Trafficking of GPCRs

314 Pages·2015·9.461 MB·English

by  Wu, Guangyu

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CONTRIBUTORS
SanaAlAwabdh
INSERMU894,andCentredePsychiatrieetNeurosciences,Universite´ ParisDescartes,
SorbonneParisCite´,Paris,France
AnnetteG.Beck-Sickinger
FacultyofBiosciences,PharmacyandPsychology,InstituteofBiochemistry,Universita¨t
Leipzig,Leipzig,Germany
ShannaL.Bowman
DepartmentofBiologicalSciences,CarnegieMellonUniversity,Pittsburgh,Pennsylvania,
USA
ChristopherCottingham
DepartmentofBiologyandChemistry,MoreheadStateUniversity,Morehead,Kentucky,
USA
Miche`leDarmon
INSERMU894,andCentredePsychiatrieetNeurosciences,Universite´ ParisDescartes,
SorbonneParisCite´,Paris,France
JasonE.Davis
DepartmentofPharmacologyandToxicology,MedicalCollegeofGeorgia,Georgia
RegentsUniversity,Augusta,Georgia,USA
DenisJ.Dupre´
DepartmentofPharmacology,DalhousieUniversity,Halifax,NovaScotia,Canada
Michel-BorisEmerit
INSERMU894,andCentredePsychiatrieetNeurosciences,Universite´ ParisDescartes,
SorbonneParisCite´,Paris,France
CraigJ.Ferryman
DepartmentofBiologyandChemistry,MoreheadStateUniversity,Morehead,Kentucky,
USA
CatalinM.Filipeanu
DepartmentofPharmacology,CollegeofMedicine,HowardUniversity,Washington,
DistrictofColumbia,USA
QinFu
DepartmentofPharmacology,SchoolofBasicMedicine,TongjiMedicalCollege,
HuazhongUniversityofScienceandTechnology,Wuhan,PRChina
EugeniaV.Gurevich
DepartmentofPharmacology,VanderbiltUniversity,Nashville,Tennessee,USA
VsevolodV.Gurevich
DepartmentofPharmacology,VanderbiltUniversity,Nashville,Tennessee,USA
ix
x Contributors
YoshikazuImanishi
DepartmentofPharmacology,SchoolofMedicine,CaseWesternReserveUniversity,
Cleveland,Ohio,USA
JustineE.Kennedy
DepartmentofMolecularPharmacologyandTherapeutics,LoyolaUniversityChicago,
HealthSciencesDivision,Maywood,Illinois,USA
WolfgangKlein
Leibniz-Institutfu€rMolekularePharmakologie(FMP),Berlin,Germany
AdrianoMarchese
DepartmentofMolecularPharmacologyandTherapeutics,LoyolaUniversityChicago,
HealthSciencesDivision,Maywood,Illinois,USA
JustineMasson
INSERMU894,andCentredePsychiatrieetNeurosciences,Universite´ ParisDescartes,
SorbonneParisCite´,Paris,France
KarinMo€rl
FacultyofBiosciences,PharmacyandPsychology,InstituteofBiochemistry,Universita¨t
Leipzig,Leipzig,Germany
InaNemet
DepartmentofPharmacology,SchoolofMedicine,CaseWesternReserveUniversity,
Cleveland,Ohio,USA
ManojkumarA.Puthenveedu
DepartmentofBiologicalSciences,CarnegieMellonUniversity,Pittsburgh,Pennsylvania,
USA
KausikRay
ScientificReviewBranch,NIDCD,NationalInstitutesofHealth,Bethesda,MD,USA
PhilipRopelewski
DepartmentofPharmacology,SchoolofMedicine,CaseWesternReserveUniversity,
Cleveland,Ohio,USA
ClaudiaRutz
Leibniz-Institutfu€rMolekularePharmakologie(FMP),Berlin,Germany
RalfSchu€lein
Leibniz-Institutfu€rMolekularePharmakologie(FMP),Berlin,Germany
QinWang
DepartmentofCell,DevelopmentalandIntegrativeBiology,UniversityofAlabamaat
Birmingham,Birmingham,Alabama,USA
JaimeWertman
DepartmentofMicrobiologyandImmunology,DalhousieUniversity,Halifax,NovaScotia,
Canada
Contributors xi
GuangyuWu
DepartmentofPharmacologyandToxicology,MedicalCollegeofGeorgia,Georgia
RegentsUniversity,Augusta,Georgia,USA
YangK.Xiang
DepartmentofPharmacology,UniversityofCalifornia,DavisCalifornia,USA
BrentYoung
DepartmentofPharmacology,DalhousieUniversity,Halifax,NovaScotia,Canada
MaoxiangZhang
DepartmentofPharmacologyandToxicology,MedicalCollegeofGeorgia,Georgia
RegentsUniversity,Augusta,Georgia,USA
PREFACE
G protein-coupled receptors (GPCRs) (also known as seven-
transmembrane domain receptors or 7TMRs) constitute the largest family
ofcellsurfacereceptorsinvolvedinsignalregulationunderdiversephysio-
logical and pathological conditions and are drug targets for many diseases.
Extensivestudiescarriedoutoverthepast2–3decadeshaveclearlydemon-
stratedthatthespatiotemporalregulationofGPCRintracellulartrafficking,
includingthecellsurfaceexport,internalization,recycling,anddegradation,
is a crucial mechanism that controls receptor transport to the right place
which in turn dictates the integrated responses of the cell to hormones
anddrugsattherighttime.Addingtothecomplexity,eachofthesetraffick-
ing processes is mediated by multiple pathways and is highly regulated by
many factors, such as structural determinants, specific motifs, interacting
proteins, posttranslational modifications, and transport machineries, alto-
gethercoordinatingreceptortransportusingveryspecializedroutes.GPCR
trafficking is rapidly evolving and has great potential to translate into new
therapeutics.
Themainpurposeofthisbookistoreviewourcurrentunderstandingof
intracellulartraffickingofsomewell-characterizedGPCRs.Inaddition,this
bookwillalsohighlighttherolesoftraffickinginregulatingthefunctionality
of the receptors and pinpoint current challenges and future directions in
studying GPCR trafficking. The contributors are experts in this area with
manyyearsofexperience.Itismyhopethatthisbookwillbeusefultograd-
uate students, postdoctoral fellows, and researchers who are interested in
general GPCR biology or intracellular trafficking of GPCRs.
Iamgratefultoeachofthecontributorsfortheirvaluabletimeandtre-
mendouseffortstomakethisbookpossible.Itismygreatpleasuretowork
with them to put together a book on this very important topic in GPCR
biology. I thank Dr. P. Michael Conn, the Chief Editor of the Progress in
Molecular Biology and Translational Science series, for inviting me to edit this
volume and always being supportive. I also would like to take this oppor-
tunity to thank my former mentor, Dr. Stephen M. Lanier, for leading
me into the GPCR field.
GUANGYU WU
xiii
CHAPTER ONE
Arrestins: Critical Players in
☆
Trafficking of Many GPCRs
Vsevolod V. Gurevich1, Eugenia V. Gurevich
DepartmentofPharmacology,VanderbiltUniversity,Nashville,Tennessee,USA
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. ArrestinsandGPCRTrafficking 2
2. Non-visualArrestinsMediateGPCRInternalizationviaCoatedPits 2
3. VisualArrestinsandTraffickingProteins 4
4. UbiquitinationandDeubiquitinationinGPCRCyclingandSignaling 6
5. FasterCyclingPreventsReceptorDownregulation 7
6. ArrestinsinReceptorRecyclingandVesicleTrafficking:Questions
WithoutAnswers 8
7. ConclusionsandFutureDirections 9
References 10
Abstract
ArrestinsspecificallybindactivephosphorylatedGprotein-coupledreceptors(GPCRs).
ReceptorbindinginducesthereleaseofthearrestinC-tail,whichinnon-visualarrestins
containshigh-affinitybindingsitesforclathrinanditsadaptorAP2.Thus,servingasa
physicallinkbetweenthereceptorandkeycomponentsoftheinternalizationmachin-
eryofthecoatedpitisthebest-characterizedfunctionofnon-visualarrestinsinGPCR
trafficking.However,arrestinsalsoregulateGPCRtraffickinglessdirectlybyorchestrat-
ingtheirubiquitinationanddeubiquitination.Severalreportssuggestthatarrestinsplay
additionalrolesinreceptortrafficking.Non-visualarrestinsappeartoberequiredforthe
recycling of internalized GPCRs, and the mechanisms of their function in this case
remain to be elucidated. Moreover, visual and non-visual arrestins were shown to
directlybindN-ethylmaleimide-sensitivefactor,animportantATPaseinvolvedinvesicle
trafficking,butneithermoleculardetailsnorthebiologicalroleoftheseinteractionsis
clear.Consideringhowmanydifferentproteinsarrestinsappeartobind,wecanconfi-
dentlyexpecttheelucidationofadditionaltrafficking-relatedfunctionsoftheseversatile
signalingadaptors.
☆Weusesystematicnamesofarrestinproteins:arrestin-1(historicnamesS-antigen,48kDaprotein,
visualorrodarrestin),arrestin-2(β-arrestinorβ-arrestin1),arrestin-3(β-arrestin2orhTHY-ARRX),
andarrestin-4(coneorX-arrestin;forunclearreasons,its geneiscalled“arrestin3”intheHUGO
database).
ProgressinMolecularBiologyandTranslationalScience,Volume132 #2015ElsevierInc. 1
ISSN1877-1173 Allrightsreserved.
http://dx.doi.org/10.1016/bs.pmbts.2015.02.010
2 VsevolodV.GurevichandEugeniaV.Gurevich
ABBREVIATIONS
AIP4 atrophin-1-interactingprotein4
AP2 adaptorprotein2
β2AR β -adrenergicreceptor
2
GPCR Gprotein-coupledreceptor
GRK Gprotein-coupledreceptorkinase
Nedd4 neuralprecursorcellexpresseddevelopmentallydown-regulatedprotein4
1. ARRESTINS AND GPCR TRAFFICKING
Preferential binding of arrestins to active phosphorylated receptors
was discovered about 30 years ago.1 The finding that arrestin binding sup-
pressesreceptorcouplingtocognateGproteinswasmadesoonafterinthe
visual system.2 The mechanism turned out to be remarkably simple: direct
competition between arrestin and G protein for overlapping sites.3,4 For
sometime,itappearedthattheonlyfunctionarrestinshaveistobindactive
phosphorylatedGprotein-coupledreceptors(GPCRs),precludingreceptor
interactions with G proteins by direct competition.3,4 The first described
non-GPCR binding partners of arrestins were trafficking proteins: clathrin
in 19965 and clathrin adaptor AP2 a few years later.6 These data demon-
stratedthatarrestinsplayanessentialrolenotonlyinGPCRdesensitization7
but also in receptor endocytosis,8 via trafficking signals added by receptor-
boundarrestins.Thediscoverythatarrestinsareubiquitinateduponreceptor
bindingandregulateubiquitinationofGPCRs9revealedyetanothermech-
anism, whereby arrestins regulate receptor trafficking indirectly. Here, we
discuss several known mechanisms of arrestin effects on GPCR trafficking
and highlight observations that suggest that there are many other mecha-
nisms that still remain to be elucidated.
2. NON-VISUAL ARRESTINS MEDIATE GPCR
INTERNALIZATION VIA COATED PITS
Arrestins promote GPCR internalization by virtue of recruitment of
clathrin and AP2 via fairly well-mapped binding sites in the C-tail of non-
visual arrestins5,6,10,11 (Fig. 1). Interestingly, the C-tail in the basal confor-
mation of all arrestins is anchored to the N-domain,12–16 whereas receptor
binding triggers its release.17–19 The expression of separated arrestin C-tail
carrying these sites inhibits GPCR internalization, apparently by winning
ArrestinsinGPCRTrafficking 3
Figure1 ArrestinsplaymanyrolesinGPCRtrafficking.Arrestins(ARR)bindactivephos-
phorylatedGPCRs(shownasaseven-helixbundle).Receptorbindinginducestherelease
ofthearrestinC-tail,whichcarriesbindingsitesforclathrin(Clath)andadaptorprotein-2
(AP2).TheinteractionsofthesesiteswithclathrinandAP2promotereceptorinternali-
zationviacoatedpits.ArrestinsalsorecruitubiquitinligasesMdfm2,Nedd4,andAIP4to
thecomplex,whichfavorsubiquitinationofbothnon-visualarrestinsandatleastsome
GPCRs. Arrestins also recruitcertaindeubiquitinationenzymes(USP20and USP33 are
shown), facilitating receptor deubiquitination. The role of arrestin interactions with
microtubules, centrosome, and N-ethylmaleimide-sensitive factor (NSF) in trafficking
ofGPCRsand/orotherproteinsremainstobeelucidated.
the competition with the arrestin–receptor complexes for clathrin and
AP2.20 This finding provided the first clear evidence of functional signifi-
cance of shielding of the arrestin C-tail in the basal conformation and its
release upon receptor binding. In free arrestins, the C-tail is anchored to
thebodyofthemolecule,whichmakesitinaccessible,preventingitscom-
petition with the receptor-bound arrestins for the components of internal-
ization machinery (reviewed in Ref. 21).
Anotherknownmechanismofarrestinrecruitmenttothecoatedpitisits
directbindingtophosphoinositides,whichwasreportedtobenecessaryfor
GPCR internalization.22 Since resident coated pit protein AP2 is also rec-
ruited to this part of the membrane via phosphoinositide binding,23 one
might think that as soon as the arrestin–receptor complex is formed, it
hasnochoicebuttomovetothecoatedpit.However,thisdoesnotappear
tobethecase.InmuscarinicM2receptor,whichwasamongthefirstshown
tobindarrestins,24twoSer/Thrclustersinthethirdcytoplasmicloopwere
identified as critical for arrestin binding and receptor desensitization.25 Yet
4 VsevolodV.GurevichandEugeniaV.Gurevich
the elimination of these clusters, and even dominant-negative dynamin
K44A mutant that blocks the internalization of β2AR in the same cells,
did not prevent M2 endocytosis, suggesting that M2 receptor does not
usecoatedpitsandinternalizesinanarrestin-independentmanner.25Inter-
estingly, overexpression of non-visual arrestins can redirect some M2 to
coated pits,25 suggesting that this receptor can use more than one route.
ManyotherGPCRswereshowntohavethatchoice.Forexample,chemo-
kine receptor CCR5 uses both phosphorylation- and arrestin-dependent
and -independent pathways.26 Cysteinyl leukotriene type 1 receptorinter-
nalizes normally in mouse embryonic fibroblasts lacking both non-visual
arrestins, yet arrestin expression facilitates its internalization,27 apparently
directing it to the arrestin-dependent pathway, which is usually not pre-
ferred, similar to M2 receptor.25 Metabotropic glutamate receptor
mGluR1a constitutively internalizes via arrestin-independent mechanism,
whereas its agonist-dependent internalization appears to be mediated by
arrestin-2.28 Endogenous and overexpressed serotonin 5HT4 receptor
internalizes via arrestin-dependent pathway, but the deletion of Ser/Thr
cluster targeted by G protein-coupled receptor kinases (GRKs) redirects
it to an alternative pathway and even facilitates its internalization.29
Thus, it appears that the ability of GPCRs to use more than one inter-
nalization pathway is a general rule, rather than an exception, likely rep-
resenting one of the many backup mechanisms cells usually have. Many
receptors have recognizable internalization motifs in their sequence, so
arrestinbindingsimplyaddsnewones.Therelativestrengthofthesemotifs,
aswellasthearrestinexpressionlevels,likelydeterminesthepathway(s)each
receptorchoosesinaparticularcell.Thedominantinternalizationpathway
of aparticular receptor isnotnecessarily thesame in differentcell types,or
evenatdifferentfunctionalstatesofthesamecell(reviewedinRef.8).Vari-
ety,ratherthanuniformity,characterizestheworldofGPCRsignalingand
trafficking.30
3. VISUAL ARRESTINS AND TRAFFICKING PROTEINS
In vertebraterodphotoreceptors, rhodopsinis localizedon the discs,
whicharedetachedfromtheplasmamembrane31andthereforearetopolog-
icallyequivalenttovesicleswithinternalizednon-visualGPCRs.Thus,ver-
tebrate rhodopsin is not supposed to be internalized. Indeed, arrestin-1,
which is the prevalent arrestin isoform in both rods and cones,32 does not
haveconventionalclathrin-orAP2-bindingelementsinitsC-tail.33How-
ever,sequencecomparisonofarrestin-1andnon-visualsubtypesshowsthat
ArrestinsinGPCRTrafficking 5
in the region homologous to AP2-binding motif in arrestin-2 and-3, only
one positive charge is missing.34 Therefore, it is hardly surprising that
arrestin-1alsobindsAP2,albeitwith(cid:1)30timesloweraffinity.34Constitu-
tively active rhodopsin–K296E is a naturally occurring mutant that causes
autosomal dominant retinitis pigmentosa in humans, apparently due to
constitutive phosphorylation and formation of a stable complex with
arrestin-1.35 The concentration of rhodopsin in the outer segment of rods
reaches (cid:1)3mM.31 Rods also express roughly 8 arrestin molecules per
10rhodopsins,36–38sotheconcentrationsofbothproteinsandtheircomplex
formedinbrightlightareveryhigh.Itturnsoutthatattheseconcentrations
evenlowaffinitymatters:thepresenceofWTarrestin-1facilitatesroddeath
inanimalsexpressingrhodopsin–K296E,withvisibleaccumulationofAP2
intheoutersegment,whereitisnotobservedinnormalmice.34Incontrast,
truncated arrestin-1 lacking the C-tail containing the low-affinity AP2-
binding site protects photoreceptors in these animals and preserves their
function.34 Thus, in rod and cone photoreceptors, both of which express
very high levels of arrestin-1,32 even relatively low-affinity interactions,
whichwouldnotmatterinothercells,withsubmicromolarconcentrations
of both non-visual arrestins,39,40 can become biologically relevant.
Interestingly, the localization of rhodopsin on invaginations of the
plasma membrane in flies, in contrast to detached discs in vertebrate rods,
is one of the many differences between vertebrate and invertebrate photo-
receptors. Another difference directly follows from this localization:
Drosophila rhodopsin is internalized, like “normal” vertebrate GPCRs, via
clathrin- and AP2-mediated mechanism.41 In fly photoreceptors, arrestin
isevenlydistributed,whereasindark-adaptedvertebraterods,itisconcen-
tratedintheinnersegment,withfairlysmallfractionintheoutersegment,
where rhodopsin resides.36–38 However, in both types of photoreceptors
upon illumination, arrestin translocates to rhodopsin-containing mem-
branes.36–38,42–45Likenon-visualarrestins,andincontrasttovertebratevisual
arrestin,22 visual arrestin in Drosophila has high-affinity phosphoinositide-
binding site.43 It was proposed that due to phosphoinositide binding,
Drosophilaarrestintranslocatestorhodopsinonphosphoinositide-richvesicles
movedwiththehelpofDrosophilamyosinIII(NINAC).42Theparticipation
of NINAC in metarhodopsin inactivation in Drosophila was independently
confirmed,46 but arrestin translocation was found to be largely driven by its
binding to rhodopsin in flies,44 just like in mice.45 Thus, the internalization
of invertebrate rhodopsin apparently follows the same rules as many non-
visual GPCRs: active receptor recruits arrestin via direct binding,47 which
then links it to the key components of the coated pit.5,6,41