,Kyowa
HakkoKirinCo.,Ltd.,Sunto-gun,Shizuoka,Japan
MasahitoKawamura
DepartmentofPharmacology,JikeiUniversitySchoolofMedicine,Minato-ku,Tokyo,
Japan
MinoruKobayashi
CentralNervousSystemResearchLaboratories,CNSR&DUnit,R&DDivision,Kyowa
HakkoKirinCo.,Ltd.,Shizuoka,Japan
xi
xii Contributors
DiogoR.Lara
Laborato´riodeNeuroqu´ımicaePsicofarmacologia,DepartamentodeBiologiaCelulare
Molecular,FaculdadedeBiocieˆncias,Pontif´ıciaUniversidadeCato´licadoRioGrandedo
Sul,PortoAlegre,Brazil
Chien-feiLee
DivisionofNeuroscience,InstituteofBiomedicalSciences,AcademiaSinica,Taipei,
Taiwan
SusanA.Masino
DepartmentofPsychologyandNeuroscienceProgram,TrinityCollege,Hartford,
Connecticut,USA
AlessiaMelani
DepartmentofNeuroscience,Psychology,DrugResearchandChildHealth
(NEUROFARBA),DivisionofPharmacologyandToxicology,UniversityofFlorence,
50139Florence,Italy
MasahiroMishina
DepartmentofNeurologicalScience,GraduateSchoolofMedicine,NipponMedical
School,andResearchTeamforNeuroimaging,TokyoMetropolitanInstituteof
Gerontology,Tokyo,Japan
AkihisaMori
StrategicProductPortfolioDepartment,KyowaHakkoKirinCo.,Ltd.,Tokyo,Japan
NicolasMorin
NeuroscienceResearchUnit,CentrederechercheduCHUdeQue´bec,andFacultyof
Pharmacy,LavalUniversity,Quebec,Quebec,Canada
MasahiroNagai
DepartmentofNeurologyandClinicalPharmacology,EhimeUniversityGraduateSchoolof
Medicine,ShitsukawaToon,Ehime,Japan
NorikoNishikawa
DepartmentofNeurologyandClinicalPharmacology,EhimeUniversityGraduateSchoolof
Medicine,ShitsukawaToon,Ehime,Japan
MasahiroNomoto
DepartmentofNeurologyandClinicalPharmacology,EhimeUniversityGraduateSchoolof
Medicine,ShitsukawaToon,Ehime,Japan
FelicitaPedata
DepartmentofNeuroscience,Psychology,DrugResearchandChildHealth
(NEUROFARBA),DivisionofPharmacologyandToxicology,UniversityofFlorence,
50139Florence,Italy
AnnaMariaPugliese
DepartmentofNeuroscience,Psychology,DrugResearchandChildHealth
(NEUROFARBA),DivisionofPharmacologyandToxicology,UniversityofFlorence,
50139Florence,Italy
Contributors xiii
Wei-MinQu
DepartmentofPharmacology,StateKeyLaboratoryofMedicalNeurobiology,Instituteof
BrainScience,ShanghaiMedicalCollegeofFudanUniversity,Shanghai,China
DanielRial
CNC-CenterforNeuroscienceandCellBiology,UniversityofCoimbra,Coimbra,
Portugal
DavidN.Ruskin
DepartmentofPsychologyandNeuroscienceProgram,TrinityCollege,Hartford,
Connecticut,USA
MasahikoTomiyama
DepartmentofNeurology,AomoriPrefecturalCentralHospital,Aomori,Japan
Shin-ichiUchida
CentralNervousSystemResearchLaboratories,Research&DevelopmentDivision,Kyowa
HakkoKirinCo.,Ltd.,Sunto-gun,Shizuoka,Japan
KojiYamada
CentralNervousSystemResearchLaboratories,CNSR&DUnit,R&DDivision,Kyowa
HakkoKirinCo.,Ltd.,Shizuoka,Japan
ZeZhang
DepartmentofPharmacology,StateKeyLaboratoryofMedicalNeurobiology,Instituteof
BrainScience,ShanghaiMedicalCollegeofFudanUniversity,Shanghai,China
PREFACE
Most diseases resulting from brain dysfunction are very tragic not only for
the patients themselves but also for their families because these diseases
deprive them of both the quality of human life and often compassion.
The brain is one of the last frontiers in modern biology, with many
unknown mechanisms. Thereby, the areas of neurology and psychiatry
arethemostchallengingforscientiststhosewhosegoalistoopenthegates
to new cures for diseases involving the brain.
Adenosine is a purine ribonucleoside and is ubiquitously distributed
throughout the mammalian body. Since the 1920s, adenosine and purine
receptors have been studied extensively in biomedical research. Approxi-
mately an 80-year journey of research already traveled by great ancestors
stands before us.
Since the beginning of research, there have been significant outcomes
ensuring that the adenosine and purine families contribute to the mamma-
lian cardiovascular system, including vasodilation and heart function. It
should be noted that the progression of receptor science has always been
supported by molecular biology for receptor classification and promoted
viatheappearanceofpharmacologicaltoolslikeselectiveagonistsandantag-
onists to identify receptor function. These tools also sometimes become
known in the development of medicines as new therapeutics themselves.
Adenosine receptor science is, of course, not an exception. In the early
1970s, it was proposed that adenosine was an important neuromodulator
in both the peripheral and central nervous systems. This was evidenced
by studies using methylxanthines, such as caffeine and theophylline, as
antagonists at adenosine receptors. Furthermore, in the beginning of the
1990s,wesawanexplosionofadenosinereceptorsciencebecausemolecular
biologyandpharmacologyidentifiedthefouradenosinereceptorsubtypes:
the A , A , A , and A receptors. At the same time, caffeine, a non-
1 2A 2B 3
selective adenosine antagonist, was still widely employed in many studies,
including human epidemiology, as a kind of unique contribution for the
field, until selective receptor agents were invented (for example, a cup of
coffee containing caffeine made science close to many people’s mind).
Recently, receptor selective agents were created to assist and accelerate
theentireresearcheffort,whichoftenbroughttolightparticularphysiolog-
icalfunctionsofadenosineasaneuromodulator/neurotransmitter.Someof
xv
xvi Preface
theadenosineagentsalsobecamenewcandidatesasmedicinesforthetreat-
ment of brain dysfunction.
Duetothenatureofadenosine,whichisaubiquitousmodulatorofcel-
lularactivity,itisnotsurprisingthatthereisagrowingbodyofinterest for
adenosine and its receptors and their role as new and broad targets for
research of brain function and dysfunction.
I invited distinguished scientists, who are working to further adenosine
receptorsciencebyseekingnewtherapiesfor anumberofCNSdiseasesas
wellasadenosinefunctioninthebrain,tocontributetothisvolume.These
scientists participated enthusiastically by sharing their new insights, knowl-
edge, therapeutic strategies, views, and future applications for adenosine
receptor science from multiple disease and brain functional perspectives,
such as Parkinson’s disease, Huntington’s disease, epilepsy, cognitive func-
tion, cerebral ischemia, sleep, depression, anxiety, and schizophrenia.
Intheearly1990s,whenIstartedtoworkintheresearchareaofaden-
osinereceptorfunctioninthebrain,IdidnothaveanyidealikeIdo today
that there could be so many aspects and practical ideas for new therapies
involvingadenosinereceptors,asdescribedinthisvolume.Now,Iamvery
confident knowing that tomorrow will be more fantastic and will produce
practical curesfor neurological and psychiatricdiseases from the continued
research and progression of adenosine receptor science.
Finally, I would like to acknowledge the tremendous efforts and huge
insightsmadeintoadenosinereceptorsciencebymycolleaguesandcontrib-
utors for this volume.
AKIHISA MORI
Cherry blossom season in Tokyo, 2014
CHAPTER ONE
Adenosine Receptor
Neurobiology: Overview
Jiang-Fan Chen*,1, Chien-fei Lee†, Yijuang Chern†
*DepartmentofNeurology,BostonUniversitySchoolofMedicine,Boston,Massachusetts,USA
†DivisionofNeuroscience,InstituteofBiomedicalSciences,AcademiaSinica,Taipei,Taiwan
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. GeneralIntroduction 2
2. SourceandRegulationofExtracellularAdenosineLevel 4
3. ARsSubtypes:ClassificationandGeneStructures 5
3.1 Anovelproteintranscribedfromadifferentframe
oftheA Rgene 6
2A
4. ExpressionofARsintheBrain 7
4.1 A receptor 7
1
4.2 A receptor 7
2A
4.3 A andA receptors 8
2B 3
5. StructureBiologyofAdenosineA Receptors 8
2A
6. CanonicalandNoncanonicalSignalingPathwaysofARs 9
6.1 A adenosinereceptor 11
1
6.2 A adenosinereceptor 12
2A
6.3 A adenosinereceptor 16
2B
6.4 A adenosinereceptor 17
3
7. InteractionsBetweenARsandOtherGPCRsandNeurotrophicFactorReceptors 18
8. ARFunctions:InsightsfromPharmacologicalandGenetic-KOApproaches 19
8.1 ARmodulationofneuronalexcitabilitybypresynapticandpostsynaptic
mechanisms 20
8.2 ARmodulationofsynapticplasticity 21
8.3 ARcontroloflearningandmemory 22
8.4 ARscontrolofsleep–wakecycle 22
8.5 A Rcontrolofmotorandpsychomotoractivities 23
2A
8.6 Adenoisnereceptorcontrolofanxiety,aggression,anddepression 24
8.7 ARcontrolofangiogenesis 25
8.8 ARcontrolofcerebralbloodflowandblood–brainbarrierintegrity 25
9. ARsandGlialFunctions 26
9.1 Glialcontrolofadenosinehomeostasis 26
9.2 GlialARs 26
InternationalReviewofNeurobiology,Volume119 #2014ElsevierInc. 1
ISSN0074-7742 Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-801022-8.00001-5
2 Jiang-FanChenetal.
10. PathophysiologicalFunctionsofARs 27
11. ARsasDrugTargets 29
Acknowledgments 30
References 30
FurtherReading 49
Abstract
Adenosineisanaturallyoccurringnucleosidethatisdistributedubiquitouslythrough-
outthebodyasametabolicintermediary.Inthebrain,adenosinefunctionsasanimpor-
tant upstream neuromodulator of a broad spectrum of neurotransmitters, receptors,
andsignalingpathways.ByactingthroughfourG-protein-coupledreceptors,adenosine
contributescriticallytohomeostasisandneuromodulatorycontrolofavarietyofnormal
andabnormalbrainfunctions,rangingfromsynapticplasticity,tocognition,tosleep,to
motoractivitytoneuroinflammation,andcelldeath.Thisreviewbegunwithanover-
viewofthegeneandgenomestructureandtheexpressionpatternofadenosinerecep-
tors (ARs). We feature several new developments over the past decade in our
understanding of AR functions in the brain, with special focus on the identification
andcharacterizationofcanonicalandnoncanonicalsignalingpathwaysofARs.Wepro-
videanupdateonfunctionalinsightsfromcomplementarygenetic-knockoutandphar-
macological studies on the AR control of various brain functions. We also highlight
severalnovelandrecentdevelopmentsofARneurobiology,including(i)recentbreak-
through in high resolution of three-dimension structure of adenosine A receptors
2A
(A Rs) in several functional status, (ii) receptor–receptor heterodimerization, (iii) AR
2A
function in glial cells, and (iv) the druggability of AR. We concluded the review with
thecontentionthatthesenewdevelopmentsextendandstrengthenthesupportfor
A andA Rsinbrainastherapeutictargetsforneurologicandpsychiatricdiseases.
1 2A
1. GENERAL INTRODUCTION
Inthebrain,adenosinedoesnotactasaclassicalneurotransmitter,since
itisnotenrichedandstoredinvesicles,andisnotreleasedinresponsetoaction
potential,anddoesnotactonlyorpredominantlyinsynapsestotransferinfor-
mation unidirectionally from the pre- to the postsynaptic components.
Instead, adenosine is generated intracellularly as a metabolic intermediary
for nucleic acids synthesis and the biological energy currency adenosine tri-
phosphate(ATP)andextracellularlybyenzymaticalconversionfromreleased
ATP into adenosinethrough coupled ectonucleotidases(CD73 andCD39).
Aswithallothercells,adenosinefunctionsasahomeostaticfactorbyitspara-
crinefunctionandcellularsignaling.Moreimportantly,adenosineinthebrain
alsoservesasacriticalneuromodulatortocontrolneuronalexcitability,release
of various neurotransmitters including glutamate, γ-aminobutyric acid
AdenosineReceptorNeurobiology:Overview 3
(GABA), acetylcholine, and dopamine, and to modulate synaptic plasticity
and function (Sebastiao & Ribeiro, 1996). As such, the level of adenosine
rises with increased neuronal activity in response to hypoxia or ischemia.
The increased extracellular adenosine tends to reset the balance (as a
“retaliatory metabolite”) and functions as an endogenous neuroprotectant
(de Mendonc¸a, Sebastia˜o, & Ribeiro, 2000). Extracellular adenosine exerts
physiologicalandpathologicaleffectsbyactingatfourtypesofevolutionarily
conservedandpharmacologicallywell-characterizedadenosinereceptor(AR)
subtypes,namelyA ,A ,A ,andA receptors(Cirera&Fredholm,2001;
1 2A 2B 3
Fredholm,IJzerman,Jacobson,Klotz,&Linden,2001).EachARsubtypehas
unique tissue distribution, pharmacological properties, different G-protein
coupling, and distinct signaling pathways (Fredholm, IJzerman, et al., 2001;
Fredholm, IJzerman, Jacobson, Linden, & Muller, 2011). The relative
potencyofadenosine(EC50)foritsreceptors,asestimatedinChinesehamster
ovarycellsstablyexpressingthereceptors,is73,150,5100,and6500nMfor
theA R(A receptor),A R(A receptor),A R(A adenosinereceptor),
1 1 2A 2A 2B 2B
and A R (A adenosine receptor), respectively (Daly & Padgett, 1992;
3 3
Peakman & Hill, 1994; Zhou et al., 1992). At physiological condition,
endogenous adenosine level is estimated at 20–200nM in the brain, which
is sufficient to activate A , A , and A receptors with approximately
1 2A 3
equipotent,withexceptionoftheA receptors,whichrequirehigheragonist
2B
concentrations (Fredholm, Irenius, Kull, & Schulte, 2001). The effects of
adenosine depend on the level of adenosine as well as the expression level
ofsubtypesinagivencelltypeorsubregionofthebrain.TheA andA recep-
1 3
tors couple to the G family of G proteins, and thus stimulate K+ channels,
i
reducetransientvoltage-dependentCa2+channelsandinhibitcAMPforma-
tion;A RscoupletothemembersoftheG family(G instriatalneurons),
2A s olf
whereasA receptorscoupletomanyGproteinsincludingG,G ,andG .
2B s q 12
Thesereceptorshavebeenimplicatedinavarietyofbiologicalfunctions,both
physiological and pathological (Fredholm, IJzerman, et al., 2001; Fredholm
et al., 2011), ranging from motor activity (Schwarzschild, Agnati, Fuxe,
Chen, & Morelli, 2006), sleep regulation (Huang et al., 2005; Lazarus
et al., 2011), cognition (Augusto et al., 2013; Wei et al., 2014; Wei,
Singer,etal.,2011),andangiogenesis(Liuetal.,2010),aswellasinvolvement
in inflammatory diseases (Eltzschig & Carmeliet, 2011; Hasko, Linden,
Cronstein, & Pacher, 2008), ischemia and reperfusion (Eltzschig & Eckle,
2011; Yu, Huang, et al., 2004), and neurodegenerative disorders
(Fredholm,2007).Lastly,oneofthemajorimpetusesforstudyingARfunc-
tioninthebrainistherealizationthatmanyoftheeffectsofcaffeine,themost