Pharmacology & Therapeutics of Constitutively Active Receptors :

420 Pages·2014·16.382 MB·English

by  Tao, Ya-Xiong

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PREFACE
Constitutiveactivity,whichissignalingintheabsenceofagonists,wasfirst
describedinearly1980sinthetypeAg-aminobutyricreceptor,anionchan-
nel.Therecordingofasingleionchannelshowedthatitcan,indeed,open
intheabsenceofanagonist.Ligandsthatdecreasetheelevatedbasalactivity
were then described for these receptors. Very quickly, studies from Nobel
Laureate Robert Lefkowitz’s laboratory showed that G protein-coupled
receptors (GPCRs) could couple to G proteins in the absence of ligands,
at least in reconstituted systems. Finally in 1989, Costa and Herz demon-
strated in neuroblastoma cells expressing d-opioid receptors endogenously,
thereissignificantbasalactivitywhichcanbedecreasedbysomeantagonists,
theso-called“negativeantagonists,”nowcommonlyreferredtoas“inverse
agonists.”
Followingthesepioneeringstudies,togetherwiththecloningofnumer-
ousGPCRsandtheirheterologousexpressionincelllines,severalimportant
discoveries were made. Mutations generated by site-directed mutagenesis
cancausesignificantincreaseinbasalactivity,presumablybybreakinginter-
actions that constrain the wild-type receptor in inactive conformation.
Numerous studies utilized this strategy to gain insights into the structure
of GPCRs before the crystal structures of GPCRs were reported. Other
studies used these data, together with homology modeling, after some of
the crystal structures of GPCRs began to appear in the literature. Some
wild-typereceptorshavesignificantbasalactivity,whichcanbedramatically
differentevenbetweencloselyrelatedreceptors.Naturallyoccurringmuta-
tions in several GPCRs that either increase or decrease basal activity can
cause significant human diseases, including cancer. Highly constitutively
active GPCRs in viruses also cause human diseases. Transgenic animals
expressing constitutively active mutant receptors present phenotypes that
suggest constitutive activity has physiological relevance in vivo. Receptor
theory was modified to account for the constitutive activity. A look back
atthedrugsthattargetGPCRsindeedrevealthatthemajorityoftheantag-
onistsareinverseagonists,notneutralantagonists.Thesearejustsomeofthe
major advances and the field is still rapidly expanding.
Inthisvolume,wetriedtocaptureaglimpseofrecentprogressinseveral
selectedGPCRs.Theofferingsincludenotonlyrhodopsin,oneofthemost
extensively studied and the first example of genetic mutations causing
ix
x Preface
human disease, but also the glycoprotein hormone receptors, the cannabi-
noidreceptor,themelanocortin-4receptor,theangiotensintype1receptor,
the dopamine receptors, the chemokine receptors, and a chemosensory
receptor, the bitter taste receptor. We also recruited a chapter on the
constitutive activity of a nuclear receptor, the androgen receptor, and
two chapters on ion channels.
IthankDr.S.J.Enna,theSeriesEditor,forhissupportforthisvolume,
and Ms. Lynn LeCount, the Managing Editor, for everything she did to
make sure this volume moves along as scheduled. I am very grateful to all
the contributors, who are all busy scientists with numerous commitments,
for taking the time to write their excellent contributions. I anticipate this
volumewillstimulatefurtherresearchinthisfascinatingfieldofconstitutive
activity.
YA-XIONG TAO
Department of Anatomy, Physiology and Pharmacology,
College of Veterinary Medicine, Auburn University,
Auburn, Alabama, USA
Volume 70 Editor
CONTRIBUTORS
IssamAbu-Taha
FacultyofMedicine,InstituteofPharmacology,UniversityDuisburg-Essen,Essen,Germany
AwatifAlbaker
OttawaHospitalResearchInstitute(NeuroscienceProgram),andDepartmentsofMedicine,
Cellular&MolecularMedicine,Psychiatry,UniversityofOttawa,Ottawa,Ontario,Canada
RajinderP.Bhullar
DepartmentofOralBiology,UniversityofManitoba,Winnipeg,Manitoba,Canada
HeikeBiebermann
InstituteofExperimentalPediatricEndocrinology,Charite´-Universita¨tsmedizinBerlin,
Berlin,Germany
GeorgeBousfield
StudiumConsortiumforResearchandTraininginReproductiveSciences(sCORTS),
Tours,France,andDepartmentofBiologicalSciences,WichitaStateUniversity,Wichita,
Kansas,USA
SiuChiuChan
MasonicCancerCenter,UniversityofMinnesota,Minneapolis,Minnesota,USA
PrashenChelikani
DepartmentofOralBiology,UniversityofManitoba,Winnipeg,Manitoba,Canada
ScottM.Dehm
MasonicCancerCenter,andDepartmentofLaboratoryMedicineandPathology,University
ofMinnesota,Minneapolis,Minnesota,USA
JamesA.Dias
StudiumConsortiumforResearchandTraininginReproductiveSciences(sCORTS),
Tours,France,andDepartmentofBiomedicalSciences,SchoolofPublicHealth,University
atAlbany,Albany,NewYork,USA
DobromirDobrev
FacultyofMedicine,InstituteofPharmacology,UniversityDuisburg-Essen,Essen,Germany
ColleenA.Flanagan
SchoolofPhysiologyandMedicalResearchCouncilReceptorBiologyResearchUnit,
FacultyofHealthSciences,UniversityoftheWitwatersrand,PrivateBag3,Wits,South
Africa
TungM.Fong
ForestResearchInstitute,JerseyCity,NewJersey,USA
XinbingHan
BostonChildren’sHospital,HarvardMedicalSchool,Boston,Massachusetts,USA
xi
xii Contributors
JordiHeijman
FacultyofMedicine,InstituteofPharmacology,UniversityDuisburg-Essen,Essen,Germany
IlpoHuhtaniemi
StudiumConsortiumforResearchandTraininginReproductiveSciences(sCORTS),
Tours,France,andInstituteofReproductiveandDevelopmentalBiology,ImperialCollege
London,London,UnitedKingdom
SadashivaS.Karnik
DepartmentofMolecularCardiology,LernerResearchInstitute,ClevelandClinic,
Cleveland,Ohio,USA
GunnarKleinau
InstituteofExperimentalPediatricEndocrinology,Charite´-Universita¨tsmedizinBerlin,
Berlin,Germany
CarolineLefebvre
OttawaHospitalResearchInstitute(NeuroscienceProgram),andDepartmentsof
Medicine,Cellular&MolecularMedicine,Psychiatry,UniversityofOttawa,Ottawa,
Ontario,Canada
DoriMiller
DepartmentofAnatomy,Physiology&Pharmacology,CollegeofVeterinaryMedicine,
AuburnUniversity,Auburn,Alabama,USA
PaulShin-HyunPark
DepartmentofOphthalmologyandVisualSciences,CaseWesternReserveUniversity,
Cleveland,Ohio,USA
BiancaPlouffe
DepartmentofBiochemistry,Universite´ deMontre´al,andInstitutderechercheen
immunologie,cancer,Montre´al,Que´bec,Canada
SaiP.Pydi
DepartmentofOralBiology,UniversityofManitoba,Winnipeg,Manitoba,Canada
EricReiter
StudiumConsortiumforResearchandTraininginReproductiveSciences(sCORTS);
BIOSGroup,INRA,UMR85,Unite´ PhysiologiedelaReproductionetdes
Comportements;CNRS,UMR7247,Nouzilly,andUniversite´ Franc¸oisRabelais,Tours,
France
Ya-XiongTao
DepartmentofAnatomy,PhysiologyandPharmacology,CollegeofVeterinaryMedicine,
AuburnUniversity,Auburn,Alabama,USA
MarioTiberi
OttawaHospitalResearchInstitute(NeuroscienceProgram),andDepartmentsof
Medicine,Cellular&MolecularMedicine,Psychiatry,UniversityofOttawa,Ottawa,
Ontario,Canada
Contributors xiii
AlfredoUlloa-Aguirre
StudiumConsortiumforResearchandTraininginReproductiveSciences(sCORTS),
Tours,France,andResearchSupportNetwork,InstitutoNacionaldeCienciasMe´dicasy
Nutricio´n“SalvadorZubira´n”andUniversidadNacionalAuto´nomadeMe´xico,Me´xico
D.F.,Mexico
HamiyetUnal
DepartmentofMolecularCardiology,LernerResearchInstitute,ClevelandClinic,
Cleveland,Ohio,USA
NielsVoigt
FacultyofMedicine,InstituteofPharmacology,UniversityDuisburg-Essen,Essen,Germany
LiliWang
DepartmentofAnatomy,Physiology&Pharmacology,CollegeofVeterinaryMedicine,
AuburnUniversity,Auburn,Alabama,USA
BoyangZhang
OttawaHospitalResearchInstitute(NeuroscienceProgram),andDepartmentsofMedicine,
Cellular&MolecularMedicine,Psychiatry,UniversityofOttawa,Ottawa,Ontario,Canada
JumingZhong
DepartmentofAnatomy,Physiology&Pharmacology,CollegeofVeterinaryMedicine,
AuburnUniversity,Auburn,Alabama,USA
CHAPTER ONE
Constitutively Active Rhodopsin
and Retinal Disease
Paul Shin-Hyun Park1
DepartmentofOphthalmologyandVisualSciences,CaseWesternReserveUniversity,Cleveland,Ohio,USA
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 2
2. RhodopsinActivity 5
2.1 Physiologyofrhodopsinactivity 5
2.2 Molecularswitchesthatlockrhodopsininaninactivestate 10
3. ConstitutiveActivityinRhodopsinthatCausesDisease 12
3.1 LebercongenitalamaurosisandvitaminAdeficiency 12
3.2 Congenitalnightblindness 15
3.3 Retinitispigmentosa 19
4. HowConstitutiveActivityCanCauseDifferentPhenotypes 22
4.1 Differentlevelsofactivityasanunderlyingcauseofdifferentphenotypes 22
4.2 Doallconstitutivelyactivemutantsadoptthesameactive-state
conformation? 23
5. Conclusion 26
ConflictofInterest 27
Acknowledgments 27
References 27
Abstract
Rhodopsinisthelightreceptorinrodphotoreceptorcellsoftheretinathatinitiatessco-
topicvision.Inthedark,rhodopsinisboundtothechromophore11-cisretinal,which
locksthereceptorinaninactivestate.Themaintenanceofaninactiverhodopsininthe
darkiscriticalforrodphotoreceptorcellstoremainhighlysensitive.Perturbationsby
mutationortheabsenceof11-cisretinalcancauserhodopsintobecomeconstitutively
active,whichleadstothedesensitizationofphotoreceptorcellsand,insomeinstances,
retinaldegeneration.Constitutiveactivitycanariseinrhodopsinbyvariousmechanisms
andcancauseavarietyofinheritedretinaldiseasesincludingLebercongenitalamau-
rosis,congenitalnightblindness,andretinitispigmentosa.Inthisreview,themolecular
andstructuralpropertiesofdifferentconstitutivelyactiveformsofrhodopsinareover-
viewed,andthepossibilitythatconstitutiveactivitycanarisefromdifferentactive-state
conformationsisdiscussed.
AdvancesinPharmacology,Volume70 #2014ElsevierInc. 1
ISSN1054-3589 Allrightsreserved.
http://dx.doi.org/10.1016/B978-0-12-417197-8.00001-8
2 PaulShin-HyunPark
ABBREVIATIONS
CNB congenitalnightblindness
CP cytoplasmicloop
EC extracellularloop
EPR electronparamagneticresonance
GPCR Gprotein-coupledreceptor
H8 amphipathicalphahelix8
LCA Lebercongenitalamaurosis
LRAT lecithinretinolacyltransferase
MI metarhodopsinI
MII metarhodopsinII
R inactivestate
*
R activestate
RIS rodinnersegment(s)
ROS rodoutersegment(s)
RP retinitispigmentosa
RPE65 retinalpigmentepithelium-specific65kDaprotein
TM transmembranealphahelix
l maximalabsorbanceoflight
max
1. INTRODUCTION
Rhodopsin is a member of the G protein-coupled receptor (GPCR)
familyofmembraneproteins.BovinerhodopsinwasthefirstGPCRtohave
its primary, secondary, and tertiary structures determined (Hargrave et al.,
1983; Nathans & Hogness, 1983; Ovchinnikov Yu, 1982; Palczewski
et al., 2000; Schertler, Villa, & Henderson, 1993). These studies revealed
astructurewithseventransmembranealphahelices(TM1–TM7)connected
by extracellular (EC1–EC3) and cytoplasmic (CP1–CP3) loops and an
amphipathic alpha helix (H8) that sits parallel to the membrane surface
(Fig. 1.1). The human gene for rhodopsin was isolated and sequenced in
themid-1980s(Nathans&Hogness,1984).Therhodopsingeneisahotspot
for inherited mutations causing retinal disease (Mendes, van der Spuy,
Chapple, & Cheetham, 2005; Nathans, Merbs, Sung, Weitz, & Wang,
1992; Stojanovic & Hwa, 2002).
Rhodopsinisthelightreceptorthatinitiatesscotopicvisioninrodphoto-
receptorcellsoftheretinauponphotoncapture.Thereceptorisembeddedata
high concentration in disk membranes of rod outer segments (ROS)
(Fig.1.2A).Intenseeffortstounderstandthestructureandfunctionofthislight
receptorhavebeenongoingforquitesometime,especiallyaftertheinitialdis-
covery that a single point mutation in the rhodopsin gene causes retinitis
pigmentosa(RP)(Dryjaetal.,1990),aretinaldegenerativedisease.Evenwith
ConstitutivelyActiveRhodopsin 3
ECAxyttroapclaesllumlaicr 56MYPWL00YLPTL4QVLLI0GMEMTHNTAFIAQF1FLKVSVFALK3Y809VATG00GLDLNTTYYMSLH1ARGMLI0YFQ0FNTLTYVL2PVLPLLFS70FY1WGL3LIVEPF0IVTG1GESE2VAMATFL0CRGGLS1VLPT3A 1SNCKYVSEF0 CG1P4RI1S01GMM2PH7G9VD00AF0ATWCMVNASYVMALLQSW1ELAING5Y 4VAP10RGGAT6CFTR0TFYE22AVLFI13I1MPFVIK00T8GNNVNHK0ICTPMFVEQ2EPSEFII0FYMLV5A02SFVFYT20APVKRFVITAKAILTWHQFVTA1YQVYEM0FQMCVVTI2MFQAP56A2222G0YET6S8I7I4NQ0000AS3SE3PTPKP01FN0I0TG2GIISVI9MFNYFM0MMF1EKPAIANN7TQFMNGYAARHN2MCL3T3D0TIG3C2L0CPGNK B
D
HOOCAPAVQSTE34T0KSVTASAE
Figure 1.1 Structureofrhodopsin.(A)Thesecondarystructureofhumanrhodopsinis
shown with residues causing constitutive activity and retinal disease when mutated,
highlighted in black (Gly90, Thr94, Ser186, Asp190, Ala292, and Ala295), except for
Lys296.Residuesformingmolecularswitchesarecoloredasfollows:green(darkgrayin
theprintversion;Glu113,Glu181,andLys296),protonatedSchiffbaseswitch;yellow(very
lightgrayintheprintversion;Cys264,Trp265,Pro267,andAla269),CWxPmotifswitch;
cyan(light grayintheprint version;Glu122,Trp126,and His211),TM3–TM5 hydrogen
bond network switch; blue (dark gray in the print version; Asn55, Asp83, Ala298,
Ala299,Asn302,Pro303,Tyr306,andPhe313),NPxxYmotifswitch;red(darkgrayinthe
printversion;Glu134,Arg135,Tyr136,Glu247,anThr251),D(E)RYmotifswitch.Residues
formingtheCWxP,NPxxY,andD(E)RYmotifsarehighlightedinbold.(B)Crystalstructures
oftheinactivestateofbovinerhodopsin(colored,PDB:1U19)andtheMIIstateofbovine
rhodopsin (gray, PDB: 3PXO) were aligned with PyMOL. Residues causing constitutive
activityandretinaldiseasewhenmutatedaredepictedasblackspheres.11-cisRetinal
isdepictedaspinkspheres.Helicesintheinactive-statestructurearecoloredasfollows:
blue(darkgrayintheprintversion),TM1;cyan(lightgrayintheprintversion),TM2;green
(darkgrayintheprintversion),TM3;limegreen(grayintheprintversion),TM4;yellow
(verylightgrayintheprintversion),TM5;orange(darkgrayintheprintversion),TM6;
red(darkgrayintheprintversion),TM7;purple(darkgrayintheprintversion),H8.
theseefforts,themechanisticdescriptionofrhodopsinactivityisincomplete.
Sincetheinitialdiscovery,morethan100pointmutationshavebeendiscov-
eredintherhodopsingenethatcauseretinaldisease(Garriga&Manyosa,2002;
Mendesetal.,2005;Nathansetal.,1992;Stojanovic&Hwa,2002).
Undernormalfunction,rhodopsiniscovalentlyboundto11-cisretinaland
isinactiveinthedark(Fig.1.2B).Rhodopsinmustbeactivatedbylighttoini-
tiatevision.Constitutiveactivityinrhodopsin(i.e.,receptoractivationinthe
absence oflight stimulation)can arise because ofmutation ortheabsenceof
bound11-cisretinalandcancausearangeofinheritedretinaldiseasesincluding
Lebercongenitalamaurosis(LCA),congenitalnightblindness(CNB),andRP
(Rao, Cohen, & Oprian, 1994; Robinson, Cohen, Zhukovsky, & Oprian,
4 PaulShin-HyunPark
A Rod
photoreceptor
cell Dark Light
Transducin
Arrestin
Outer
segment
Inner
segment/perinuclear
region
B Rhodopsin MII
Light
Light
Rho MII MII MII Ops
γ
α β P P P Arr
GTPGDP
11-cis Retinal
Figure1.2 Rodphotoreceptorcellsandphototransduction.(A)Cartoondepictionofa
rodphotoreceptorcell.Thecartoonofthecellontheleftshowsthestructureofarod
photoreceptorcellwithdiskmembranesintheROSandmitochondria,Golgiapparatus,
endoplasmicreticulum,andnucleusintheRIS/perinuclearregion.Rhodopsinisembed-
dedindiskmembranesoftheoutersegment.Thecartoonsofthecellinthemiddleand
on the right illustrate the levels of transducin (green; gray in the print version) and
arrestin(blue;blackintheprintversion)intheROSandRIS/perinuclearregioninthe
dark and in the light. (B) Life cycle of rhodopsin. Rhodopsin is covalently bound to
11-cisretinalinthedark.Lightisomerizes11-cisretinaltoall-transretinal,whichpro-
motestheactivationofrhodopsinandformationoftheMIIstate.MIIbindsandactivates
theheterotrimericGproteintransducin(green;lightgrayintheprintversion)toinitiate
phototransduction.MIIisinactivatedviaphosphorylationbyrhodopsinkinaseandthe
bindingofarrestin(blue;darkgrayintheprintversion).TheMIIstatedecaystoopsin
upon release of all-trans retinal from the chromophore-binding pocket. Opsin must
reconstitutewith11-cisretinaltoregeneraterhodopsin.