SEÇÃO 1   PRINCÍPIOS GERAIS

3 Como agem os fármacos:

aspectos moleculares

RECEPTORES
CONSIDERAÇÕES GERAIS
Neste capítulo, passamos dos princípios gerais da
ação dos fármacos esboçados no Capítulo 2 às
moléculas que estão envolvidas no reconhecimento
dos sinais químicos e em sua tradução em respostas
celulares. A farmacologia molecular vem avançando
rapidamente, e o novo conhecimento está mudando
nossa compreensão sobre a ação dos fármacos e
também abrindo muitas novas possibilidades tera-
pêuticas, discutidas mais adiante, em outros capítulos.
Em primeiro lugar, consideraremos os tipos de
proteínas-alvo sobre as quais os fármacos agem.
A seguir, descreveremos as principais famílias de
receptores e canais iônicos que foram reveladas por
 VUHFHSWRUHV)LJ¬$VmRRVHOHPHQWRVVHQVRUHVQRVLV
2
WHPDGHFRPXQLFDo}HVTXtPLFDVTXHFRRUGHQDPDIXQomR
GHWRGDVDVGLIHUHQWHVFpOXODVGRRUJDQLVPRVHQGRPHQ
VDJHLURVTXtPLFRVRVYiULRVKRUP{QLRVWUDQVPLVVRUHVH
RXWURVPHGLDGRUHVGLVFXWLGRVQD6HomRGHVWHOLYUR0XLWRV
IiUPDFRVWHUDSHXWLFDPHQWH~WHLVDJHPRXFRPRDJRQLVWDV
RXFRPRDQWDJRQLVWDVQRVUHFHSWRUHVGHPHGLDGRUHVHQGy
JHQRVFRQKHFLGRV1DPDLRUSDUWHGRVFDVRVRPHGLDGRU
HQGyJHQRIRLGHVFREHUWRDQWHV²FRPIUHTXrQFLDPXLWRV
DQRVDQWHV²GHRUHFHSWRUWHUVLGRFDUDFWHUL]DGRIDUPDFR
OyJLFDHELRTXLPLFDPHQWHPDVQRV~OWLPRVDQRVPXLWRV
UHFHSWRUHVIRUDPLQLFLDOPHQWHLGHQWLILFDGRVFRPEDVHHP
VXDVFDUDFWHUtVWLFDVIDUPDFROyJLFDVRXPROHFXODUHV(P
DOJXQVFDVRVFRPRRGRVUHFHSWRUHVFDQDELQRLGHVHGRV
clonagem e estudos estruturais. Por fim, discutire- UHFHSWRUHVRSLRLGHV&DSV¬H¬RVPHGLDGRUHVHQGyJH
mos as várias formas de conexão receptor-efetor QRVIRUDPLGHQWLILFDGRVPDLVWDUGHHPRXWURVFRQKHFLGRV
(mecanismos de transdução de sinal) por meio das
quais os receptores são acoplados à regulação da
função celular. A relação entre estrutura molecular
de um receptor e sua ligação funcional a um tipo
particular de sistema efetor é o tema principal. Nos
próximos dois capítulos, veremos como esses eventos
moleculares alteram aspectos importantes da função
celular – uma base útil para a compreensão dos efei-
tos dos fármacos sobre organismos vivos íntegros.
Aprofundamos em mais detalhes do que o neces-
sário para entender a farmacologia de hoje em nível
básico, com a intenção de que os estudantes possam,
caso queiram, pular ou ler superficialmente esses
capítulos sem perder o fio da meada; no entanto,
estamos convictos de que a farmacologia de ama-
nhã estará solidamente alicerçada nos avanços da
biologia celular e molecular aqui discutidos.
ALVOS PARA A AÇÃO DE FÁRMACOS
SRUUHFHSWRUHVyUImRVDVHJXLURPHGLDGRUSHUPDQHFHGHV
FRQKHFLGRVHpTXHH[LVWH
CANAIS IÔNICOS
2 VFDQDLVL{QLFRV  VmREDVLFDPHQWHSRUW}HVSUHVHQWHVQDV
PHPEUDQDVFHOXODUHVTXHGHPRGRVHOHWLYRSHUPLWHPD
SDVVDJHPGHGHWHUPLQDGRVtRQVHTXHVmRLQGX]LGRVDVH
DEULURXVHIHFKDUSRUXPDYDULHGDGHGHPHFDQLVPRV2V
FDQDLVFRQWURODGRVSRUOLJDQWHV HRVFDQDLVFRQWURODGRVSRUYRO
WDJHP VmRGRLVWLSRVLPSRUWDQWHV2SULPHLURDEUHDSHQDV
TXDQGRXPDRXPDLVPROpFXODVDJRQLVWDVVmROLJDGDVHVmR
SURSULDPHQWHFODVVLILFDGRVFRPRUHFHSWRUHVMiTXHpQHFHV
ViULDDOLJDomRGHXPDJRQLVWDSDUDTXHVHMDPDWLYDGRV
2VFDQDLVFRQWURODGRVSRUYROWDJHPVmRUHJXODGRVQmRSRU
OLJDomRGHXPDJRQLVWDPDVVLPSRUDOWHUDo}HVQRSRWHQFLDO
WUDQVPHPEUDQD
'
 HIRUPDJHUDORVIiUPDFRVSRGHPDOWHUDUDIXQomRGRV
FDQDLVL{QLFRVGHYiULDVPDQHLUDV
 $WUDYpVGDOLJDomRjSUySULDSURWHtQDGRFDQDOTXHUQR
ORFDOGHOLJDomRRUWRVWpULFDGROLJDQWHTXHUHPRXWURV
2VDOYRVSURWHLFRVSDUDDDomRGHIiUPDFRVVREUHDVFpOXODVGH
ORFDLVDORVWpULFDRXQRFDVRPDLVVLPSOHVH[HPSOLILFDGR
PDPtIHURV)LJ¬ TXHVmRGHVFULWRVQHVWHFDStWXORSRGHP
SHODDomRGRVDQHVWpVLFRVORFDLVQRVFDQDLVGHVyGLR
VHUQRJHUDOGLYLGLGRVHP
GHSHQGHQWHVGDYROWDJHP&DS¬DPROpFXODGR
‡ UHFHSWRUHV IiUPDFROLJDVHILVLFDPHQWHDRFDQDO)LJ¬%HGHVVH
‡ FDQDLVL{QLFRV PRGREORTXHLDDSHUPHDELOLGDGHDRVtRQV2VIiUPDFRV
‡ HQ]LPDV TXHVHOLJDPDORFDLVDORVWpULFRVQRFDQDOGDSURWHtQDH
‡ WUDQVSRUWDGRUHVPROpFXODVFDUUHJDGRUDV TXHSRUHVVDUD]mRDOWHUDPRVLVWHPDGHDEHUWXUDGR
FDQDOLQFOXHP
$
 PDLRULDGRVIiUPDFRVLPSRUWDQWHVDJHVREUHXPRXRXWUR
² E
 HQ]RGLD]HStQLFRVVHGDWLYRV&DS¬(VVHV
GHVVHVWLSRVGHSURWHtQDPDVH[LVWHPH[FHo}HV3RUH[HPSORD
IiUPDFRVOLJDPVHDXPDUHJLmRGRFRPSOH[R
FROFKLFLQDXWLOL]DGDQRWUDWDPHQWRGHDWDTXHVDJXGRVGHJRWD
UHFHSWRUFORUHWR*$%$$XPFDQDODWLYDGRSRU
&DS¬LQWHUDJHFRPDSURWHtQDHVWUXWXUDOWXEXOLQDHQTXDQ
OLJDQWHTXHpGLIHUHQWHGRORFDOGHOLJDomRGH
WRDOJXQVIiUPDFRVLPXQRVVXSUHVVRUHVS¬H[DFLFORVSRULQD
*$%$IDFLOLWDQGRDDEHUWXUDGRFDQDODWUDYpVGR
&
 DS¬OLJDPVHDSURWHtQDVFLWRVyOLFDVFRQKHFLGDVFRPR
QHXURWUDQVPLVVRULQLELWyULR*$%$&DS¬
LPXQRILOLQDV$QWLFRUSRVWHUDSrXWLFRVTXHDJHPVHTXHVWUDQGR
DVFLWRFLQDVPHGLDGRUHVSURWHLFRVHQYROYLGRVQDLQIODPDomR
&
 DS¬WDPEpPVmRXVDGRV$OYRVSDUDIiUPDFRVTXLPLR
WHUDSrXWLFRV&  DSV¬ HPTXHDLQWHQomRpVXSULPLURV
PLFURUJDQLVPRVLQYDVRUHVRXDVFpOXODVFDQFHUtJHQDVLQFOXHP
'1$HFRQVWLWXLQWHVGDSDUHGHFHOXODUDVVLPFRPRRXWUDV
 2VFDQDLVL{QLFRVHDVSURSULHGDGHVHOpWULFDVTXHHOHVFRQIHUHPjV

FpOXODVHVWmRHQYROYLGRVHPWRGDVDVFDUDFWHUtVWLFDVKXPDQDVTXHQRV
GLVWLQJXHPGDVSHGUDVGRFDPSR$UPVWURQJ&09ROWDJHJDWHG.
22 SURWHtQDV FKDQQHOVKWWSZZZVWNHRUJ

C0015.indd 22 04/11/15 1:13 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
ENZIMAS
A RECEPTORES Abertura/fechamento 9
 iULRVIiUPDFRVVmRGLUHFLRQDGRVSDUDDVHQ]LPDV)LJ¬&
Direto de canais iônicos &RPIUHTXrQFLDDPROpFXODGRIiUPDFRpXPVXEVWUDWRDQiOR
Ativação/inibição
enzimática JRTXHDJHFRPRXPLQLELGRUFRPSHWLWLYRGDHQ]LPDS¬H[R
Agonista/ Mecanismos Modulação de FDSWRSULODJLQGRVREUHDHQ]LPDFRQYHUVRUDGHDQJLRWHQVLQD
agonista de transdução canais iônicos & DS¬HPRXWURVFDVRVDOLJDomRpLUUHYHUVtYHOHQmRFRPSH
inverso Transcrição WLWLYDS¬H[DDVSLULQDDJLQGRQDFLFORR[LJHQDVH&DS¬2V
do DNA IiUPDFRVSRGHPWDPEpPDJLUFRPRIDOVRVVXEVWUDWRVHPTXH
DPROpFXODGRIiUPDFRVRIUHWUDQVIRUPDo}HVTXtPLFDVGDQGR
Antagonista Sem efeito RULJHPDXPSURGXWRDQ{PDORTXHSHUWXUEDDYLDPHWDEyOLFD
Mediadores endógenos bloqueados
QRUPDO8PERPH[HPSORpRIiUPDFRDQWLQHRSOiVLFRIOXRUX
UDFLODTXHVXEVWLWXLDXUDFLODFRPRLQWHUPHGLiULRQDELRVVtQ
WHVHGDVSXULQDVPDVQmRSRGHVHUFRQYHUWLGRHPWLPLGLODWR
B CANAIS IÔNICOS EORTXHDQGRDVVLPDVtQWHVHGR'1$HLPSHGLQGRDGLYLVmR
Bloqueadores Bloqueio FHOXODU&DS¬
da permeação '
 HYHVHPHQFLRQDUWDPEpPTXHRVIiUPDFRVSRGHPH[LJLU
Aumento ou diminuição GHJUDGDomRHQ]LPiWLFDSDUDFRQYHUWrORVGHIRUPDLQDWLYDD
Moduladores da probabilidade XPDSUyGURJDRXSUyIiUPDFR&DS¬SDUDDIRUPDDWLYD
de abertura S¬H[RHQDODSULOpFRQYHUWLGRHPHQDODSULODWSRUHVWHUDVHV
TXHLQLEHPDHQ]LPDGHFRQYHUVmRGDDQJLRWHQVLQD$OpPGLV
VRFRPRGLVFXWLGRQR&DStWXOR¬DWR[LFLGDGHGRIiUPDFRIUH
C ENZIMAS TXHQWHPHQWHUHVXOWDGDFRQYHUVmRHQ]LPiWLFDGDPROpFXODGR
Inibidor Inibição da reação IiUPDFRSDUDXPPHWDEyOLWRUHDWLYR2SDUDFHWDPRO&DS¬
normal FDXVDGDQRDRItJDGRHPVXDYLD1RTXHFRQFHUQHjDomR
SULPiULDGRIiUPDFRHVVHpXPHIHLWRFRODWHUDOLQGHVHMiYHO
PDVGHHQRUPHLPSRUWkQFLDSUiWLFD
Falso Produção de
substrato metabólito anômalo
TRANSPORTADORES
Pró-fármaco Produção de (
 PJHUDODPRYLPHQWDomRGHtRQVHSHTXHQDVPROpFXODV
fármaco ativo RUJkQLFDVDWUDYpVGDVPHPEUDQDVFHOXODUHVRFRUUHDWUDYpV
GRVFDQDLVDQWHULRUPHQWHRXDWUDYpVGDDomRGHXPDSURWHtQD
WUDQVSRUWDGRUDYLVWRTXHDVHVSpFLHVSHUPDQHQWHVVmRHP
D TRANSPORTADORES JHUDOPXLWRSRODUHVLQVXILFLHQWHPHQWHOLSRVVRO~YHLVSDUD
SHQHWUDUQDVPHPEUDQDVOLStGLFDVSRUVLPHVPDV)LJ¬'
Transporte 0XLWRVGHVVHVWUDQVSRUWDGRUHVVmRFRQKHFLGRVH[HPSORVGH
normal
DOJXQVFRPLPSRUWkQFLDIDUPDFROyJLFDHPSDUWLFXODULQFOXHP
DTXHOHVUHVSRQViYHLVSHORWUDQVSRUWHGHtRQVHPXLWDVPROpFX
ODVRUJkQLFDVSHORW~EXORUHQDOSHORHSLWpOLRLQWHVWLQDOHSHOD
Inibidor ou Transporte EDUUHLUDKHPDWRHQFHIiOLFDRWUDQVSRUWHGH1DH&DSDUDIRUD
bloqueado GDVFpOXODVHDFDSWDomRGRVSUHFXUVRUHVGHQHXURWUDQVPLVVRUHV
Falso Acúmulo de FRPRDFROLQDRXGRVSUySULRVQHXURWUDQVPLVVRUHVFRPRDV
substrato composto anômalo DPLQDVHRVDPLQRiFLGRVSHORVWHUPLQDLVQHUYRVRVEHPFRPR
RWUDQVSRUWHGHPROpFXODVGHIiUPDFRVHVHXVPHWDEyOLWRVDWUD
YpVGHPHPEUDQDVFHOXODUHVHEDUUHLUDVHSLWHOLDLV)DODUHPRV
Agonista/substrato Produto anômalo PDLVVREUHWUDQVSRUWDGRUHVQRVSUy[LPRVFDStWXORV
(
 PPXLWRVFDVRVDKLGUyOLVHGR$73IRUQHFHDHQHUJLDQHFHV
Antagonista/inibidor Pró-fármaco
ViULDSDUDRWUDQVSRUWHGHVXEVWkQFLDVFRQWUDVHXJUDGLHQWHHOH
Fig. 3.1 Tipos de alvos para a ação de fármacos. WURTXtPLFR7DLVSURWHtQDVWUDQVSRUWDGRUDVLQFOXHPXPORFDO
SDUDOLJDomRGH$73GLVWLQWRHVmRGHQRPLQDGDVWUDQVSRUWD
GRUHV$%&FDVVHWHGHOLJDomRGH$73([HPSORVLPSRUWDQWHV
LQFOXHPDERPEDGHVyGLR1D . $73DVH&DS¬HRVWUDQV
² IiUPDFRVYDVRGLODWDGRUHVGDFODVVHGLKLGURSLULGLQD SRUWDGRUHVGHUHVLVWrQFLDDP~OWLSORVIiUPDFRV50)TXHHMHWDP
&DS¬TXHLQLEHPDDEHUWXUDGRVFDQDLVGHFiOFLR IiUPDFRVFLWRWy[LFRVGHFpOXODVFDQFHUtJHQDVHPLFURELDQDV
WLSR/&DS¬ FRQIHULQGRUHVLVWrQFLDDHVVHVDJHQWHVWHUDSrXWLFRV&DS¬
² VXOIRQLOXUHLDV&DS¬XWLOL]DGDVQRWUDWDPHQWR (PRXWURVFDVRVLQFOXLQGRRVWUDQVSRUWDGRUHVQHXURWUDQVPLV
GRGLDEHWHVTXHDWXDPQRFDQDOGHSRWiVVLRVHQVtYHO VRUHVRWUDQVSRUWHGHPROpFXODVRUJkQLFDVHVWiDVVRFLDGRDR
DR$73GDVFpOXODVbSDQFUHiWLFDVHGHVVDIRUPD WUDQVSRUWHGHtRQVJHUDOPHQWH1D DPERVQDPHVPDGLUHomR
DXPHQWDPDVHFUHomRGHLQVXOLQD VLPSRUWHRXQDGLUHomRRSRVWDDQWLSRUWHHSRUWDQWRVHEDVHLD
 $WUDYpVGHDomRLQGLUHWDTXHHQYROYHDSURWHtQD*H QRJUDGLHQWHHOHWURTXtPLFRGH1DJHUDGRSHODERPEDGHVyGLR
RXWURVLQWHUPHGLiULRVSiJ GHSHQGHQWHGH$73$VSURWHtQDVWUDQVSRUWDGRUDVLQFRUSRUDP
 $WUDYpVGDDOWHUDomRGRQtYHOGHH[SUHVVmRGRVFDQDLV XPORFDOGHUHFRQKHFLPHQWRTXHDVWRUQDHVSHFtILFDVSDUD
L{QLFRVQDVXSHUItFLHFHOXODU3RUH[HPSORDJDEDSHQWLQD XPDHVSpFLHSDUWLFXODUDVHUWUDQVSRUWDGDHHVVHVORFDLVGH
UHGX]DLQFRUSRUDomRGHFDQDLVGHFiOFLRGRWLSR1QD UHFRQKHFLPHQWRWDPEpPSRGHPVHUDOYRVSDUDIiUPDFRVFXMR
PHPEUDQDSODVPiWLFD&DS¬ HIHLWRpEORTXHDURVLVWHPDGHWUDQVSRUWH
$LPSRUWkQFLDGRVWUDQVSRUWDGRUHVFRPRIRQWHGHYDULDomR
$GLDQWHDSUHVHQWDVHXPUHVXPRGRVGLIHUHQWHVJUXSRVGH LQGLYLGXDOQDVFDUDFWHUtVWLFDVIDUPDFRFLQpWLFDVGHGLIHUHQWHVIiU
FDQDLVL{QLFRVHGHVXDVIXQo}HV PDFRVYHPVHWRUQDQGRFDGDYH]PDLVUHFRQKHFLGD&DS¬ 23

C0015.indd 23 04/11/15 1:13 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

PROTEÍNAS RECEPTORAS
CLONAGEM DE RECEPTORES
1
 RVDQRVDIDUPDFRORJLDHQWURXHPXPDQRYDIDVH
TXDQGRRVUHFHSWRUHVTXHDWpHQWmRKDYLDPVLGRHQWLGDGHV
WHyULFDVFRPHoDUDPDHPHUJLUFRPRUHDOLGDGHVELRTXtPLFDV
FRPRUHVXOWDGRGRGHVHQYROYLPHQWRGDVWpFQLFDVGHPDUFDomR
GHJHQHVUHFHSWRUHVVtPLOHVHVWmRSUHVHQWHV²HKiPXLWRVDLQGD
SRUFDWDORJDU
2VUHFHSWRUHVVmRSURWHtQDVQRUPDOPHQWHLQWHJUDGDVQD
PHPEUDQDOLStGLFDHSRUHVVHPRWLYRGHGLItFLOFULVWDOL]DomR
2EWHUFULVWDLVGHXPDSURWHtQDSHUPLWHDDQiOLVHGHVXDHVWUX
WXUDHPDOWDUHVROXomRSRUPHLRGHWpFQLFDVGHGLIUDomRGHUDLRV
;%RDSDUWHGRTXHFRQKHFHPRVVREUHDHVWUXWXUDGRVFDQDLV
L{QLFRVDGYpPGRFRQKHFLPHQWRGRUHFHSWRUQLFRWtQLFRGH
&DS¬TXHWRUQDUDPSRVVtYHOH[WUDLUHSXULILFDURPDWHULDO DFHWLOFROLQD1RV~OWLPRVDQRVDVVLVWLXVHDJUDQGHVSURJUHVVRV
GRUHFHSWRU QDFULVWDOL]DomRGHRXWURWLSRGHUHFHSWRUHV$WpRPRPHQWR
8 PDYH]TXHDVSURWHtQDVUHFHSWRUDVIRUDPLVRODGDVH ERDSDUWHGDLQIRUPDomRREWLGDHVWiUHODFLRQDGDFRPDIRUPD
SXULILFDGDVIRLSRVVtYHODQDOLVDUDVHTXrQFLDGHDPLQRiFLGRV FRPRRVOLJDQWHVVHXQHPDRVUHFHSWRUHVRXVHMDGRPtQLRV
GHXPSHTXHQRWUHFKRSHUPLWLQGRTXHDVHTXrQFLDEiVLFD H[WUDFHOXODUHVPDVDJRUDHVWDPRVFRPHoDQGRDDSUHQGHU
GR51$PIRVVHGHGX]LGDHTXHXP'1$FRPSOHWRIRVVH PDLVVREUHDVPXGDQoDVFRQIRUPDFLRQDLVGRVUHFHSWRUHV
LVRODGRSRUPpWRGRVGHFORQDJHPFRQYHQFLRQDLVDFRPHoDU LQGX]LGDVSHORVDJRQLVWDVHGHFRPRWHPLQtFLRDFDVFDWDGH
GHXPDELEOLRWHFDGH'1$FREWLGDGHXPWHFLGRIRQWHULFRQR
UHFHSWRUGHLQWHUHVVH2VSULPHLURVFORQHVGHUHFHSWRUIRUDP
REWLGRVGHVVDPDQHLUD0DLVWDUGHIRUDPDPSODPHQWHXVDGDV
DFORQDJHPSRUH[SUHVVmRHFRPDVHTXHQFLDomRGHWRGRR
JHQRPDKXPDQRGHYiULDVHVSpFLHVLQFOXLQGRRVHUKXPDQR
WDPEpPDVHVWUDWpJLDVGHFORQDJHPFRPEDVHQDKRPRORJLDGH
VHTXrQFLDVTXHQmRUHTXHUHPLVRODPHQWRHSXULILFDomRSUpYLRV
GDSURWHtQDUHFHSWRUD$VVLPDWXDOPHQWHDOJXPDVFHQWHQDV
VLQDOL]DomR$XGHWH%RXYLHU
$JRUDTXHRVJHQHVIRUDPSHUIHLWDPHQWHLGHQWLILFDGRVSDV
VRXVHDHQIDWL]DUDFDUDFWHUL]DomRIDUPDFROyJLFDGRVUHFHSWR
UHVHDGHILQLomRGHVXDVFDUDFWHUtVWLFDVPROHFXODUHVHIXQo}HV
ILVLROyJLFDV
TIPOS DE RECEPTOR
2VUHFHSWRUHVHYRFDPPXLWRVWLSRVGLIHUHQWHVGHHIHLWRVFHOXOD
GHUHFHSWRUHVGHWRGDVDVTXDWURIDPtOLDVHVWUXWXUDLVSiJ
UHV$OJXQVGHOHVVmRPXLWRUiSLGRVFRPRDTXHOHVHQYROYLGRV
IRUDPFORQDGDV2VOLJDQWHVHQGyJHQRVGHPXLWRVGHVVHVQRYRV
QDWUDQVPLVVmRVLQiSWLFDRSHUDQGRGHQWURGHPLOLVVHJXQGRV
UHFHSWRUHVLGHQWLILFDGRVSHODFORQDJHPJHQpWLFDSHUPDQHFHP
HQTXDQWRRXWURVHIHLWRVPHGLDGRVSRUUHFHSWRUFRPRRVSUR
GHVFRQKHFLGRVDWpHQWmRVHQGRGHVFULWRVFRPR´UHFHSWRUHV
GX]LGRVSHORKRUP{QLRGDWLUHRLGHRXSRUYiULRVKRUP{QLRV
yUImRVµ $LGHQWLILFDomRGHOLJDQWHVSDUDHVVHVSUHVXPLGRV
HVWHURLGHVRFRUUHPGHQWURGHDOJXPDVKRUDVRXGLDV([LVWHP
UHFHSWRUHVpYLDGHUHJUDGLItFLO1RHQWDQWRH[LVWHPDOJXQV
WDPEpPPXLWRVH[HPSORVGHHVFDODVGHWHPSRLQWHUPHGLiULDV
FDVRVS¬H[RUHFHSWRUFDQDELQRLGH&DS¬HPTXHOLJDQWHV
²DVFDWHFRODPLQDVSRUH[HPSORFRVWXPDPDJLUHPTXHVWmRGH
HQGyJHQRVLPSRUWDQWHVIRUDPYLQFXODGRVDUHFHSWRUHVDWp
VHJXQGRVHQTXDQWRPXLWRVSHSWtGHRVOHYDPPDLVWHPSRSDUD
HQWmRyUImRVHRXWURVFRPRRV33$5VUHFHSWRUHVDWLYDGRV
SURGX]LUVHXVHIHLWRV'HIRUPDQmRVXUSUHHQGHQWHPXLWRV
SRUSUROLIHUDGRUHVGHSHUR[LVVRPRHPHUJLUDPFRPRDOYRV
WLSRVGLIHUHQWHVGHYtQFXORVHQWUHDRFXSDomRGRUHFHSWRUHD
LPSRUWDQWHVGHIiUPDFRVWHUDSrXWLFRV&DS¬HPERUDR
VXEVHTXHQWHUHVSRVWDHVWmRHQYROYLGRV&RPEDVHQDHVWUXWXUD
OLJDQWHHQGyJHQRSHUPDQHoDGHVFRQKHFLGR+iFHUWRRWLPLVPR
PROHFXODUHQDQDWXUH]DGHVVHYtQFXORRPHFDQLVPRGHWUDQV
GHTXHLUmRVXUJLUQRYRVDJHQWHVWHUDSrXWLFRVFXMRDOYRVHMD
GXomRSRGHPRVGLVWLQJXLUTXDWURWLSRVGHUHFHSWRUHVRX
HVVHJUXSRGHUHFHSWRUHVyUImRV
VXSHUIDPtOLDV)LJV¬H¬H7DEHOD¬
0
 XLWDVLQIRUPDo}HVIRUDPREWLGDVSHODLQWURGXomRHP
OLQKDJHQVFHOXODUHVGR'1$FORQDGRTXHFRGLILFDRVUHFHSWR ‡ 7LSR&DQDLVL{QLFRVFRQWURODGRVSRUOLJDQWHVWDPEpP
UHVLQGLYLGXDLVSURGX]LQGRDVVLPFpOXODVFDSD]HVGHH[SUHV FRQKHFLGRVFRPRUHFHSWRUHVLRQRWUySLFRV $FDGHLD
VDURVUHFHSWRUHVDOLHQtJHQDVHPIRUPDIXQFLRQDO7DLVFpOXODV GHGHVFREHUWDVTXHFXOPLQRXFRPDFDUDFWHUL]DomR
PDQLSXODGDVSHUPLWHPXPFRQWUROHPXLWRPDLVSUHFLVRGRV PROHFXODUGHVVHVUHFHSWRUHVIRLGHVFULWDSRU+DOOLZHOO
UHFHSWRUHVH[SUHVVRVGRTXHVHULDSRVVtYHOFRPFpOXODVQDWX 7LSLFDPHQWHHVVHVVmRRVUHFHSWRUHVQRVTXDLVRV
UDLVRXWHFLGRVLQWDFWRVHDWpFQLFDpDPSODPHQWHXWLOL]DGD QHXURWUDQVPLVVRUHVUiSLGRVDJHP7DEHOD¬
SDUDHVWXGDUDVFDUDFWHUtVWLFDVIDUPDFROyJLFDVHGHOLJDomR ‡ 7LSR5HFHSWRUHVDFRSODGRVjSURWHtQD**3&5V
GRVUHFHSWRUHVFORQDGRV2VUHFHSWRUHVKXPDQRVH[SUHVVDGRV
TXHHPJHUDOGLIHUHPHPVHTXrQFLDHQDVSURSULHGDGHVIDU
PDFROyJLFDVGHVHXVFRUUHVSRQGHQWHVHPDQLPDLVSRGHPVHU
HVWXGDGRVGHVVDPDQHLUD
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C0015.indd 24 04/11/15 1:13 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
1.Canais iônicos 2.Receptores acoplados à 3.Receptores 4.Receptores
controlados por ligantes proteína G ligados nucleares
(receptores ionotrópicos) (metabotrópicos) a quinases

Íons Íons

R R R E R/E
G G
ou ou NÚCLEO
Hiperpolarização Alteração da Segundos mensageiros
ou Fosforilação R
despolarização excitabilidade de proteína
Transcrição
de gene
Transcrição de gene
Liberação Fosforilação Outro
de Ca2+ de proteína
Síntese de proteína Síntese de proteína

Efeitos celulares Efeitos celulares Efeitos celulares Efeitos celulares

Escala de tempo
Milissegundos Segundos Horas Horas
Exemplos
Receptor nicotínico Receptor muscarínico Receptores Receptor
da ACh da ACh de citocinas de estrógenos
Fig. 3.2 Tipos de relação entre receptor e efetor. ACh, acetilcolina; E, enzima; G, proteína G; R, receptor.

KpOLFH~QLFDWUDQVPHPEUDQD(PPXLWRVFDVRVRGRPtQLR IDUPDFROyJLFDV 2VUHFHSWRUHVQLFRWtQLFRVGHDFHWLOFROLQDVmR

LQWUDFHOXODUWHPQDWXUH]DHQ]LPiWLFDFRPDWLYLGDGH WtSLFRVQHVVHDVSHFWRVXEWLSRVGLVWLQWRVRFRUUHPHPGLIHUHQWHV
SURWHtQDTXLQDVHRXJXDQLOLOFLFODVH UHJL}HVGRHQFpIDOR7DEHOD¬HHVWHVGLIHUHPGRUHFHSWRUGR
‡ 7LSR5HFHSWRUHVQXFOHDUHV6mRUHFHSWRUHVTXH P~VFXOR$OJXPDVGDVGLIHUHQoDVIDUPDFROyJLFDVFRQKHFLGDV
UHJXODPDWUDQVFULomRJrQLFD 2VUHFHSWRUHVGHVVH
WLSRWDPEpPUHFRQKHFHPPXLWDVPROpFXODVHVWUDQKDV
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ESTRUTURA MOLECULAR DOS RECEPTORES
$
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) LJXUD¬ (PERUDUHFHSWRUHVLQGLYLGXDLVPRVWUHPXPD
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HRVFRPSULPHQWRVGRVSULQFLSDLVGRPtQLRVLQWUDFHOXODUHVH
H[WUDFHOXODUHVWDPEpPYDULHPHQWUHRVPHPEURVGDPHVPD
IDPtOLDRVPRGHORVHVWUXWXUDLVJHUDLVHDVYLDVGHWUDQVGXomR
S¬H[VHQVLELOLGDGHDDJHQWHVEORTXHDGRUHVHQWUHRVUHFHSWR
UHVGHDFHWLOFROLQDGRP~VFXORHGRHQFpIDORVHFRUUHODFLRQDP
FRPGLIHUHQoDVHVSHFtILFDVQDVHTXrQFLDQRHQWDQWRDWpRQGH
VDEHPRVWRGRVRVUHFHSWRUHVQLFRWtQLFRVGDDFHWLOFROLQDUHV
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WLSRGHUHVSRVWDVLQiSWLFD$VVLPDUD]mRGHWDQWDVYDULDQWHV
WHUHPVXUJLGRDLQGDpXPHQLJPD
▼%RDSDUWHGDVYDULDo}HVQDVHTXrQFLDTXHOHYDPjGLYHUVLGDGHGRV
UHFHSWRUHVDSDUHFHQRQtYHOJHQ{PLFRRXVHMDGLIHUHQWHVJHQHVGmR
RULJHPDVXEWLSRVGLVWLQWRVGHUHFHSWRU8PDYDULDomRDGLFLRQDOGHFRUUH
GHXPVSOLFLQJDOWHUQDWLYRGR51$PTXHVLJQLILFDTXHXP~QLFRJHQH
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GHVLQDODVVRFLDGDVVmRPXLWRFRQVLVWHQWHV$SHUFHSomRGHTXH
DSHQDVTXDWURVXSHUIDPtOLDVGHUHFHSWRUHVIRUQHFHPXPDEDVH
VyOLGDSDUDVHLQWHUSUHWDURFRPSOH[RFRQMXQWRGHLQIRUPDo}HV
VREUHRVHIHLWRVGHXPDJUDQGHSURSRUomRGRVIiUPDFRVDWp
DJRUDHVWXGDGDIRLXPGRVPDLVDQLPDGRUHVGHVHQYROYLPHQWRV
QDIDUPDFRORJLDPRGHUQD
HETEROGENEIDADE E SUBTIPOS DE RECEPTORES
&RQVLGHUDQGRGHWHUPLQDGDIDPtOLDGHUHFHSWRUHVJHUDOPHQWH
RFRUUHPPXLWDVYDULHGDGHVPROHFXODUHVRXVXEWLSRVFRPXPD
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VHTXrQFLDVHIUHTXHQWHPHQWHWDPEpPHPVXDVSURSULHGDGHV
 2WHUPRUHFHSWRUQXFOHDUQmRpPXLWRDGHTXDGRSRUTXHDOJXQVHVWmR

FRGLILFDQWHVtQWURQVTXHVmRUHPRYLGDVSHORVSOLFLQJGR51$PDQWHV
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GHOLJDomRGLVWLQWDVHGLIHUHQWHVPHFDQLVPRVGHWUDQVGXomRGHVLQDO
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C0015.indd 25 04/11/15 1:13 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

GHVVHDF~PXORGHGDGRVIRUDPPHQFLRQDGRVDQWHULRUPHQWH
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A Tipo 1 Canais N Domínio
HQWHQGHURVIiUPDFRVLQGLYLGXDLVHVHXVHIHLWRVQRVRUJDQLVPRV
YLYRVEHPFRPRGHVHQYROYHUIiUPDFRVPHOKRUHVTXHRVH[LV
iônicos de ligação
WHQWHVpLPSRUWDQWHPDQWHUPRVDIDUPDFRORJLDPROHFXODUHP
controlados
por ligantes C IRFR2´QRYRULWRµSURYRXVHUHYHODGRUGHPXLWDVPDQHLUDV
(receptores
x 4 ou 5 PDVDJUDQGHFRPSOH[LGDGHGHFRPSRUWDPHQWRVGDVPROpFX
ionotrópicos) ODVVLJQLILFDTXHWHPRVXPORQJRFDPLQKRDWpDWLQJLUDXWRSLD
UHGXFLRQLVWDTXHDELRORJLDPROHFXODUSURPHWLD4XDQGRFKH
Revestimento JDUPRVOiHVWHOLYURVHUiPXLWRPHQRU3RUHQTXDQWRWHQWDPRV
do canal VHOHFLRQDURVSULQFtSLRVJHUDLVVHPQRVSHUGHUPRVHPXP
DSURIXQGDPHQWRH[FHVVLYRQRVGHWDOKHV
$VHJXLUGHVFUHYHPRVDVFDUDFWHUtVWLFDVGHFDGDXPDGDV
B Tipo 2 N Domínios TXDWURVXSHUIDPtOLDVGHUHFHSWRUHV
Receptores de ligação
acoplados à TIPO 1: CANAIS IÔNICOS ATIVADOS POR
proteína G
(receptores LIGANTES
metabotrópicos)
Domínio de 1
 HVWDGHVFULomRJHUDOGDHVWUXWXUDGRVFDQDLVL{QLFRVDWLYD
acoplamento GRVSRUOLJDQWHVYDPRVQRVGHEUXoDULQLFLDOPHQWHVREUHR
à proteína G UHFHSWRUQLFRWtQLFRGHDFHWLOFROLQDTXHVHHQFRQWUDQDMXQomR
C QHXURPXVFXODU&DS¬7UDWDVHGHXPGRVUHFHSWRUHVPDLV
FRQKHFLGRVFRPHVWUXWXUDHIXQomRVHPHOKDQWHVDRXWURV
UHFHSWRUHVFLVORRSDVVLPFKDPDGRVSRUTXHSRVVXHPXPODUJR
C N GRPtQLRLQWUDFHOXODUHQWUHRVGRPtQLRVWUDQVPHPEUDQDUHV
Tipo 3 Domínio
Receptores de ligação HTXHFRQWrPYiULRVUHVtGXRVGHFLVWLQD>)LJ¬$@TXH
ligados a WDPEpPLQFOXHPR*$%$$HRVUHFHSWRUHVGHJOLFLQD&DS¬
quinases EHPFRPRRV¬UHFHSWRUHV+7&DSV¬H¬([LVWHPRXWURV
WLSRVGHFDQDLVL{QLFRVDWLYDGRVSRUOLJDQWHV²QRWDGDPHQWH
RV¬UHFHSWRUHVLRQRWUySLFRVGHJOXWDPDWR&DS¬HRVUHFHS
Domínio WRUHVSXULQpUJLFRV3;&  DSV¬H¬ ²TXHGLIHUHPHPYiULRV
catalítico DVSHFWRVGRUHFHSWRUQLFRWtQLFRGHDFHWLOFROLQD
C
ESTRUTURA MOLECULAR
 VFDQDLVL{QLFRVDWLYDGRVSRUOLJDQWHVWrPWUDoRVHVWUXWXUDLV
2
D C Domínio HPFRPXPFRPRXWURVFDQDLVL{QLFRVGHVFULWRVQDSiJLQD
Tipo 4 de ligação 2UHFHSWRUQLFRWtQLFRGDDFHWLOFROLQD)LJ¬IRLRSULPHLURD
Receptores
nucleares VHUFORQDGRFRQVLVWLQGRHPXPDPRQWDJHPHPIRUPDGHSHQ
Domínio de WkPHURGHGLIHUHQWHVVXEXQLGDGHVGDVTXDLVH[LVWHPTXDWUR
ligação ao WLSRVGHQRPLQDGRVabgHdFDGDTXDOFRPSHVRPROHFXODU
DNA (“dedos 0U HQWUH¬N'D$VVXEXQLGDGHVDSRQWDPXPDPDUFDQWH
de zinco”) KRPRORJLDQDVHTXrQFLDHFDGDXPDGHODVFRQWpPTXDWUR
N aKpOLFHVTXHDWUDYHVVDPDPHPEUDQDQHODLQVHULGDVFRPR
Fig. 3.3 Estrutura geral de quatro famílias de receptores.
Os segmentos retangulares representam regiões hidrofóbicas
a-helicoidais da proteína compreendendo aproximadamente
vinte aminoácidos, que formam os domínios transmembrana dos
receptores. [A] Tipo 1: canais iônicos controlados por ligantes.
O exemplo aqui ilustrado apresenta a estrutura da subunidade
PRVWUDGRQD)LJXUD¬%$HVWUXWXUDSHQWDPpULFDabgd
SRVVXLGRLVSRQWRVGHOLJDomRSDUDDDFHWLOFROLQDFDGDXPQD
LQWHUIDFHHQWUHXPDGDVGXDVVXEXQLGDGHVa HVXDYL]LQKD
$PERVGHYHPOLJDUVHDPROpFXODVGHDFHWLOFROLQDSDUDTXHR
UHFHSWRUVHMDDWLYDGR(VVHUHFHSWRUpVXILFLHQWHPHQWHJUDQGH
SDUDVHUYLVWRHPHOHWURPLFURJUDILDHD)LJXUD¬%PRVWUDVXD
HVWUXWXUDFRPEDVHSULQFLSDOPHQWHQRVHVWXGRVGHGLIUDomR
do receptor nicotínico de acetilcolina. A estrutura da subunidade
de outros canais iônicos operados por ligantes é apresentada
na Figura 3.20. Muitos canais iônicos controlados por ligantes
compreendem quatro ou cinco subunidades do tipo mostrado,
e o complexo inteiro contém 16-20 segmentos transmembrana
circundando um canal iônico central. [B] Tipo 2: Receptores
HOHWU{QLFDGHDOWDUHVROXomR0L\D]DZDHWDO¬&DGDVXEX
QLGDGHDWUDYHVVDDPHPEUDQDTXDWURYH]HVGHPRGRTXHR
FDQDOFRPSUHHQGHQmRPHQRVGHYLQWHKpOLFHVTXHDWUDYHVVDP
DPHPEUDQDFLUFXQGDQGRXPSRURFHQWUDO
▼2VGRLVORFDLVGHOLJDomRGDDFHWLOFROLQDVHVLWXDPQDUHJLmRH[WUDFHOX
ODUGRVWHUPLQDLV1GDVGXDVVXEXQLGDGHVa8PDGDVKpOLFHVWUDQVPHP
acoplados à proteína G. [C] Tipo 3: receptores ligados a EUDQD0GHFDGDXPDGDVFLQFRVXEXQLGDGHVIRUPDRUHYHVWLPHQWR
quinases. A maior parte dos receptores de fatores de crescimento GRFDQDOL{QLFR)LJ¬$VFLQFRKpOLFHV0TXHIRUPDPRSRURVmR
incorpora o domínio de ligação ao ligante e o domínio enzimático GHIRUPDGDVSDUDGHQWURDPHLRFDPLQKRGDHVSHVVXUDGDPHPEUDQD
(quinase) na mesma molécula, como aqui mostrado, enquanto IRUPDQGRXPDFRQVWULomR4XDQGRDVPROpFXODVGHDFHWLOFROLQDVHOLJDP
os receptores de citocinas não possuem um domínio de quinase RFRUUHXPDDOWHUDomRFRQIRUPDFLRQDOQDSDUWHH[WUDFHOXODUGRUHFHSWRU
intracelular, mas se relacionam com moléculas de quinases UHYLVmRSRU*D\H<DNHO¬TXHWRUFHDVVXEXQLGDGHVaID]HQGRFRP
citosólicas. Outras variantes estruturais também existem. [D] Tipo TXHRVVHJPHQWRV0DEDXODGRVVHDIDVWHPXQVGRVRXWURVSURPRYHQGR
4: receptores nucleares que controlam a transcrição de genes. DVVLPDDEHUWXUDGRFDQDO0L\D]DZDHWDO¬$ERUGDGRFDQDOFRQ
WpPXPDVpULHGHUHVtGXRVDQL{QLFRVRTXHWRUQDRFDQDOVHOHWLYDPHQWH
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HPJHUDO1RYRVVXEWLSRVHLVRIRUPDVGHUHFHSWRUHVFRQWLQXDP UHFHSWRUHVQLFRWtQLFRVWDPEpPVHMDPSHUPHiYHLVDR&D
VHQGRGHVFREHUWRVHDWXDOL]Do}HVUHJXODUHVGRFDWiORJRVmR 2XVRGHPXWDJrQHVHGLUHFLRQDGDDRORFDOTXHSHUPLWHTXHSHTXH
GLVSRQLELOL]DGDVZZZJXLGHWRSKDUPDFRORJ\RUJ2VSUR QDVUHJL}HVRXUHVtGXRV~QLFRVGDVHTXrQFLDGHDPLQRiFLGRVVHMDP
26 EOHPDVGHFODVVLILFDomRQRPHQFODWXUDHWD[RQRPLDUHVXOWDQWHV DOWHUDGRVPRVWURXTXHDPXWDomRGHXPUHVtGXRFUtWLFRQDKpOLFH

C0015.indd 26 04/11/15 1:13 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
Tabela 3.1 Os quatro tipos principais de receptores

Tipo 1: canais iônicos Tipo 2: receptores Tipo 3: receptores Tipo 4: receptores

controlados por ligantes acoplados à proteína G ligados a quinases nucleares

Localização Membrana Membrana Membrana Intracelular

Efetor Canal iônico Canal ou enzima Proteína quinases Transcrição gênica
Acoplamento Direto Proteína G ou arrestina Direto Via DNA
Exemplos Receptor nicotínico da Receptor muscarínico da Insulina, fatores de Receptores de esteroides
acetilcolina, receptor acetilcolina, adrenoceptores crescimento, receptores de
GABAA citocinas
Estrutura Organização oligomérica Estrutura monomérica ou Hélice transmembrana Estrutura monomérica
de subunidades oligomérica compreendendo única ligando o domínio com domínios de ligação
circundando um poro sete hélices transmembrana extracelular do receptor ao ao receptor e domínios de
central com um domínio intracelular domínio da quinase ligação ao DNA
acoplador de proteína G

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pFDUDFWHUL]DGRSRUb  a¬ Ȁ ¬ HQTXDQWRSDUDXPIiUPDFRGHEDL[D
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MECANISMO DE COMPORTA )LJ¬,VVRLPSOLFDDH[LVWrQFLDGHPDLVGRTXHXPDFRQIRUPDomR
2
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3DUDDOpPGLVVRDGHVVHQVLELOL]DomRGRVFDQDLVL{QLFRVRSHUDGRVSRU
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p
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OLJDQWHV&DS¬WDPEpPLPSOLFDXPRXPDLVHVWDGRVFRQIRUPDFLRQDLV
DGLFLRQDLVLQGX]LGRVSRUDJRQLVWDV(VVDVGHVFREHUWDVH[LJHPPDLV
DSHUIHLoRDPHQWRGRPRGHORVLPSOHVHPTXHXP~QLFRHVWDGR5
UHSUHVHQWDGRHVmRXPERPH[HPSORGDIRUPDFRPRRFRPSRUWDPHQWR
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&DS¬RXRJOXWDPDWRQRVLVWHPDQHUYRVRFHQWUDO&DS¬
SURYRFDDXPHQWRQDSHUPHDELOLGDGHDR1DH.HHPDOJXQV
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VHGHYHSULQFLSDOPHQWHDR1DGHVSRODUL]DQGRDFpOXODH
DXPHQWDQGRDSUREDELOLGDGHGHJHUDUXPSRWHQFLDOGHDomR
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DFRSODPHQWRHQWUHRUHFHSWRUHRFDQDOL{QLFRpGLUHWRHDHVWUX
TIPO 2: RECEPTORES ACOPLADOS
À PROTEÍNA G
$JUDQGHIDPtOLD*3&5HQJOREDPXLWRVGRVUHFHSWRUHVTXH
VmRIDPLOLDUHVDRVIDUPDFRORJLVWDVFRPR$&K5PXVFDUtQLFRV
DGUHQRFHSWRUHVUHFHSWRUHVGHGRSDPLQDUHFHSWRUHV+7
UHFHSWRUHVRSLRLGHVUHFHSWRUHVSDUDPXLWRVSHSWtGHRVUHFHSWR
UHVGHSXULQDVHPXLWRVRXWURVLQFOXLQGRRVTXLPLRUUHFHSWRUHV
HQYROYLGRVQRROIDWRHQDGHWHFomRGHIHURP{QLRVHWDPEpP
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C0015.indd 27 04/11/15 1:13 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

A Canais iônicos regulados por ligantes

β δ • São chamados às vezes de receptores ionotrópicos.
α α
ACh ACh • Estão envolvidos principalmente na transmissão
6 nm sináptica rápida.
• Existem várias famílias estruturais, sendo a mais
comum a organização heteromérica de quatro ou cinco
Exterior subunidades, com hélices transmembrana dispostas
em torno de um canal central aquoso.
• A ligação do ligante e a abertura do canal ocorrem em
Membrana 3 nm uma escala de tempo de milissegundos.
• Os exemplos incluem os receptores nicotínicos da
Citosol 2 nm
acetilcolina, do GABA tipo A (GABAA), receptores de
glutamato (NMDA) e de ATP (P2X).

α-Hélices formando a comporta

0XLWRVQHXURWUDQVPLVVRUHVH[FHWRRVSHSWtGLRVSRGHP
LQWHUDJLUWDQWRFRPRV*3&5VFRPRFRPRVFDQDLVDWLYDGRV
β δ SRUOLJDQWHVSHUPLWLQGRTXHDPHVPDPROpFXODSURGX]D
DWUDYpVGRVFDQDLVL{QLFRVDWLYDGRVSRUOLJDQWHVHIHLWRVUiSL
GRVPDVWDPEpPOHQWRVDWUDYpVGRV*3&5V3RURXWURODGR
Poro de ~0,7 RVKRUP{QLRVSHSWtGHRVLQGLYLGXDLVJHUDOPHQWHDJHPVREUH
nm de diâmetro α α RV*3&5VRXVREUHRVUHFHSWRUHVOLJDGRVDTXLQDVHVDGLDQWH
SRUpPUDUDPHQWHVREUHDPERVHXPDHVFROKDVHPHOKDQWH
ACh ACh VHDSOLFDDYiULRVOLJDQWHVTXHDWXDPVREUHRVUHFHSWRUHV
γ
QXFOHDUHV 
2 JHQRPDKXPDQRLQFOXLQGRRVJHQHVTXHFRGLILFDPFHUFD
GH*3&5VH[FOXLQGRRVUHFHSWRUHVGHRGRUFRQVWLWXLD
B FODVVH~QLFDPDLVFRPXPGHDOYRVSDUDIiUPDFRVWHUDSrXWLFRV
HDFUHGLWDVHTXHYiULRVDOYRVSURPLVVRUHVSDUDWDLVIiUPDFRV
DLQGDGHYDPVHULGHQWLILFDGRV3DUDXPDEUHYHUHYLVmRFRQ
VXOWDU+LOO

ESTRUTURA MOLECULAR
2
 SULPHLUR*3&5DVHUWRWDOPHQWHFDUDFWHUL]DGRIRLRUHFHSWRU
b DGUHQpUJLFR&DS¬TXHIRLFORQDGRHP5DSLGDPHQ
WHDELRORJLDPROHFXODUDOFDQoRXDIDUPDFRORJLDHDPDLRULD
GRVUHFHSWRUHVTXHIRUDPLGHQWLILFDGRVSRUVXDVSURSULHGDGHV
IDUPDFROyJLFDVHVWiDJRUDFORQDGD2TXHSDUHFLDVHUUHYROXFLR
QiULRHPpDJRUDFRQVLGHUDGROXJDUFRPXP5HFHQWHPHQ
WHDGLILFXOGDGHGDFULVWDOL]DomRGRV*3&5VIRLXOWUDSDVVDGD
Fig. 3.4 Estrutura do receptor nicotínico da acetilcolina :HLVH.RELOND¬SRVVLELOLWDQGRRHPSUHJRGHWpFQLFDV
(um típico canal iônico controlado por ligante). [A] Diagrama SRWHQWHVGHFULVWDORJUDILDFRPUDLRV;QRHVWXGRGHWDOKDGR
esquemático em visão lateral (acima) e transversal (abaixo). GDHVWUXWXUDPROHFXODUGHVVHVUHFHSWRUHV)LJ¬3DUDDOpP
As cinco subunidades do receptor (a 2, b, g, d) formam um GLVVRIRUDPGHVHQYROYLGRVPpWRGRVGHIOXRUHVFrQFLDSDUD
agregado que circunda um poro transmembrana central, cujo HVWXGDUDFLQpWLFDGDOLJDomRGRVOLJDQWHVHDVPXGDQoDVFRQ
revestimento é formado pelos segmentos helicoidais M2 de IRUPDFLRQDLVVXEVHTXHQWHVDVVRFLDGDVjDWLYDomR/RKVHHW
cada subunidade. Esses segmentos contêm predomínio de
aminoácidos carregados negativamente, o que torna o poro
seletivo para cátions. Existem dois pontos de ligação para
acetilcolina na porção extracelular do receptor, na interface
entre a subunidade a e as subunidades adjacentes. Quando
ocorre a ligação com a acetilcolina, as a-hélices entortadas ou
se endireitam ou giram e se afastam, abrindo, assim, o poro do
canal. [B] Imagem de alta resolução que apresenta um esquema
revisto dos domínios intracelulares. (Painel [A] baseado em
Unwin N 1993 Nicotinic acetylcholine receptor at 9A resolution.
J Mol Biol 229, 1.101-1.124, and Unwin N 1995 Acetylcholine
receptor channel imaged in the open state. Nature 373, 37-43;
painel [B] reproduzido com autorização de Unwin N 2005
Refined structure of the nicotinic acetylcholine receptor at 4A
resolution. J Mol Biol 346(4), 967-989.)
 (QWUHWDQWRRVH[HPSORVGHSURPLVFXLGDGHHVWmRDXPHQWDQGR2V

DO¬%RFNHQKDXHUHWDO¬(VVHIDWRWHPOHYDGRDR
FRQKHFLPHQWRGHLQIRUPDo}HVLPSRUWDQWHVVREUHDVFRQIRUPD
o}HVGDOLJDomRGRVDQWDJRQLVWDDJRQLVWDVDRVUHFHSWRUHVEHP
FRPRVREUHDVLQWHUDo}HVGRVUHFHSWRUHVDFRSODGRVjSURWHtQD
*$SDUWLUGHVVHVHVWXGRVpSRVVtYHODIHULUFRPPDLRUFODUH]D
RPHFDQLVPRGHDWLYDomRGRV*3&5VHRVIDWRUHVGHWHUPLQDQ
WHVQDHILFiFLDGRVDJRQLVWDVEHPFRPRREWHUPHOKRUHVEDVHV
SDUDDFRQFHSomRGHQRYRVOLJDQWHV*3&5
2VUHFHSWRUHVDFRSODGRVjSURWHtQD*FRQVLVWHPQXPD~QLFD
FDGHLDGHSROLSHSWtGHRVQRUPDOPHQWHGHUHVtGXRV
PDVHPDOJXQVFDVRVDWLQJLQGRUHVtGXRV$DQDWRPLD
JHUDOpDSUHVHQWDGDQD)LJXUD¬%6XDHVWUXWXUDHQJORED

KRUP{QLRVHVWHURLGHVQRUPDOPHQWHILpLVDRVUHFHSWRUHVQXFOHDUHV
LQWHUDJHPRFDVLRQDOPHQWHFRPFDQDLVL{QLFRVHRXWURVDOYRV)DONHQVWHLQ
HWDO¬HDOJXQVHLFRVDQRLGHVDJHPQRVUHFHSWRUHVQXFOHDUHVEHP
FRPRQRV*3&5V$QDWXUH]DWHPDPHQWHPXLWRDEHUWDHPERUDWDLV
H[HPSORVVHMDPUHVSRQViYHLVSRUGHL[DURVIDUPDFRORJLVWDVDERUUHFLGRV
28 HRVHVWXGDQWHVHPGHVHVSHUR

C0015.indd 28 04/11/15 1:13 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
Receptores de cistina (cys-loop) Receptores de NMDA Receptores P2X
N N
CANAIS C
ATIVADOS POR
LIGANTES
(5, 4 ou 3
subunidades)
C
Exemplos: nAChR, GABAA, Exemplos: NMDA Exemplo: P2XR
5-HT3, IP3R, RyR
Fig. 3.5 Arquitetura molecular dos canais iônicos ativados por ligantes. Os retângulos azuis e vermelhos representam as a-hélices
transmembranares, e os ganchos azuis representam as regiões de formação dos poros P loop. Os receptores cys-loop são pentaméricos.
Os receptores do tipo NMDA são tetraméricos, e os P2X, triméricos. Receptor 5-HT3, 5-hydroxitriptamina tipo 3; receptor GABAA, GABA
tipo A; IP3R, receptor do inositol trifosfato; nAChR, receptor nicotínico de acetilcolina; NMDA, N-metil D-Aspartato; P2XR, receptor de purina
P2X; RyR, receptor de rianodina.

Tabela 3.2 Famílias de receptores acoplados à proteína Ga

Família Receptoresb Características estruturais

A: família da rodopsina O maior grupo. Receptores para a maioria dos Cauda extracelular (N terminal) curta. O
neurotransmissores aminados, muitos neuropeptídeos, ligante liga-se a hélices transmembrana
purinas, prostanoides, canabinoides etc. (aminas) ou a alças extracelulares (peptídeos)
B: família dos receptores de Receptores para hormônios peptídicos, incluindo Cauda extracelular intermediária
secretina/glucagon secretina, glucagon, calcitonina incorporando o domínio de ligação ao ligante
C: família do receptor Grupo pequeno. Receptores metabotrópicos de Cauda extracelular longa incorporando o
metabotrópico de glutamato/ glutamato, receptores GABAB, receptores sensíveis domínio de ligação ao ligante
sensor de cálcio ao Ca2+

a
Uma quarta família distinta inclui muitos receptores para feromônios, mas nenhum receptor farmacológico.
b
Para listas completas, consulte www.guidetopharmacology.org.

VHWHKpOLFHVa WUDQVPHPEUDQDUHVVHPHOKDQWHVjVGRVFDQDLV UHVSRQViYHOSHODWUDQVGXomRQRVEDVWRQHWHVUHWLQLDQRV(VVDSURWHtQD

L{QLFRVDQWHULRUPHQWHGLVFXWLGRVFRPXPGRPtQLRWHUPLQDO1 pDEXQGDQWHQDUHWLQDHVHXHVWXGRpPXLWRPDLVIiFLOGRTXHRGDV
H[WUDFHOXODUGHFRPSULPHQWRYDULiYHOHXPGRPtQLRWHUPLQDO SURWHtQDVUHFHSWRUDVTXHQmRVmRDEXQGDQWHVpFRQVWUXtGDHPXP
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&LQWUDFHOXODU
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PDVSRXFDHQWUHRVGLIHUHQWHVJUXSRV3DUWLOKDPDPHVPD XPIyWRQHQmRSRUXPDPROpFXODGHDJRQLVWD&RPHIHLWRDURGRS
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WDKHOLFRLGDOPDVGLIHUHPHPRXWURVDVSHFWRVSULQFLSDOPHQWH PROpFXODGHDJRQLVWDFKDPDGDUHWLQDODTXDOVRIUHLVRPHUL]DomRGD
QRFRPSULPHQWRGRWHUPLQDO²1H[WUDFHOXODUHQDORFDOL]DomR IRUPDWUDQVLQDWLYDSDUDDIRUPDFLVDWLYDTXDQGRDEVRUYHXPIyWRQ
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FDOFLWRQLQDHJOXFDJRQ$IDPtOLD&pDPHQRUVHXVSULQFLSDLV
PHPEURVVmRRVUHFHSWRUHVPHWDERWUySLFRVSDUDJOXWDPDWRH
([SHULPHQWRVGHPXWDJrQHVHGLUHFLRQDGDDORFDLVPRVWUDP
TXHDWHUFHLUDDOoDFLWRSODVPiWLFDpDUHJLmRGDPROpFXODTXH
VHDFRSODjSURWHtQD*SRLVDGHOHomRRXDPRGLILFDomRGHVVD
SRUomRUHVXOWDPHPUHFHSWRUHVTXHDWpVHOLJDPDOLJDQWHV
PDVTXHVmRLQFDSD]HVGHVHDVVRFLDUjVSURWHtQDV*RXGH
SURGX]LUUHVSRVWDV(PJHUDOGHWHUPLQDGRVXEWLSRGHUHFHS
*$%$&DS¬HRVUHFHSWRUHVVHQVtYHLVDR&D&DS¬
▼$FRPSUHHQVmRGDIXQomRGHVVHWLSRGHUHFHSWRUGHYHPXLWRDR
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WRUDFRSODVHVHOHWLYDPHQWHDXPDSURWHtQD*HPSDUWLFXODU
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 2UHFHSWRUVHQVRUGH&D&RQLJUDYHHWDO¬pXP*3&5LQFRPXP
 TXLQDVHVLQWUDFHOXODUHVSRGHUHVXOWDUHPGHVVHQVLELOL]DomR
TXHpDWLYDGRQmRSHORVPHGLDGRUHVFRQYHQFLRQDLVPDVVLPSHOR&D GRUHFHSWRUSiJ
H[WUDFHOXODUQDIDL[DGHD¬PPROO²XPDDILQLGDGHH[WUHPDPHQWH 1
 DVPROpFXODVPHQRUHVWDOFRPRQRUDGUHQDOLQDQRUHSLQH
EDL[DHPFRPSDUDomRFRPRXWURVDJRQLVWDVGH*3&5V(VVHUHFHSWRUp IULQDHDFHWLOFROLQDRGRPtQLRGDOLJDomRDROLJDQWHQRVUHFHS
H[SUHVVRHPFpOXODVGDJOkQGXODSDUDWLUHRLGHHWHPSRUIXQomRUHJXODU
DFRQFHQWUDomRGH&DH[WUDFHOXODUDWUDYpVGRFRQWUROHGDVHFUHomRGR WRUHVGHFODVVH$HVWiLQVHULGRQDIHQGDHQWUHRVVHJPHQWRV
SDUDWRUP{QLR&DS¬(VVHPHFDQLVPRKRPHRVWiWLFRpEDVWDQWHGLVWLQWR aKHOLFRLGDLVGHQWURGDPHPEUDQD)LJV¬%H¬VLPLODU
GRVPHFDQLVPRVGHUHJXODomRGR&DLQWUDFHOXODUGLVFXWLGRVQR&DStWXOR¬ DRHVSDoRRFXSDGRSHORUHWLQDOQDPROpFXODGHURGRSVLQD2V 29

C0015.indd 29 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

Modulador
A Aberturas do canal nicotínico de acetilcolina
alostérico
0

Número de canais abertos

positivo
Exterior da célula

Membrana
3 pA 2 Agonista

10 ms

B Aberturas do canal NMDA

Interior
Estados de condutividade

da célula
Fig. 3.7 Estrutura do receptor muscarínico M4. Imagem
18 pS de alta resolução que apresenta a conformação do receptor
muscarínico M4 ligado a um agonista (ortostérico) e também
38 pS a um modulador alostérico positivo. Os cilindros em amarelo
representam os domínios transmembranares. A extensão total
2 pA dos domínios N- e C- terminal e o terceiro circuito intracelular
não estão representados. (Cortesia de A Christopoulos.)
20 ms

Fig. 3.6 Aberturas de canais registradas através da técnica

de Patch-clamp. [A] Canais iônicos ativados por acetilcolina
RECEPTORES ATIVADOS POR PROTEASES
na placa motora terminal da rã. A pipeta é pressionada contra a ▼(PERUDDDWLYDomRGRV*3&5VVHMDQRUPDOPHQWHDFRQVHTXrQFLD
superfície da membrana com 10 mmol/l ACh. Os desvios abaixo GDOLJDomRGHXPDJRQLVWDGLIXVRWDPEpPSRGHVHUUHVXOWDQWHGD
apresentam o fluxo da corrente através dos canais iônicos na DWLYDomRSRUXPDSURWHDVH-iIRUDPLGHQWLILFDGRVTXDWURWLSRVGH
zona da membrana em que foi aplicada a pipeta. No final do UHFHSWRUHVDWLYDGRVSRUSURWHDVH3$5V GRLQJOrVSURWHDVHDFWLYDWHG
registro, é possível ver a abertura discreta entre os dois canais. UHFHSWRUVUHYLVDGRVSRU5DPDFKDQGUDQH+ROOHQEHUJ¬0XLWDV
[B] Correntes num único canal receptor de NMDA registradas SURWHDVHVFRPRDWURPELQDXPDSURWHDVHHQYROYLGDQDFDVFDWDGD
nos neurônios cerebrais na conformação exterior da parte da FRDJXODomRVDQJXtQHD&DS¬DWLYDPRV3$5VDRUHPRYHUHPD
membrana da célula (patch). O NMDA foi adicionado ao exterior
da parte da membrana da célula (patch) para ativar o canal.
O canal abre-se em vários níveis de condutância. Em [B] as
H[WUHPLGDGHGDFDXGD1WHUPLQDOH[WUDFHOXODUGRUHFHSWRU)LJ¬
SDUDH[SRUFLQFRRXVHLVUHVtGXRV1WHUPLQDLVTXHVHOLJDPDRVGRPt
QLRVGRUHFHSWRUQDVDOoDVH[WUDFHOXODUHVIXQFLRQDQGRFRPRXP
´DJRQLVWDDSULVLRQDGRµ5HFHSWRUHVGHVVHWLSRRFRUUHPHPYiULRV
aberturas no nível mais alto de condutância e os encerramentos
subsequentes são lentos, indicando que um canal está aberto
(não é provável que dois canais abram e fechem ao mesmo
tempo), enquanto em [A] existem níveis discretos que indicam
dois canais. (Painel [A] cortesia de D Colquhoun e DC Ogden;
WHFLGRV5DPDFKDQGUDQH+ROOHQEHUJ¬HSDUHFHPGHVHPSHQKDU
XPSDSHOQDLQIODPDomRHHPRXWUDVUHVSRVWDVDOHV}HVGHWHFLGRQDV
TXDLVVmROLEHUDGDVSURWHDVHVWHFLGXDLV8PUHFHSWRUGDIDPtOLDGRV
3$5VR3$5pDWLYDGRSRUXPDSURWHDVHOLEHUDGDGHPDVWyFLWRV
HpH[SUHVVRHPQHXU{QLRVVHQVRULDLV$FUHGLWDVHTXHHVVHUHFHSWRU
painel [B] reproduzido com autorização de Cull-Candy SG & GHVHPSHQKHSDSHOUHOHYDQWHQDGRUGDLQIODPDomR&DS¬8PD
Usowicz MM 1987 Nature 325, 525-528.) PROpFXOD3$5SRGHVHUDWLYDGDVRPHQWHXPDYH]SRUTXHQmRKi
FRPRDFOLYDJHPVHUUHYHUWLGDGHPRGRTXHpSUHFLVRRFRUUHUUHV
VtQWHVHFRQWtQXDGDSURWHtQDUHFHSWRUD$LQDWLYDomRVHGiDWUDYpVGH
XPDFOLYDJHPSURWHROtWLFDTXHDWDROLJDQWHRXDWUDYpVGDGHVVHQVLEL
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OLJDQWHVSHSWtGLFRVFRPRDVXEVWkQFLD3&DS¬OLJDPVH
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pLQWHUQDOL]DGRHGHJUDGDGRVHQGRVXEVWLWXtGRSRUXPDSURWHtQD
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PROTEÍNAS G E SUA FUNÇÃO
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PHGLiULDQDKLHUDUTXLDRUJDQL]DFLRQDOLQWHUYLQGRHQWUHRV
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FRPRIRQWHGHLQVSLUDomRTXtPLFD 
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FDQDLVL{QLFRV²DEULJDGDGHVROGDGRVUDVRVTXHH[HFXWDP
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SURFHVVR6mRDVSURWHtQDV´GHPHLRFDPSRµTXHQDUHDOLGD
GHIRUDPGHQRPLQDGDVSURWHtQDV*GHYLGRjVXDLQWHUDomR
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UREyWLFDHILFLHQWH$JRUDFRPDVHVWUXWXUDVGHFULVWDOSRGHUHPRVHVWDUD PDLVGHWDOKDGDVVREUHDHVWUXWXUDHDVIXQo}HVGDVSURWHtQDV
30 FDPLQKRGHXPDHUDPDLVVRILVWLFDGDQDGHVFREHUWDGHIiUPDFRV *YHUDVUHYLV}HVGH0LOOLJDQH.RVWHQLV H2OGKDPH

C0015.indd 30 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
N
Agonista preso
Clivagem pela trombina
N
N Fragmento N
liberado
Fosforilação

INATIVO ATIVO DESSENSIBILIZADO

P

Fig. 3.8 Ativação de um receptor ativado por protease pela clivagem do domínio N-terminal extracelular. A inativação ocorre por
fosforilação. A recuperação requer nova síntese do receptor.

RUHFHSWRU(VVDLQWHUDomRRFRUUHGHQWURGHPVFDXVDQGRD
Receptores acoplados à proteína G GLVVRFLDomRGR*'3OLJDGRHVXDVXEVWLWXLomRSRU*73SHU
PXWD*'3*73RTXHSRUVXDYH]OHYDjGLVVRFLDomRGR
• São denominados algumas vezes receptores WUtPHURGDSURWHtQD*OLEHUDQGRDVVXEXQLGDGHVa*73Hbg  
metabotrópicos ou receptores com sete domínios HVWDVVmRDVIRUPDV´DWLYDVµGDSURWHtQD*TXHVHGLIXQGHP
transmembrana (7-TDM). QDPHPEUDQDHSRGHPDVVRFLDUVHDGLYHUVDVHQ]LPDVHFDQDLV
• As estruturas compreendem sete a-hélices que L{QLFRVFDXVDQGRDDWLYDomRGRDOYR)LJ¬2ULJLQDOPHQWH
atravessam a membrana, em geral ligadas, formando DFUHGLWDYDVHTXHDSHQDVDVXEXQLGDGHaWLQKDIXQomRVLQDOL
estruturas diméricas. ]DGRUDHRFRPSOH[RbgVHUYLULDDSHQDVFRPRXP´DFRPSD
• A terceira alça intracelular interage com a proteína G.
• A proteína G é uma proteína de membrana que
compreende três subunidades (a, b, g), com a
subunidade a apresentando atividade GTPásica.
• Quando o trímero se liga a um receptor ocupado por
um agonista, a subunidade a se liga a GTP, dissocia-se
e, então, fica livre para ativar um efetor (p. ex., uma
QKDQWHµFKDSHURQHTXHPDQWHULDDVVXEXQLGDGHVa VROWDVH
IRUDGRDOFDQFHGDVYiULDVSURWHtQDVHIHWXDGRUDVTXHGHRXWUR
PRGRVHULDPSRUHODVH[FLWDGDV1RHQWDQWRRVFRPSOH[RV
bg WrPVXDVSUySULDVDWULEXLo}HVHFRQWURODPRVHIHWRUHVGH
PRGRPXLWRVHPHOKDQWHDRGDVVXEXQLGDGHVa$DVVRFLDomR
GDVVXEXQLGDGHVa RXbg FRPDVHQ]LPDVDOYRRXRVFDQDLV
SRGHFDXVDUDWLYDomRRXLQLELomRGHSHQGHQGRGHTXHSURWHtQD
enzima de membrana). Em alguns casos, a subunidade
bg é a espécie ativadora.
• A ativação do efetor termina quando ocorre a hidrólise
da molécula de GTP ligada, o que permite que a
subunidade a se recombine com bg.
*HVWiHQYROYLGD7DEHOD¬$DWLYDomRGDSURWHtQD*UHVXOWD
HPDPSOLILFDomRSRUTXHXP~QLFRFRPSOH[RDJRQLVWDUHFHSWRU
SRGHDWLYDUSRUVXDYH]YiULDVSURWHtQDV*HFDGDXPDGHODV
SRGHSHUPDQHFHUDVVRFLDGDjVHQ]LPDVHIHWRUDVSRUWHPSR
VXILFLHQWHSDUDSURGX]LUPXLWDVPROpFXODVGRFRPSRVWR2
• Existem vários tipos de proteína G, que interagem com
diferentes receptores e controlam diferentes efetores.
• Exemplos incluem o receptor muscarínico da
acetilcolina, adrenoceptores, receptores de
neuropeptídeos e de quimiocinas, e os receptores
ativados por protease.
+
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Hg SHUPDQHFHPXQLGDVQDIRUPDGHXPFRPSOH[Rb g
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$VSURWHtQDV5*6H[HUFHPDVVLPHIHLWRLQLELWyULRQDVLQDOL]DomRGH
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*'3DRFXSDURORFDOQDVXEXQLGDGHa4XDQGRR*3&5pDWL HVLVWHPDVHIHWRUHVHPXPDFpOXODSRGHSDUHFHUTXHWRGD
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HLQGX]LQGRXPDLQWHUDomRGHJUDQGHDILQLGDGHHQWUHabg H DPERVRFRUUHQGRQDVFpOXODVPXVFXODUHVFDUGtDFDVSURGX]HP 31

C0015.indd 31 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

Estado de repouso
Receptor Receptor ocupado por um agonista

Alvo Alvo Target Alvo

1 2 1 2
α βγ α βγ
Inativo GDP Inativo Inativo GDP Inativo

GTP

GTP hidrolisado Proteínas-alvo

ativadas
Alvo Alvo Alvo Alvo
1 α 2 1 α 2
βγ βγ
Ativo GDP Ativo Ativo GTP Ativo
+
P

Fig. 3.9 A função da proteína G. A proteína G consiste em três subunidades (a, b, g) que ficam ancoradas à membrana através de
resíduos de lipídeos fixos. O acoplamento da subunidade a a um receptor ocupado por um agonista promove a troca do GDP ligado pelo
GTP intracelular; o complexo a-GTP, então, se dissocia do receptor e do complexo bg, interagindo com uma proteína-alvo (alvo 1, que
pode ser uma enzima, como adenil-ciclase ou fosfolipase C). O complexo bg também ativa uma proteína-alvo (alvo 2, que pode ser um
canal iônico ou uma quinase). A atividade GTPase da subunidade a aumenta quando a proteína-alvo é ligada, resultando em hidrólise do
GTP ligado para GDP, o que faz com que a subunidade a volte a se ligar com bg.

Tabela 3.3 Os principais subtipos de proteína G e suas funçõesa

Subtipos Receptores associados Efetores principais Notas

Subunidades Ga
Gas Muitos receptores para Estimula a adenililciclase, aumentando a formação Ativadas pela toxina do cólera,
aminas e outros (p. ex., de AMPc que bloqueia a atividade GTPase,
catecolaminas, histamina, impedindo, assim, a inativação
serotonina)
Gai Como para GaS, e também Inibe a adenililciclase, diminuindo a formação de Bloqueadas pela toxina pertússis,
receptores opioides e AMPc que impede a dissociação do
canabinoides complexo abg
Gao Como para GaS, e também ? Efeitos limitados da subunidade a (os efeitos Bloqueada pela toxina pertússis.
receptores opioides e devem-se principalmente às subunidades bg) Ocorre principalmente no sistema
canabinoides nervoso
Gaq Receptores de aminas, Ativa a fosfolipase C, aumentando a produção —
peptídeos e prostanoides dos segundos mensageiros inositol trisfosfato e
diacilglicerol (págs. 34 e 35)
Subunidades Gbg
Todos os GPCRs Ativam canais de potássio Muitas isoformas de bg
Inibem canais de cálcio controlados por voltagem identificadas, mas as funções
Ativam as GPCR quinases (GRKs, pág. 36) específicas ainda não são
Ativam a cascata de proteínas quinases ativadas conhecidas.
por mitógenos
Interage com algumas formas de adenil-ciclase e
com fosfolipase Cb

GPCR, receptor acoplado à proteína G (G-protein-coupled receptor).

a
Esta tabela lista apenas as isoformas de maior significância farmacológica. Muitas outras foram identificadas, algumas, inclusive, têm
funções no olfato, paladar, transdução visual e em outras funções fisiológicas (Offermanns, 2003).
32

C0015.indd 32 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
Receptor Enzima- Receptor
inibitório alvo estimulatório
Fig. 3.10 Controle bidirecional de Gi Gs
uma enzima-alvo como a adenilato
ciclase, por Gs e Gi. A heterogeneidade Ri Rs
das proteínas G permite que receptores
βγ αi αs βγ
diferentes exerçam efeitos opostos em
uma mesma enzima-alvo.

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GHKHWHURJHQHLGDGHPROHFXODUMiTXHHVVHpRFDPLQKRGDHYROXomR RXWURVS¬H[3'( VmRVHOHWLYRVSDUD*03F$PDLRUSDUWH 33

C0015.indd 33 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

Aumento da lipólise
Lipase (inativa)
ATP

ADP
Lipase (ativa)
Proteína quinase
ATP (inativa)
AC
AMPc Glicogênio Redução da síntese de glicogênio
sintase (ativa)
ATP
Proteína quinase
(ativa)
ADP
G Glicogênio sintase
(inativa)

Agonista
R Fosforilase Aumento da quebra de glicogênio
quinase (inativa)
ATP
Fosforilase b
(inativa)
ADP
ATP
Fosforilase
quinase (ativa) Glicogênio
ADP
ATP
Fosforilase a
(ativa)
ADP
Glicose-1-fosfato

Fig. 3.11 Regulação do metabolismo energético pelo AMPc. AC, adenilil ciclase.

pPRGHUDGDPHQWHLQLELGDSRUIiUPDFRVFRPRDVPHWLO[DQWLQDV DYHVPDULQKDV(OHVFRQVWDWDUDPTXHDVHFUHomRHUDDFRPSD
S¬H[WHRILOLQDHFDIHtQD&DSV¬H¬2UROLSUDPXVDGR QKDGDGHDXPHQWRGDUHQRYDomRGHXPDFODVVHPHQRUGH
QRWUDWDPHQWRGDDVPD&DS¬pVHOHWLYRSDUD3'(H[SUHVVD IRVIROLStGHRVGHPHPEUDQDFRQKHFLGRVFRPRIRVIRLQRVLWtGHRV
QDVFpOXODVLQIODPDWyULDVPLOULQRQD XVDGDQRWUDWDPHQWR FROHWLYDPHQWHGHVLJQDGRVGH3,V)LJ¬3RVWHULRUPHQWH
GDLQVXILFLrQFLDFDUGtDFD&DS¬pVHOHWLYDSDUD3'(D 0LFKHOOH%HUULGJHGHVFREULUDPTXHPXLWRVKRUP{QLRVTXH
TXDOpH[SUHVVDQRP~VFXORFDUGtDFRDV LOGHQDILOD PDLV SURGX]HPHOHYDomRQDFRQFHQWUDomRLQWUDFHOXODUGH&DOLYUH
FRQKHFLGDFRPR9LDJUDŠ & DS¬ pVHOHWLYDSDUD3'( H LQFOXLQGRSRUH[HPSORDJRQLVWDVPXVFDUtQLFRVHDJRQLVWDVGH
FRQVHTXHQWHPHQWHUHIRUoDRVHIHLWRVYDVRGLODWDGRUHVGRy[LGR a DGUHQRFHSWRUHVTXHDJHPQRP~VFXOROLVRHQDVJOkQGXODV
QLWURVR12HGHIiUPDFRVTXHOLEHUDP12FXMRVHIHLWRVVmR VDOLYDUHVHYDVRSUHVVLQDTXHDWXDVREUHDVFpOXODVKHSiWLFDV
PHGLDGRVSHOR*03F&DS¬$VLPLODULGDGHHQWUHDOJXPDV WDPEpPDXPHQWDPDUHQRYDomRGH3,3RVWHULRUPHQWHGHV
Do}HVGHVVHVIiUPDFRVFRPDVGDVDPLQDVVLPSDWRPLPpWLFDV FREULXVHTXHXPPHPEURHPSDUWLFXODUGDIDPtOLD3,FKDPD
&DS¬SURYDYHOPHQWHUHIOHWHVXDSURSULHGDGHFRPXPTXH GRIRVIDWLGLOLQRVLWROELVIRVIDWR3,3TXHSRVVXLJUXSRV
pDGHDXPHQWDUDFRQFHQWUDomRLQWUDFHOXODUGH$03F(VWmR DGLFLRQDLVGHIRVIDWROLJDGRVDRDQHOLQRVLWROGHVHPSHQKD
HPGHVHQYROYLPHQWRLQLELGRUHVVHOHWLYRVGDVYiULDV3'(V SDSHOFKDYH23,3 pRVXEVWUDWRGHXPDHQ]LPDOLJDGDj
SULQFLSDOPHQWHSDUDRWUDWDPHQWRGHGRHQoDVFDUGLRYDVFXOD PHPEUDQDDIRVIROLSDVH&b3/&bTXHHIHWXDVXDFOLYDJHP
UHVHUHVSLUDWyULDV HPGLDFLOJOLFHURO'$*HLQRVLWROWULIRVIDWR,3)LJ¬ 
RVTXDLVDWXDPFRPRVHJXQGRVPHQVDJHLURVFRQIRUPHGLV
O sistema fosfolipase C/fosfato de inositol FXWLGRPDLVDGLDQWHSiJ$DWLYDomRGD3/&bSRUYiULRV
 VLVWHPDIRVIRLQRVLWtGHRXPLPSRUWDQWHVLVWHPDLQWUDFHOXODU
2 DJRQLVWDVpPHGLDGDSRUXPDSURWHtQD**T7DEHOD¬$SyV
GHVHJXQGRVPHQVDJHLURVIRLGHVFREHUWRQDGpFDGDGH DFOLYDJHPGR3,3RVWDWXVTXRpUHVWDEHOHFLGRFRPRPRVWUDD
SRU+RNLQH+RNLQTXHHVWDYDPLQWHUHVVDGRVSULQFLSDOPHQWH ) LJXUD¬VHQGRR'$*IRVIRULODGRGHVWLQDGRDIRUPDUiFLGR
34 QRPHFDQLVPRGHVHFUHomRGHVDLVSHODVJOkQGXODVQDVDLVGDV IRVIDWtGLFR3$HQTXDQWRR,3 pGHVIRVIRULODGRHDVHJXLU

C0015.indd 34 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
H[WUHPDPHQWH~WHLVQRHVWXGRGDVIXQo}HVGD3.&8PGRV
VXEWLSRVpDWLYDGRSHORPHGLDGRUOLStGLFRRiFLGRDUDTXLG{QLFR

Ácido araquidônico
&DS¬SURGX]LGRSHODDomRGDIRVIROLSDVH$VREUHRVIRV
IROLStGHRVGDPHPEUDQDGHPRGRTXHWDPEpPSRGHRFRUUHU
Ácido graxo

DDWLYDomRGD3.&SRUDJRQLVWDVTXHDWLYDPDTXHODHQ]LPD
$VYiULDVLVRIRUPDVGD3.&FRPRDVWLURVLQDVTXLQDVHVGLV
FXWLGDVDGLDQWHSiJDJHPHPPXLWDVSURWHtQDVIXQFLRQDLV
GLIHUHQWHVFRPRFDQDLVL{QLFRVUHFHSWRUHVHQ]LPDVLQFOXLQGR
DAG RXWUDVTXLQDVHVIDWRUHVGHWUDQVFULomRHSURWHtQDVGRFLWRHV
PA TXHOHWR$IRVIRULODomRGHSURWHtQDVSHODVTXLQDVHVGHVHPSH
QKDIXQomRFHQWUDOQDWUDQVGXomRGHVLQDOUHJXODQGRPXLWRV
O O DVSHFWRVGLIHUHQWHVGDIXQomRFHOXODU$FRQH[mR'$*3.&
PIP2 PLA2 IRUQHFHXPPHFDQLVPRSHORTXDORV*3&5VSRGHPPRELOL]DU
C C C HVVHH[pUFLWRGHDJHQWHVFRQWURODGRUHV
O Canais iônicos como alvos das proteínas G
PLC
P 2XWUDIXQomRLPSRUWDQWHGRVUHFHSWRUHVDFRSODGRVjSURWHtQD
PLD *pRFRQWUROHGDIXQomRGRVFDQDLVL{QLFRVGLUHWDPHQWHDWUDYpV
HO 1 OH GHPHFDQLVPRVTXHQmRHQYROYHPVHJXQGRVPHQVDJHLURV
6 2
I(1,4,5)P3 FRPR$03FRXIRVIDWRVGHLQRVLWRO$LQWHUDomRGLUHWDGRFDQDO
5 3 SURWHtQD*DWUDYpVGDVVXEXQLGDGHVbgGDVSURWHtQDV*LH*R
P 4 OH DSDUHQWDVHUXPPHFDQLVPRJHUDOSDUDFRQWUROHGRVFDQDLV.
P H&D1RP~VFXORFDUGtDFRSRUH[HPSORpGHVVDIRUPDTXHR
P$&K5VDXPHQWDDSHUPHDELOLGDGHGH.KLSHUSRODUL]DQGR
Fig. 3.12 Estrutura do fosfatidilinositol bisfosfato (PIP2),
mostrando pontos de clivagem por diferentes fosfolipases
para produzir mediadores ativos. A clivagem pela fosfolipase
A2 (PLA2) produz ácido araquidônico. A clivagem pela fosfolipase
C (PLC) produz inositol trisfosfato (I(1, 4, 5)P3) e diacilglicerol
(DAG). PA, ácido fosfatídico; PLD, fosfolipase D.
SRUWDQWRDVFpOXODVHLQLELQGRDDWLYLGDGHHOpWULFD&DS¬
0HFDQLVPRVVHPHOKDQWHVRSHUDPQRVQHXU{QLRVRQGHPXLWRV
IiUPDFRVLQLELWyULRVFRPRSRUH[HPSORRVDQDOJpVLFRVRSLRL
GHVUHGX]HPDH[FLWDELOLGDGHDRDEULUHPGHWHUPLQDGRVFDQDLV
.²FRQKHFLGRVFRPRFDQDLVGH.UHWLILFDGRVLQWHUQDPHQWH
SHODSURWHtQD**,5.²RXDWUDYpVGDLQLELomRGRVFDQDLV
1H&DWLSR34GHSHQGHQWHVGDYROWDJHPHGHVVDIRUPD
UHGX]LQGRDOLEHUDomRGRQHXURWUDQVPLVVRU&DSV¬H¬
UHDFRSODGRDR3$SDUDIRUPDU3,3 PDLVXPDYH] 2OtWLR 2VSULQFLSDLVSDSpLVSURYiYHLVGRV*3&5VQRFRQWUROHGDV
XPDJHQWHXVDGRHPSVLTXLDWULD&DS¬EORTXHLDHVVDYLD HQ]LPDVHGRVFDQDLVL{QLFRVHVWmRDSUHVHQWDGRVGHIRUPD
GHUHFLFODJHP)LJ¬ UHVXPLGDQD)LJXUD¬
Fosfatos de inositol e cálcio intracelular
Sistema Rho/Rho quinase
2LQRVLWROWULVIRVIDWR,3pXPPHGLDGRUKLGURVVRO~YHO
TXHpOLEHUDGRQRFLWRVROHDJHHPXPUHFHSWRUHVSHFtILFR²R ▼(VVDYLDGHWUDQVGXomRGHVLQDO%LVKRSH+DOOpDWLYDGDSRU
UHFHSWRU,3²TXHpXPFDQDOGHFiOFLRFRQWURODGRSRUOLJDQWH
SUHVHQWHQDPHPEUDQDGRUHWtFXORHQGRSODVPiWLFR$IXQomR
SULQFLSDOGR,3GHVFULWDHPPDLVGHWDOKHVQR&DStWXOR¬p
FRQWURODUDOLEHUDomRGH&DGDVUHVHUYDVLQWUDFHOXODUHV&RPR
PXLWRVHIHLWRVGHIiUPDFRVHKRUP{QLRVHQYROYHPR&DLQWUD
FHOXODUHVVDYLDpSDUWLFXODUPHQWHLPSRUWDQWH2,3pFRQYHU
FHUWRV*3&5VHWDPEpPSRUPHFDQLVPRVQmR*3&5TXHVHDFRSODP
DSURWHtQDV*GRWLSR*$VXEXQLGDGHa OLYUHGDSURWHtQD*
LQWHUDJHFRPRIDWRUGHWURFDGRQXFOHRWtGHRJXDQRVLQDTXHIDFLOLWDD¬SHU
PXWD*'3*73HPRXWUD*73DVH5KR$5KR*'3TXHpD¬IRUPDGH
UHSRXVRpLQDWLYDPDVTXDQGRRFRUUHDSHUPXWD*'3*73D¬5KR
pDWLYDGDHSRUVXDYH]DWLYDD5KRTXLQDVH$5KRTXLQDVHIRV
IRULODPXLWRVVXEVWUDWRVSURWHLFRVHFRQWURODXPDDPSODYDULHGDGHGH
WLGRGHQWURGDFpOXODSDUDRWHWUDIRVIDWR,3SRUXPD IXQo}HVFHOXODUHVLQFOXLQGRFRQWUDomRHSUROLIHUDomRGRP~VFXOROLVR
TXLQDVHHVSHFtILFD$IXQomRH[DWDGR,3DLQGDpLQFHUWDPDV DQJLRJrQHVHHUHPRGHODomRVLQiSWLFD3RUDXPHQWDUDYDVRFRQVWULomR
DOJXPDVHYLGrQFLDVVXJHUHPTXHHOHHRVIRVIDWRVGHLQRVLWRO GDDUWpULDSXOPRQDULQGX]LGDSRUKLSy[LDDDWLYDomRGD5KRTXLQDVH
DWXDPQDVLQDOL]DomRGRFRQWUROHGDH[SUHVVmRJrQLFD pFRQVLGHUDGDLPSRUWDQWHQDSDWRJrQHVHGDKLSHUWHQVmRSXOPRQDU
&DS¬,QLELGRUHVHVSHFtILFRVGD5KRTXLQDVHS¬H[IDVXGLOHVWmR
Diacilglicerol e proteína quinase C HPGHVHQYROYLPHQWRSDUDXPDJUDQGHJDPDGHLQGLFDo}HVFOtQLFDV²
XPDiUHDDVHUREVHUYDGD
2GLDFLOJOLFHUROpSURGX]LGRDVVLPFRPRR,3VHPSUHTXH
RFRUUHKLGUyOLVHGH3,LQGX]LGDSRUUHFHSWRUHV2SULQFLSDO
O sistema das MAP-quinase
HIHLWRGR'$*pDWLYDUXPDSURWHtQDTXLQDVHDSURWHtQDTXLQDVH
&3.&TXHFDWDOLVDDIRVIRULODomRGHYiULDVSURWHtQDVLQWUDFH ▼2VLVWHPDGDV0$3TXLQDVHHQYROYHYiULDVYLDVGHWUDQVGXomRGH
VLQDO)LJ¬TXHVmRDWLYDGDVQmRVySRUYiULDVFLWRFLQDVHIDWRUHV
OXODUHV2'$*GLIHUHQWHPHQWHGRVIRVIDWRVGHLQRVLWROpEDV
GHFUHVFLPHQWRTXHDWXDPQRVUHFHSWRUHVRSHUDGRVSRUTXLQDVHVSiJ
WDQWHOLSRItOLFRHVHPDQWpPQDPHPEUDQD/LJDVHDXPSRQWR )LJ¬PDVWDPEpPSRUOLJDQWHVGH*3&5V$OLJDomRGH*3&5V
HVSHFtILFRQDPROpFXODGD3.&ID]HQGRFRPTXHDHQ]LPD DGLIHUHQWHVJUXSRVGH0DSTXLQDVHVSRGHHQYROYHUDVVXEXQLGDGHV
PLJUHGRFLWRVROSDUDDPHPEUDQDGDFpOXODWRUQDQGRVHHQWmR aHbgGDSURWHtQD*EHPFRPR6UFHDUUHVWLQDV²SURWHtQDVWDPEpP
DWLYDGD([LVWHPSHORPHQRVGH]GLIHUHQWHVVXEWLSRVGH3.& HQYROYLGDVQDGHVVHQVLELOL]DomRGR*3&5SiJ3LHUFHH/HINR
HPPDPtIHURVFRPGLVWULEXLo}HVFHOXODUHVGLVWLQWDVHTXHIRV
IRULODPGLIHUHQWHVSURWHtQDV9iULRVVmRDWLYDGRVSRU'$*HSRU
QtYHLVLQWUDFHOXODUHVHOHYDGRVGH&DDPERVSURGX]LGRVSHOD
DWLYDomRGH*3&5V$V3.&VVmRDWLYDGDVWDPEpPSRUpVWHUHV
GHIRUEROFRPSRVWRVDOWDPHQWHLUULWDQWHVSURGX]LGRVSRUFHUWDV
ZLW]¬2VLVWHPDGD0DSTXLQDVHFRQWURODPXLWRVGRVSURFHVVRV
HQYROYLGRVQDH[SUHVVmRJHQpWLFDQDGLYLVmRFHOXODUQDDSRSWRVHH
QDUHJHQHUDomRGRVWHFLGRV
OUTROS DESENVOLVIMENTOS NA BIOLOGIA
SODQWDVTXHSURPRYHPDIRUPDomRGHWXPRUHVTXHWrPVLGR DO GPCR
▼1RLQtFLRGRVDQRVDFUHGLWDYDVHTXHMiVHFRQKHFLDHPFHUWD
PHGLGDDIXQomRGR*3&5WDOFRPRGHVFULWRDVHJXLU'HVGHHQWmR
 $EUHYLDo}HVDOWHUQDWLYDVSDUDHVVHVPHGLDGRUHVVmR3WG,QV3,3WG,QV
 RHQUHGRWHPVHFRPSOLFDGRHGHVHQYROYLPHQWRVSRVWHULRUHVOHYDUDP
33,3,QV3,3H,QV3,3 jQHFHVVLGDGHGHXPDUHYLVmRVXEVWDQFLDOGRPRGHOREiVLFR 35

C0015.indd 35 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

PI PIP2
Quinases Receptor

P P

P
P Fosfolipase C
Ácido fosfatídico DAG
Quinase
Ativação da
proteína quinase C
P OH

Inositol P P
1-fosfatase Fosfatases
P Liberação de
Inositol IP P Ca2+ intracelular
I(1,4,5)P3

Inibida
pelo Li+
P P ? Entrada de Ca2+
através da membrana
P P P
P P
I(1,3,4)P3 I(1,3,4,5)P4
Fig. 3.13 Ciclo do fosfatidilinositol (PI). A ativação da fosfolipase C mediada por receptor resulta na clivagem do fosfatidilinositol
bisfosfato (PIP2), formando diacilglicerol (DAG) (que ativa a proteína quinase C) e inositol trisfosfato (IP3) (que libera Ca2+ intracelular). Não
se sabe ao certo a função do inositol tetrafosfato (IP4), que é formado a partir do IP3 e de outros fosfatos de inositol, mas pode facilitar
a entrada de Ca2+ através da membrana plasmática. O IP3 é inativado por desfosforilação em inositol. O DAG é convertido em ácido
fosfatídico, e esses dois produtos são usados para regenerar o PI e o PIP2.

Dessensibilização do GPCR $IRVIRULODomRSRU3.$H3.&HPUHVtGXRVGLIHUHQWHVGRVYLVDGRV

SHORV*5.VFRQGX]QRUPDOPHQWHXPDOLJDomRIUDFDHQWUHRUHFHSWRU
▼7DOFRPRGHVFULWRQR&DStWXOR¬DGHVVHQVLELOL]DomRpFDUDFWHUtV
DWLYRHDSURWHtQD*HSRUHVVDUD]mRRHIHLWRGRDJRQLVWDpUHGX]LGR
WLFDGDPDLRUSDUWHGRV*3&5VHRVPHFDQLVPRVVXEMDFHQWHVWrP
,VVRSRGHFRQGX]LUDXPDGHVVHQVLELOL]DomRKRPyORJDRXKHWHUyORJD
VLGRHVWXGDGRVH[DXVWLYDPHQWH$GHVVHQVLELOL]DomRKRPyORJD UHV
GHSHQGHQGRGHRXWURVUHFHSWRUHVTXHQmRDTXHOHVHQYROYLGRVFRP
WULQJHVHDRVUHFHSWRUHVDWLYDGRVSHORDJRQLVWDGHVVHQVLELOL]DGRU
RDJRQLVWDGHVVHQVLELOL]DGRVHUHPVLPXOWDQHDPHQWHGHVIRVIRULODGRV
HQTXDQWRDGHVVHQVLELOL]DomRKHWHUyORJDDIHWDWDPEpPRXWURV*3&5V
SHODVTXLQDVHVDOJXPDVLQFOXVLYHQmRPXLWRVHOHWLYDV3URYDYHOPHQ
+iGRLVSURFHVVRVSULQFLSDLVHQYROYLGRV) HUJXVRQ¬.HOO\
WHRVUHFHSWRUHVIRVIRULODGRVSHODVTXLQDVHVGRVVHJXQGRVPHQVDJHL
HWDO¬
URVQmRVmRLQWHUQDOL]DGRVHVmRUHDWLYDGRVSHODIRVIRULODomRDWUDYpV
‡ IRVIRULODomRGRUHFHSWRU GHIRVIDWDVHVTXDQGRRDJRQLVWDpUHPRYLGR
‡ LQWHUQDOL]DomRGRUHFHSWRUHQGRFLWRVH
$VHTXrQFLDGH*3&5VLQFOXLGHWHUPLQDGRVUHVtGXRVVHULQDHWUHRQL Oligomerização do GPCR
QDSULQFLSDOPHQWHQDH[WUHPLGDGHGR&WHUPLQDOFLWRSODVPiWLFRTXH ▼$YLVmRFRQYHQFLRQDOGHTXH*3&5VH[LVWHPHIXQFLRQDPFRPR
SRGHVRIUHUIRVIRULODomRDWUDYpVGH*3&5TXLQDVHV*5.VHVSHFtILFDV SURWHtQDVPRQRPpULFDVHPFRQWUDVWHFRPRVFDQDLVL{QLFRVTXH
DFRSODGDVjPHPEUDQDHSRUTXLQDVHVFRPRD3.$HD3.& HPJHUDOIRUPDPFRPSOH[RVPXOWLPpULFRVSiJIRLDEDODGD
1
 DDWLYDomRGRUHFHSWRU*5.H*5.VmRUHFUXWDGRVSDUDD SHORWUDEDOKRUHDOL]DGRFRPRUHFHSWRU*$%$%  ([LVWHPGRLV
PHPEUDQDSODVPiWLFDDRVHOLJDUHPDVXEXQLGDGHVbg GLVSHUVDV VXEWLSRVGHVVH*3&5FRGLILFDGRVSRUJHQHVGLIHUHQWHVHRUHFHS
GDSURWHtQD*3RVWHULRUPHQWHRV*5.VIRVIRULODPRVUHFHSWRUHV WRUIXQFLRQDOFRQVLVWHHPXPKHWHURGtPHURGHDPERV&DS¬
HPVHXHVWDGRDWLYDGRRXVHMDOLJDGRVDRDJRQLVWD2UHFHSWRU
IRVIRULODGRDWXDFRPRXPORFDOGHOLJDomRGDVDUUHVWLQDVSURWHt
QDVLQWUDFHOXODUHVTXHEORTXHLDPDLQWHUDomRHQWUHRUHFHSWRUHDV
SURWHtQDV*SURGX]LQGRXPDGHVVHQVLELOL]DomRKRPyORJD VHOHWLYD$
OLJDomRGDDUUHVWLQDWDPEpPVLQDOL]DRUHFHSWRUSDUDHQGRFLWRVH
8PDVLWXDomRVHPHOKDQWHRFRUUHFRPRVUHFHSWRUHVGHJOXWDPD
WRDFRSODGRVjSURWHtQD*&XULRVDPHQWHHPERUDWDLVGtPHURV
SRVVXDPGRLVORFDLVSRWHQFLDLVGHOLJDomRDDJRQLVWDV²XPHP
FDGDVXEXQLGDGH²DSHQDVXPpIXQFLRQDOHDVLQDOL]DomRpIHLWD
DWUDYpVGRGtPHURSDUDRRXWURUHFHSWRUQRGtPHURDFRSODGRj
DWUDYpVGHYHVtFXODVUHYHVWLGDVSRUFODWULQD)LJ¬ 2UHFHSWRU SURWHtQD*)LJ¬
LQWHUQDOL]DGRSRGHHQWmRVHUGHVIRVIRULODGRHUHLQVHULGRQDPHP 2XWURV*3&5VVmRIXQFLRQDLVFRPRPRQ{PHURV$JRUDSDUHFHSUR
EUDQDSODVPiWLFDUHVVHQVLELOL]DomRRXHQFDPLQKDGRSDUDRVOLVRV YiYHOTXHDPDLRULDVHQmRWRGRVRV*3&5VSRVVDPH[LVWLUFRPR
VRPDVRQGHpGHJUDGDGRLQDWLYDomR$SDUHQWHPHQWHHVVHWLSRGH ROLJ{PHURVKRPpULFRVRXKHWHURPpULFRVRXVHMDGtPHURVRXJUDQGHV
GHVVHQVLELOL]DomRRFRUUHQDPDLRULDGRV*3&5VPDVFRPGLIHUHQoDV ROLJ{PHURV3ULQVWHUHWDO¬1RJUXSRGRVUHFHSWRUHVRSLRLGHV
36 VXWLVTXHIDVFLQDPRVDILFLRQDGRV &DS¬RUHFHSWRUmIRLFULVWDOL]DGRFRPRGtPHURHKHWHURGtPHURV

C0015.indd 36 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
Receptores Proteínas G

Enzimas- Guanilil Adenilil

alvo ciclase ciclase Fosfolipase C

Segundos GMPc AMPc IP3 DAG AA

mensageiros
↑[Ca2+]i Eicosanoides
Proteínas Liberados
quinases PKG PKA PKC como
Fig. 3.14 Controle dos sistemas hormônios
efetores celulares pela proteína G locais
e segundos mensageiros. AA, ácido
araquidônico; DAG, diacilglicerol; IP3, inositol
trisfosfato. Estão ausentes nesta figura as
vias de sinalização nas quais as arrestinas
se ligam aos GPCRs (e não às proteínas Efetores Enzimas, proteínas Proteínas Canais
G) para desencadear os eventos seguintes de transporte etc. contráteis iônicos
(downstream) (ver o texto).

Efetores controlados por proteínas G

Duas vias fulcrais de segundos mensageiros são
controladas por receptores via proteínas G:
• Adenilil ciclase/AMPc:
– podem ser ativadas ou inibidas por ligantes
farmacológicos, dependendo da natureza do receptor e
da proteína G
– a adenilil ciclase catalisa a formação do mensageiro
intracelular AMPc
– o AMPc ativa várias proteínas quinases que controlam a
função celular de muitas maneiras diferentes, por meio
de fosforilação de várias enzimas, transportadores e
outras proteínas
• Fosfolipase C/trisfosfato de inositol (IP3)/diacilglicerol
(DAG):
– catalisa a formação de dois mensageiros intracelulares,
IP3 e DAG, a partir de fosfolipídeos de membrana
– o IP3 atua aumentando o Ca2+ citosólico livre, pela
liberação de Ca2+ de compartimentos intracelulares
– o aumento do Ca2+ livre dá início a vários eventos,
incluindo contração, secreção, ativação de enzimas e
hiperpolarização de membranas
– o DAG ativa a proteína quinase C, que controla muitas
funções celulares através da fosforilação de várias
proteínas
As proteínas G ligadas a receptores controlam também:
• Canais iônicos
– abertura de canais de potássio que resulta numa
hiperpolarização da membrana
– inibição de canais de cálcio, reduzindo, assim, a
liberação de neurotransmissores
• Fosfolipase A2 (e, portanto, a formação de ácido
araquidônico e eicosanoides)

HVWiYHLVHIXQFLRQDLVGRVUHFHSWRUHVκ  Hd  FXMDVSURSULHGDGHV Receptores constitutivamente ativos

IDUPDFROyJLFDVVmRGLVWLQWDVGDTXHODVDSUHVHQWDGDVSRUTXDOTXHUGDV
▼2VUHFHSWRUHVDFRSODGRVjSURWHtQD*SRGHPHVWDUDWLYRVFRQVWLWX
PROpFXODVRULJLQiULDVIRUDPFULDGRVHPOLQKDJHQVFHOXODUHV7DPEpP
WLYDPHQWHLHHVSRQWDQHDPHQWHQDDXVrQFLDGHTXDOTXHUDJRQLVWD
VHGHVFREULXPDLRUGLYHUVLGDGHGHFRPELQDo}HVGR*3&5FRPRSRU
&DS¬HUHYLVmRSRU&RVWDH&RWHFFKLD¬,VVRIRLGHPRQVWUDGR
H[HPSORHQWUHUHFHSWRUHVGHGRSDPLQD'HVRPDWRVWDWLQDQRV
SULPHLUDPHQWHSDUDRb DGUHQRFHSWRU&DS¬HPTXHPXWDo}HV
TXDLVDPERVRVOLJDQWHVDJHPFRPSRWrQFLDDXPHQWDGD'LYDJDQGR
QDWHUFHLUDDOoDLQWUDFHOXODURXVLPSOHVPHQWHVXSHUH[SUHVVmRGR
XPSRXFRPDLVQRFDPSRGDSHVTXLVDGHDWULEXLo}HVIXQFLRQDLVR
UHFHSWRUUHVXOWDPHPVXDDWLYDomRFRQVWLWXWLYD$WXDOPHQWHH[LVWHP
UHFHSWRUGHGRSDPLQD' SRGHDFRSODUVHGLUHWDPHQWHDXPFDQDO
PXLWRVH[HPSORVGH*3&5VQDWLYRVTXHPRVWUDPDWLYLGDGHFRQV
L{QLFRFRQWURODGRSRUOLJDQWHRUHFHSWRUGH*$%$$LQLELQGRDIXQ
WLWXWLYDTXDQGRH[SUHVVRVLQYLWUR2UHFHSWRUGHKLVWDPLQD+WDPEpP
omRGHVWH~OWLPRVHPDLQWHUYHQomRGHQHQKXPDSURWHtQD*/LXHW
PRVWUDDWLYLGDGHFRQVWLWXWLYDLQYLYRHLVVRSRGHVHUXPIHQ{PHQR
DO¬$WpDJRUDHVVDVLQWHUDo}HVIRUDPHVWXGDGDVSULQFLSDOPHQWH
PXLWRJHUDO,VVRVLJQLILFDTXHRVDJRQLVWDVLQYHUVRV&DS¬TXH
HPOLQKDJHQVFHOXODUHVGHVHQYROYLGDVSRUHQJHQKDULDJHQpWLFDPDV
VXSULPHPHVVDDWLYLGDGHEDVDOSRGHPH[HUFHUHIHLWRVGLVWLQWRVDRV
WDPEpPRFRUUHPHPFpOXODVQDWLYDV&RPSOH[RVGLPpULFRVIXQFLRQDLV
GRVDJRQLVWDVQHXWURVTXHEORTXHLDPRVHIHLWRVGRDJRQLVWDVHP
HQWUHUHFHSWRUHVGHDQJLRWHQVLQD$7HEUDGLFLQLQD%RFRUUHPHP
DIHWDUDDWLYLGDGHEDVDO
SODTXHWDVKXPDQDVHPRVWUDPPDLRUVHQVLELOLGDGHjDQJLRWHQVLQDGR
TXHDUHFHSWRUHVGH$7´SXURVµ$EG$OODHWDO¬(PPXOKHUHV
JUiYLGDVFRPKLSHUWHQVmRWR[HPLDSUpHFOkPSWLFDRQ~PHURGHVVHV
GtPHURVDXPHQWDGHYLGRjH[SUHVVmRDXPHQWDGDGHUHFHSWRUHV%
UHVXOWDQGR²SDUDGR[DOPHQWH²HPDXPHQWRGHVHQVLELOLGDGHjDomR
YDVRFRQVWULWRUDGDDQJLRWHQVLQD(VVHpRSULPHLURH[HPSORGRSDSHO
GDGLPHUL]DomRHPXPDGRHQoDKXPDQD
e
 PXLWRFHGRSDUDGL]HUTXDOLPSDFWRHVVDYHUVDWLOLGDGHUHFpP
GHVFREHUWDGRV*3&5VHPVHFRQHFWDUFRPRXWURVUHFHSWRUHVSDUD
IRUPDUFRPELQDo}HVIXQFLRQDLVWHUiQDIDUPDFRORJLDFRQYHQFLRQDOH
QDWHUDSrXWLFDPDVSRGHVHUFRQVLGHUiYHO
Especificidade do agonista
▼$FUHGLWDYDVHTXHDFRQH[mRHQWUHGHWHUPLQDGR*3&5HXPDYLD
GHWUDQVGXomRGHVLQDOGHSHQGHVVHSULQFLSDOPHQWHGDHVWUXWXUDGR
UHFHSWRUHVSHFLDOPHQWHQDUHJLmRGDWHUFHLUDDOoDLQWUDFHOXODUTXH
FRQIHUHHVSHFLILFLGDGHDFHUWDSURWHtQD*DSDUWLUGDTXDORUHVWDQWHGD
YLDGHWUDQVGXomRGHVLQDOSURVVHJXH,VVRVLJQLILFDULDTXHFRQVRDQWH
RPRGHORGHGRLVHVWDGRVGLVFXWLGRQR&DStWXOR¬WRGRVRVDJRQLVWDV
FRPDomRHPXPUHFHSWRUHPSDUWLFXODUHVWDELOL]DULDPRPHVPRHVWD
GRDWLYDGR5
HGHYHULDPDWLYDUDPHVPDYLDGHWUDQVGXomRGHVLQDO 37

C0015.indd 37 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

A Receptor acoplado a MAP-quinases B Arrestina acoplada a MAP-quinases

A A A

A A A A A

P P P P P P
GRK ARR ARR
RAF1 ASK1 Src
Endocitose ERK

MEK1 MKK4/7 MKK3/6

A A
ERK1/2 JNK1–3 p38
P P P P
ARR E ARR JN
Expressão genética alterada RK K3
Fig. 3.15 Ativação da cascata Map-quinase do GPCR. [A] Ativação sequencial de múltiplos compostos da cascata MAP-quinase.
A ativação da cascata MAP-quinase do GPCR pode envolver as subunidades G a e bg (não apresentado). [B] Ativação do ERK e do JNK3
através da interação com as arrestinas (bARR). A ativação do ERK pode acontecer tanto na membrana plasmática envolvendo Src como através
de ativação direta após internalização do complexo receptor/arrestina. ARR, arrestina; GRK, receptor de quinases acopladas à proteína G.

A Dessensibilização do receptor Formação de vesículas

revestidas de clatrina
A A
E
α
β γ
P
P GRK
β γ
ARR
A Dyn
Dyn
Dyn
GDP P P
ARR
Reinserção P P
A
ARRP
P

Internalização

A
Reciclagem
A A
P P
A
ARR

PP2A
Degradação P P ARR
lisossômica P
P PP2A
P
Desfosforilação
Fig. 3.16 Dessensibilização e movimentação dos receptores acoplados à proteína G (GPCRs). Na ativação prolongada do agonista
do GPCR, determinados receptores de quinases acoplados à proteína G (GRKs) são recrutados para a membrana plasmática e fosforilam o
receptor. A essa altura, a arrestina (ARR) liga e desloca o GPCR para vesículas revestidas de clatrina para uma subsequente internalização
nos endossomas, num processo dependente de dinamina. O GPCR, então, é desfosforilado por uma fosfatase (PP2A) ou é reenviado para
a membrana plasmática, ou ainda é degradado pelos lisossomas. ARR, arrestina; Dyn, dinamina; GRK, receptor de quinases acoplados à
proteína G; PP2A, fosfatase 2A.

SURGX]LQGRRPHVPRWLSRGHUHVSRVWDFHOXODU+RMHHVWiFODURTXH
HVVDYLVmRpXPDVXSHUVLPSOLILFDomR(PPXLWRVFDVRVSRUH[HPSOR
FRPDJRQLVWDVTXHDJHPHPUHFHSWRUHVGDDQJLRWHQVLQDRXDJRQLVWDV
LQYHUVRVQRbDGUHQRFHSWRURVHIHLWRVFHOXODUHVVmRTXDOLWDWLYDPHQWH
GLIHUHQWHVFRPGLIHUHQWHVOLJDQWHVOHYDQGRDFUHUQDH[LVWrQFLDGHPDLV
38 GHXP²SURYDYHOPHQWHPXLWRV²HVWDGRV5
DJRQLVPRWHQGHQFLRVR&DS¬$OLJDomRGDVDUUHVWLQDVDRV*3&5VLQLFLD
RSURFHVVRGHVLQDOL]DomRGD0DSTXLQDVHGHPRGRTXHRVDJRQLVWDV
TXHLQGX]HPD´GHVVHQVLELOL]DomRµ*5.DUUHVWLQDYmRWHUPLQDU
SDUWHGDVLQDOL]DomR*3&5PDVWDPEpPSRGHUmRDWLYDUDVLQDOL]DomR
DWUDYpVGDVDUUHVWLQDVRTXHSRGHFRQWLQXDUPHVPRGHSRLVGHR
SRUYH]HVUHIHULGRFRPR FRPSRVWRUHFHSWRUDUUHVWLQDWHUVLGRLQWHUQDOL]DGR)LJ¬

C0015.indd 38 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
2
 DJRQLVPRWHQGHQFLRVRWHPLPSOLFDo}HVSURIXQGDV²RTXHDWpFRQV YDULHGDGHGHSURWHtQDVPHGLDGRUDVLQFOXLQGRIDWRUHVGHFUHV
WLWXLXPDKHUHVLDSDUDDOJXQVIDUPDFRORJLVWDVTXHHVWmRDFRVWXPDGRV FLPHQWRHFLWRFLQDV&DS¬HKRUP{QLRVFRPRDLQVXOLQD
DUHIOHWLUVREUHRVDJRQLVWDVHPWHUPRVGHVXDDILQLGDGHHHILFiFLDH &DS¬HDOHSWLQD&DS¬FXMRVHIHLWRVVmRH[HUFLGRVSULQ
QDGDPDLVHVVHVIDWRVDEULUmRXPDQRYDGLPHQVmRQDPDQHLUDGH
FLSDOPHQWHHPQtYHOGHWUDQVFULomRJrQLFD$PDLRULDGHVVHV
HQWHQGHUDHILFiFLDHDHVSHFLILFLGDGHGRVIiUPDFRV.HOO\HWDO¬
RAMPs
▼$VSURWHtQDVPRGLILFDGRUDVGDDWLYLGDGHGRVUHFHSWRUHV5$03V
UHFHSWRUHVpFRQVWLWXtGDGHJUDQGHVSURWHtQDVTXHFRQVLVWHP
HPXPDFDGHLD~QLFDGHDWpUHVtGXRVFRPXPD~QL
FDUHJLmRKHOLFRLGDOWUDQVPHPEUDQDUDTXDOOLJDXPDPSOR
GRPtQLRH[WUDFHOXODUGHOLJDQWHVDXPGRPtQLRLQWUDFHOXODUGH
GRLQJOrVUHFHSWRUDFWLYLW\PRGLI\LQJSURWHLQVFRQVWLWXHPXPDIDPtOLD
GHSURWHtQDVGHPHPEUDQDTXHVHDVVRFLDPDYiULRV*3&5VHDOWHUDP
WDPDQKRHIXQomRYDULiYHLV$HVWUXWXUDEiVLFDpPRVWUDGDQD
VXDVFDUDFWHUtVWLFDVIXQFLRQDLV)RUDPGHVFREHUWDVHPTXDQGRVH )
 LJXUD¬&SRUpPH[LVWHPPXLWDVYDULDQWHVPDLVDGLDQWH
YHULILFRXTXHRUHFHSWRUIXQFLRQDOPHQWHDWLYRGHXPQHXURSHSWtGHR 0DLVGHFHPUHFHSWRUHVGHVVHWLSRIRUDPFORQDGRVHH[LVWHP
RSHSWtGHRUHODFLRQDGRFRPRJHQHGDFDOFLWRQLQD&*53&DS¬ PXLWDVYDULDo}HVHVWUXWXUDLV3DUDPDLRUHVGHWDOKHVYHMDD
FRQVLVWHHPXPFRPSOH[RIRUPDGRSRUXP*3&5²FKDPDGRUHFHSWRU UHYLVmR+XEEDUGH0LOOHU(OHVWrPLPSRUWDQWHSDSHO
VHPHOKDQWHDRUHFHSWRUGHFDOFLWRQLQD&5/5GRLQJOrVFDOFLWRQLQ QRFRQWUROHGDGLYLVmRQRFUHVFLPHQWRHQDGLIHUHQFLDomR
UHFHSWRUOLNHUHFHSWRU²TXHSRUVLQmRDSUHVHQWDDWLYLGDGHHRXWUDSUR FHOXODUHVDVVLPFRPRQDLQIODPDomRQDUHSDUDomRWHFLGXDO
WHtQDGHPHPEUDQD5$036XUSUHHQGHQWHPHQWHR&5/5TXDQGR QDDSRSWRVHHQDVUHVSRVWDVLPXQROyJLFDVDVVXQWRVGLVFXWLGRV
DFRSODGRDRXWUD5$035$03GHPRQVWURXXPDIDUPDFRORJLD
PDLVDGLDQWHQRV&DStWXORV¬H¬
EHPGLIHUHQWHVHQGRDWLYDGRSRURXWURSHSWtGHRDDGUHQRPHGX
OLQD(PRXWUDVSDODYUDVDHVSHFLILFLGDGHDRDJRQLVWDpFRQIHULGD
2VSULQFLSDLVWLSRVVmRRVVHJXLQWHV
SHOD5$03DVVRFLDGDDVVLPFRPRSHORSUySULR*3&56XUJLUDP
PDLV5$03VHDWpRSUHVHQWHTXDVHWRGRVRVH[HPSORVLPSOLFDP
UHFHSWRUHVSHSWtGLFRVH[FHWRQRFDVRGRUHFHSWRUVHQVtYHODRFiOFLR
$V5$03VVmRXPH[HPSORGHFRPRDVLQWHUDo}HVSURWHtQDSURWHtQD
LQIOXHQFLDPRFRPSRUWDPHQWRIDUPDFROyJLFRGRVUHFHSWRUHVGHIRUPD
DOWDPHQWHVHOHWLYDSRGHQGRWRUQDUVHQRYRVDOYRVQRGHVHQYROYLPHQ
5HFHSWRUHVWLURVLQDTXLQDVH 57.V(VVHVUHFHSWRUHVWrP
DHVWUXWXUDEiVLFDPRVWUDGDQD)LJXUD¬$  LQFRUSRUDQGR
XPDSRUomRGHWLURVLQDTXLQDVHQDUHJLmRLQWUDFHOXODU(VWmR
LQFOXtGRVUHFHSWRUHVSDUDPXLWRVIDWRUHVGHFUHVFLPHQWR
FRPRRIDWRUGHFUHVFLPHQWRHSLGpUPLFR HRIDWRUGHFUHV
FLPHQWRQHXURQDOHWDPEpPRJUXSRGHUHFHSWRUHV7ROOVtPL
WRGHIiUPDFRV6H[WRQHWDO¬ OHVTXHUHFRQKHFHPOLSRSROLVVDFDUtGHRVEDFWHULDQRVHWrP
LPSRUWDQWHSDUWLFLSDomRQDUHDomRGRRUJDQLVPRjLQIHFomR
Sinalização independente das proteínas G
▼ $RXVDUPRVDH[SUHVVmR´UHFHSWRUHVDFRSODGRVjSURWHtQD*µ
SDUDGHVFUHYHUDFODVVHGHUHFHSWRUHVFDUDFWHUL]DGDSRUVXDHVWUXWXUD
KHSWDKHOLFRLGDOHVWDPRVVHJXLQGRGRJPDVGHWH[WRVFRQYHQFLRQDLV
PDVQHJOLJHQFLDQGRRIDWRGHTXHDVSURWHtQDV*QmRVmRR~QLFR
YtQFXORHQWUH*3&5VHRVYiULRVVLVWHPDVHIHWRUHVTXHUHJXODP1HVVH
FRQWH[WRpLPSRUWDQWHDVLQDOL]DomRPHGLDGDDWUDYpVGHDUUHVWLQDV
&DS¬2UHFHSWRUGHLQVXOLQD&DS¬WDPEpPSHUWHQFH
jFODVVHGRV57.VHPERUDSRVVXDXPDHVWUXWXUDGLPpULFD
PDLVFRPSOH[D
5HFHSWRUGHVHULQDWUHRQLQDTXLQDVHV(VVDSHTXHQDFODVVH
pVLPLODUDRV57.VHPHVWUXWXUDSRUpPIRVIRULODUHVtGXRVGH
VHULQDHRXWUHRQLQDHPYH]GHWLURVLQD2SULQFLSDOH[HPSOR
OLJDGDVDRUHFHSWRUSiJHQmRDWUDYpVGHSURWHtQDV*UHYLVmRGH pRUHFHSWRUSDUDRIDWRUGHFUHVFLPHQWRWUDQVIRUPDGRU7*)
3LHUFHH/HINRZLW]¬'HOFRXUWHWDO¬$VDUUHVWLQDVSRGHP GRLQJOrVWUDQVIRUPLQJJURZWKIDFWRU
DJLUFRPRLQWHUPHGLiULRVQDDWLYDomRGR*3&5GDFDVFDWDGH0$3 5HFHSWRUHVGHFLWRFLQDV(VVHVUHFHSWRUHV)LJ¬%FDUH
TXLQDVH)LJ¬ FHPGHDWLYLGDGHHQ]LPiWLFDLQWUtQVHFD4XDQGRRFXSDGRV
+iPXLWRVH[HPSORVHPTXHDVYiULDV´SURWHtQDVDGDSWDGRUDVµ DWLYDPYiULDVWLURVLQDTXLQDVHVWDOFRPRDV-DN-DQXVTXLQD
TXHOLJDPRVUHFHSWRUHVGRWLSRWLURVLQDTXLQDVHDVHXVHIHWRUHV VH2VOLJDQWHVSDUDHVVHVUHFHSWRUHVLQFOXHPFLWRFLQDVFRPR
SiJWDPEpPSRGHPLQWHUDJLUFRPRV*3&5V%U]RVWRZVNLH LQWHUIHURQDV HIDWRUHVHVWLPXODQWHVGHFRO{QLDHQYROYLGRV
.LPPHO¬SHUPLWLQGRTXHRVPHVPRVVLVWHPDVHIHWRUHVSRVVDP QDVUHVSRVWDVLPXQROyJLFDV
VHUUHJXODGRVSRUUHFHSWRUHVGHDPERVRVWLSRV
5HVXPLQGRRVLPSOHVGRJPDHPTXHVHDSRLDPPXLWRVGH
QRVVRVFRQKHFLPHQWRVDWXDLVVREUHRV*3&5VFRPR MECANISMOS DA FOSFORILAÇÃO PROTEICA
XPJHQH*3&5²XPDSURWHtQD*3&5²XP*3&5 E DA CASCATA DAS QUINASES
IXQFLRQDO²XPDSURWHtQD*²XPDUHVSRVWD $
 IRVIRULODomRGHSURWHtQDV& RKHQ¬ pXPPHFDQLV
HVWiGDQGRVLQDLVGHPXGDQoD(PSDUWLFXODU PRFKDYHSDUDFRQWURODUDIXQomRGHSURWHtQDVS¬H[HQ]LPDV
‡ XPJHQHDWUDYpVGHVSOLFLQJDOWHUQDWLYRHGLomRGH51$
HWFSRGHGDURULJHPDPDLVGHXPDSURWHtQDGHUHFHSWRU
‡ XPDSURWHtQD*3&5SRGHDVVRFLDUVHDRXWUDVRXD
RXWUDVSURWHtQDVFRPRDV5$03VHGDURULJHPDPDLV
GHXPWLSRGHUHFHSWRUIXQFLRQDO
‡ GLIHUHQWHVDJRQLVWDVSRGHPDIHWDURUHFHSWRU
GHGLYHUVDVPDQHLUDVHSURGX]LUUHVSRVWDV
TXDOLWDWLYDPHQWHGLIHUHQWHV
‡ DYLDGHWUDQVGXomRGHVLQDOQmRUHTXHU
LPSUHWHULYHOPHQWHXPDSURWHtQD*HGHPRQVWUD
LQWHUDo}HVFRPUHFHSWRUHVOLJDGRVjWLURVLQDTXLQDVH
2VUHFHSWRUHVDFRSODGRVjSURWHtQD*VmRPROpFXODVHYLGHQ
WHPHQWHYHUViWHLVHDYHQWXUHLUDVDRUHGRUGDVTXDLVJLUDERD
SDUWHGDIDUPDFRORJLDPRGHUQDHQLQJXpPGHYHLPDJLQDUTXH
WHQKDPRVFKHJDGRDRILPGDKLVWyULD
TIPO 3: RECEPTORES LIGADOS A QUINASES
E RECEPTORES CORRELATOS
(VVHVUHFHSWRUHVGHPHPEUDQDVmREDVWDQWHGLIHUHQWHVGRV
FDQDLVFRQWURODGRVSRUOLJDQWHVHGRV*3&5VWDQWRHPHVWUX
FDQDLVL{QLFRVUHFHSWRUHVSURWHtQDVGHWUDQVSRUWHHQYROYLGDV
QDUHJXODomRGRVSURFHVVRVFHOXODUHV)RVIRULODomRHGHVIRV
IRULODomRVmRUHDOL]DGDVSRUTXLQDVHV HIRVIDWDVHVUHVSHFWLYD
PHQWH²HQ]LPDVGDVTXDLVDOJXPDVFHQWHQDVGHVXEWLSRVHVWmR
UHSUHVHQWDGDVQRJHQRPDKXPDQR²DVTXDLVSRUVXDYH]
HVWmRHODVPHVPDVVXMHLWDVjUHJXODomRGHSHQGHQGRGHVHX
HVWDGRGHIRVIRULODomR$WXDOPHQWHKiPXLWRVHVIRUoRVSDUD
PDSHDUDVFRPSOH[DVLQWHUDo}HVHQWUHDVPROpFXODVVLQDOL]DGR
UDVHQYROYLGDVHPHIHLWRVGHIiUPDFRVHHPSURFHVVRVILVLRSD
WROyJLFRVFRPRRQFRJrQHVHQHXURGHJHQHUDomRLQIODPDomRH
PXLWRVRXWURV3RGHPRVDTXLDSUHVHQWDUDSHQDVDOJXQVSRXFRV
DVSHFWRVIDUPDFRORJLFDPHQWHUHOHYDQWHVGDTXLORTXHVHWRUQRX
XPWHPDGHJUDQGHVSURSRUo}HV
(
 PPXLWRVFDVRVDOLJDomRGROLJDQWHDRUHFHSWRUOHYDj
GLPHUL]DomR$DVVRFLDomRGRVGRLVGRPtQLRVGHTXLQDVHLQWUD
FHOXODUHVSHUPLWHTXHRFRUUDXPDDXWRIRVIRULODomRP~WXDGH
UHVtGXRVGHWLURVLQDLQWUDFHOXODUHV2VUHVtGXRVGHWLURVLQD
IRVIRULODGRVDWXDPHQWmRFRPRSRQWRVGHDQFRUDJHPGHDOWD
DILQLGDGHSDUDRXWUDVSURWHtQDVLQWUDFHOXODUHVTXHFRQVWLWXHP
RSUy[LPRSDVVRQDFDVFDWDGHWUDQVGXomRGHVLQDO8PLPSRU
WDQWHJUXSRGHVVDVSURWHtQDVpFRQKHFLGRFRPRSURWHtQDVGH
GRPtQLR6+UHIHULQGRVHjKRPRORJLD6UFSRLVHVVHGRPtQLR
WXUDFRPRHPIXQomR(OHVPHGHLDPDVDo}HVGHXPDDPSOD IRLLGHQWLILFDGRSHODSULPHLUDYH]QRSURGXWRGRRQFRJHQH6UF 39

C0015.indd 39 04/11/15 1:14 PM

 3 SEÇÃO 1 PRINCÍPIOS GERAIS

Mudança de
A Fator de conformação Autofosforilação Fosforilação
crescimento Dimerização da tirosina de Grb2
Domínio Ativação de Ras
receptor Troca GDP/GTP
α hélice
transmembrana
MEMBRANA

Domínio tirosina P P P P P Ras

quinase Grb2 GDP
GTP Ativação
Resíduo Raf
de tirosina
Fosforilação
Grb2
Ligação da proteína Mek
CASCATA DAS
de domínio SH2 (Grb2) QUINASES Fosforilação
MAP-quinase
Fosforilação
Vários fatores
de transcrição

NÚCLEO
Transcrição gênica

B Citocina Dimerização
Alteração conformacional Fosforilação do receptor
Ligação de Jak + Jak

MEMBRANA

Jak Jak Jak P Jak Jak P

P P

Ligação e fosforilação Dimerização P Stat

da proteína de Stat de Stat Stat P
domínio SH2
(Stat)

NÚCLEO
Transcrição gênica
Fig. 3.17 Mecanismos de transdução de receptores acoplados a quinases. A primeira etapa que ocorre após a ligação do agonista é
a dimerização, que leva à autofosforilação do domínio intracelular de cada receptor. Então, proteínas com domínio SH2 ligam-se ao receptor
fosforilado, e são, elas próprias, também fosforiladas. Duas vias bem caracterizadas são mostradas: [A] A via do fator de crescimento
(Ras/Raf/proteína ativada por mitógeno [MAP] quinase) (Cap. 5). O Grb2 também pode ser fosforilado, mas isso altera negativamente sua
sinalização. [B] Esquema simplificado da via da citocina (Jak/Stat) (Cap. 18). Alguns receptores de citocina podem existir previamente como
dímeros em vez de sofrerem dimerização na ligação à citocina. Várias outras vias existem, e essas cascatas de fosforilação interagem com
componentes dos sistemas de proteínas G.
40

C0015.indd 40 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
▼'XDVYLDVEHPGHILQLGDVGHWUDQVGXomRGHVLQDOHVWmRUHVXPLGDV
Receptores ligados a quinases QD)LJXUD¬$YLD5DV5DIPHGHLDRHIHLWRGHPXLWRVIDWRUHV
GHFUHVFLPHQWRHPLWyJHQRV5DVTXHpXPSURGXWRSURWRRQFR
• Receptores para diversos fatores de crescimento JHQHIXQFLRQDFRPRXPDSURWHtQD*HWUDQVPLWHRVLQDODWUDYpV
incorporam a tirosina quinase em seu domínio
intracelular.
• Receptores de citocinas possuem um domínio
intracelular que liga e ativa quinases citosólicas quando
o receptor é ocupado.
GDSHUPXWD*'3*73DSDUWLUGDSURWHtQDGHGRPtQLR6+*UE
$DWLYDomRGH5DVSRUVXDYH]DWLYD5DITXHpDSULPHLUDGHXPD
VHTXrQFLDGHWUrVVHULQDWUHRQLQDTXLQDVHVHPTXHFDGDXPDIRV
IRULODHDWLYDDSUy[LPDGDVHTXrQFLD$~OWLPDGHODVDTXLQDVHGD
SURWHtQDDWLYDGDSRUPLWyJHQR0$3GRLQJOrVPLWRJHQDFWLYDWHG
• Todos os receptores compartilham uma arquitetura
comum, que consiste em um grande domínio
extracelular de ligação ao ligante, conectado ao
domínio intracelular através de uma única hélice
transmembrana.
• A transdução de sinais geralmente envolve a
dimerização de receptores, seguida de autofosforilação
de resíduos de tirosina. Os resíduos de fosfotirosina
atuam como aceptores dos domínios SH2 de várias
proteínas intracelulares, permitindo, dessa maneira, o
SURWHLQTXHWDPEpPpDWLYDGDSHORV*3&5VDQWHULRUPHQWHIRV
IRULODXPRXPDLVIDWRUHVGHWUDQVFULomRTXHLQLFLDPDH[SUHVVmR
JrQLFDUHVXOWDQGRHPGLYHUVRVWLSRVGHUHVSRVWDFHOXODULQFOXLQGR
DGLYLVmRFHOXODU(VVDFDVFDWDGD0$3TXLQDVHGHWUrVHWDSDVID]
SDUWHGHPXLWDVYLDVVLQDOL]DGRUDVLQWUDFHOXODUHVHQYROYLGDVHPXPD
DPSODJDPDGHSURFHVVRVPyUELGRVLQFOXLQGRWXPRUHVPDOLJQRV
LQIODPDomRQHXURGHJHQHUDomRDWHURVFOHURVHHPXLWRVRXWURV$V
TXLQDVHVIRUPDPXPDJUDQGHIDPtOLDFRPGLIHUHQWHVVXEWLSRVH[H
FXWDQGRIXQo}HVHVSHFtILFDV$FUHGLWDVHTXHHODVUHSUHVHQWHPXP
DOYRLPSRUWDQWHSDUDIXWXURVDJHQWHVWHUDSrXWLFRV0XLWRVFkQFHUHV
HVWmRDVVRFLDGRVDPXWDo}HVQRVJHQHVTXHFRGLILFDPDVSURWHtQDV
HQYROYLGDVQHVVDFDVFDWDOHYDQGRjVXDDWLYDomRQDDXVrQFLDGRVLQDO
controle de muitas funções celulares. GRIDWRUGHWUDQVFULomR& DSV¬H¬ 3DUDPDLVGHWDOKHVFRQVXOWHD
• Estão envolvidos principalmente em eventos que UHYLVmRGH$YUXFK
controlam o crescimento e a diferenciação celulares, 8PDVHJXQGDYLDDYLD-DN6WDW)LJ¬%HVWiHQYROYLGDQDV
e atuam indiretamente por regulação da transcrição UHVSRVWDVDPXLWDVFLWRFLQDV2FRUUHGLPHUL]DomRGHVVHVUHFHSWRUHV
gênica. TXDQGRDFLWRFLQDVHOLJDHLVVRDWUDLXPDXQLGDGHWLURVLQDTXLQDVH
• Duas vias importantes são: FLWRVyOLFD-DNSDUDVHDVVRFLDUDHHQWmRIRVIRULODURGtPHURGRUHFHS
– A via Ras/Raf/proteína ativada por mitógenos (MAP) WRU$V-DNVSHUWHQFHPDXPDIDPtOLDGHSURWHtQDVGDTXDOGLIHUHQWHV
quinase, que é importante na divisão, no crescimento PHPEURVDSUHVHQWDPHVSHFLILFLGDGHSDUDGLIHUHQWHVUHFHSWRUHVGH
e na diferenciação celulares. FLWRFLQDV(QWUHRVDOYRVSDUDDIRVIRULODomRSHOD-DNHVWiXPDIDPtOLD
– A via Jak/Stat, ativada por muitas citocinas, controla
a síntese e a liberação de muitos mediadores
inflamatórios.
• Alguns poucos receptores de hormônios (p. ex., fator
GHIDWRUHVGHWUDQVFULomR6WDWV(VWHVVmRSURWHtQDVGHGRPtQLR6+
TXHVHOLJDPDRVJUXSDPHQWRVIRVIRWLURVLQDQRFRPSOH[RUHFHSWRU-DN
VHQGRHODVSUySULDVIRVIRULODGDV$6WDWDVVLPDWLYDGDPLJUDSDUDR
Q~FOHRHDWLYDDH[SUHVVmRJrQLFD
 XWURVPHFDQLVPRVLPSRUWDQWHVVHFRQFHQWUDPQDIRVIDWLGLOLQRVL
2
natriurético atrial) possuem uma arquitetura similar e WROTXLQDVH3,TXLQDVHV9DQKDHVHEURHFNHWDO¬XPDIDPtOLD
estão ligados à guanilil ciclase. GHHQ]LPDVXEtTXDVTXHpDWLYDGDWDQWRSRU*3&5VTXDQWRSRU
57.VHVHOLJDDRJUXSDPHQWRIRVIDWRSUHVHQWHQDSRVLomR¬GD
3,3 SDUDIRUPDUD3,3 2XWUDVSURWHtQDVTXLQDVHVSULQFLSDO
(VVDVSURWHtQDVSRVVXHPXPDVHTXrQFLDDOWDPHQWHFRQVHUYDGD
GHFHUFDGHFHPDPLQRiFLGRVIRUPDQGRXPORFDOGHUHFR
QKHFLPHQWRSDUDRVUHVtGXRVGHIRVIRWLURVLQDGRUHFHSWRU
PHQWHDSURWHtQDTXLQDVH%3.%WDPEpPFRQKHFLGDFRPR$NW
DSUHVHQWDPSRQWRVGHUHFRQKHFLPHQWRSDUD3,3 HHQWmRVmR
DWLYDGDVFRQWURODQGRXPDJUDQGHYDULHGDGHGHIXQo}HVFHOXODUHV
LQFOXLQGRDSRSWRVHGLIHUHQFLDomRSUROLIHUDomRHWUiIHJR$3.%
WDPEpPSURYRFDDDWLYDomRGHy[LGRQtWULFRVLQWDVHQRHQGRWpOLR
YDVFXODU&DS¬
3URWHtQDVGHGRPtQLR6+LQGLYLGXDLVPXLWDVGDVTXDLVMiVmR
7UDEDOKRVUHFHQWHVVREUHDVYLDVGHWUDQVGXomRGHVLQDOSURGX]LUDP
FRQKHFLGDVOLJDPVHVHOHWLYDPHQWHDGHWHUPLQDGRVUHFHSWRUHV
XPDGHVQRUWHDQWHSURIXVmRGHGHWDOKHVPROHFXODUHVFRPIUHTXrQFLD
GHPRGRTXHRSDGUmRGHHYHQWRVGHVHQFDGHDGRVSHORVIDWRUHV H[SUHVVRVHPXPMDUJmRTXHWHQGHDGHVHQFRUDMDURVPDLVWtPLGRV
GHFUHVFLPHQWRSDUWLFXODUHVpDOWDPHQWHHVSHFtILFR2PHFDQLV (QWUHWDQWRDSHUVHYHUDQoDVHUiUHFRPSHQVDGDSRLVQmRUHVWDPG~YL
PRpUHVXPLGRQD)LJXUD¬ GDVGHTXHQRYRVIiUPDFRVLPSRUWDQWHVVXUJLUmRSDUWLFXODUPHQWH
2TXHRFRUUHTXDQGRDSURWHtQDGHGRPtQLR6+VHOLJDDR QDViUHDVGHLQIODPDomRLPXQRORJLDHFkQFHUWHQGRHVVDVSURWHtQDV
UHFHSWRUIRVIRULODGRYDULDVLJQLILFDWLYDPHQWHGHDFRUGRFRP FRPRDOYR2EWHYHVHDYDQoRQRWUDWDPHQWRGDOHXFHPLDPLHORLGH
RUHFHSWRUHQYROYLGRPXLWDVSURWHtQDVGHGRPtQLR6+VmR FU{QLFDFRPDLQWURGXomRGRSULPHLURLQLELGRUHVSHFtILFRGHTXLQDVH
HQ]LPDVFRPRSURWHtQDVTXLQDVHVRXIRVIROLSDVHV$OJXQV RLPDWLQLEHXPIiUPDFRTXHLQLEHXPDWLURVLQDTXLQDVHHVSHFtILFD
IDWRUHVGHFUHVFLPHQWRDWLYDPXPVXEJUXSRHVSHFtILFRGH HQYROYLGDQDSDWRJrQHVHGDGRHQoD&DS¬
IRVIROLSDVH&3/&gHGHVVHPRGRSURYRFDPTXHEUDGHIRV $IRUPDOLJDGDjPHPEUDQDGDJXDQLOLOFLFODVHHQ]LPDUHV
IROLStGHRVIRUPDomRGH,3HOLEHUDomRGH&DSiJ2XWUDV SRQViYHOSHODIRUPDomRGRVHJXQGRPHQVDJHLUR*03FHP
SURWHtQDVFRQWHQGRGRPtQLR6+UHDOL]DPRDFRSODPHQWRGH
SURWHtQDVFRQWHQGRIRVIRWLURVLQDVFRPYiULDVRXWUDVSURWHtQDV
IXQFLRQDLVLQFOXVLYHPXLWDVTXHHVWmRHQYROYLGDVQRFRQWUROH
GHGLYLVmRHGLIHUHQFLDomRFHOXODUHV2UHVXOWDGRILQDOpDWLYDU
RXLQLELUYLDIRVIRULODomRGLYHUVRVIDWRUHVGHWUDQVFULomRTXH
PLJUDPSDUDRQ~FOHRHVXSULPHPRXLQGX]HPDH[SUHVVmR
GHGHWHUPLQDGRVJHQHV3DUDPDLVGHWDOKHVYHMD-LQH3DZVRQ
UHVSRVWDjOLJDomRGHSHSWtGHRQDWULXUpWLFR&DSV¬H¬
DVVHPHOKDVHDRJUXSRGRVUHFHSWRUHVGDWLURVLQDTXLQDVHHp
DWLYDGDGHIRUPDVHPHOKDQWHDWUDYpVGDGLPHUL]DomRTXDQGR
XPDJRQLVWDHVWiOLJDGR
$
 )LJXUD¬LOXVWUDGHPRGRPXLWRVLPSOLILFDGRHHVTXH
PiWLFRRSDSHOFHQWUDOGDVSURWHtQDVTXLQDVHVQDVYLDVGH
WUDQVGXomRGHVLQDO0XLWDVGDVSURWHtQDVHQYROYLGDVVHQmR
2IDWRUQXFOHDUNDSSD% 1)κ% pXPIDWRUGHWUDQV WRGDVLQFOXLQGRRVUHFHSWRUHVHDVSUySULDVTXLQDVHVVmRVXEV
FULomRTXHGHVHPSHQKDSDSHOFKDYHHPYiULDVFRPSOLFDo}HV WUDWRVSDUDTXLQDVHVGHPRGRTXHKiPXLWRVPHFDQLVPRVGH
LQFOXLQGRLQIODPDomRHFkQFHU&  DSV¬H¬.DULQHWDO¬ IHHGEDFNHLQWHUDo}HVFUX]DGDVHQWUHDVYiULDVYLDVGHVLQDOL]D
(PJHUDOHVWiSUHVHQWHQRFLWRSODVPDFRPSOH[DGRFRPXP omR7HQGRHPYLVWDTXHH[LVWHPPDLVGHTXLQKHQWDVSURWHtQDV
LQLELGRU,κ%$IRVIRULODomRGR,κ%RFRUUHTXDQGRXPDTXL TXLQDVHVHXPQ~PHURLJXDOPHQWHHOHYDGRGHUHFHSWRUHVH
QDVHHVSHFtILFD,..pDWLYDGDHPUHVSRVWDDYiULDVFLWRFLQDV
LQIODPDWyULDVHDJRQLVWDVGH*3&5,VVRUHVXOWDQDGLVVRFLDomR
GRFRPSOH[R,κ%1)κ%HQDPLJUDomRGHVWH~OWLPRSDUDR
Q~FOHRRQGHHQWmRDWLYDYiULRVJHQHVSUyLQIODPDWyULRV
C0015.indd 41
RXWUDVPROpFXODVVLQDOL]DGRUDVDUHGHGHLQWHUDo}HVSRGH
SDUHFHUHVSDQWRVDPHQWHFRPSOH[D'LVVHFDUVHXVGHWDOKHV
WRUQRXVHRWHPDSULQFLSDOGDELRORJLDFHOXODU3DUDRVIDU
PDFRORJLVWDVDLGHLDGHXPDFRQH[mRVLPSOHVHQWUHUHFHSWRU
41
04/11/15 1:14 PM
 3 SEÇÃO 1 PRINCÍPIOS GERAIS

Receptores
GPCRs Receptores ligados
ligados à GC a quinases
IP3

AMPc DAG Ca2+ GMPc Autofosforilação

GRKs PKA PKC CaM PKG

quinases

CASCATAS DE QUINASES

PROTEÍNAS-ALVO

Enzimas Receptores Canais Transportadores Fatores de Proteínas Mecanismos

iônicos transcrição contráteis de secreção

RESPOSTAS

Respostas Respostas Apoptose Transformação Crescimento Diferenciação

fisiológicas imunológicas maligna
Fig. 3.18 Papel central das cascatas de quinases na transdução de sinais. As cascatas de quinases (p. ex., aquelas mostradas na
Fig. 3.15) são ativadas por GPCRs, diretamente ou por meio de diferentes segundos mensageiros, por receptores que geram GMPc, ou
ainda por receptores acoplados a quinases. As cascatas das quinases regulam diversas proteínas-alvo, que, por sua vez, produzem uma
grande variedade de efeitos de curto e longo prazos. CaM-quinase, quinase dependente de Ca2+/calmodulina; DAG, diacilglicerol; GC,
guanilil ciclase; GRK, GPCR quinase; IP3, inositol trisfosfato; PKA, proteína quinase dependente de AMPc; PKC, proteína quinase C; PKG,
proteína quinase dependente de GMPc.

HUHVSRVWDTXHQRUWHRXRSHQVDPHQWRDWUDYpVGRVpFXOR;; TIPO 4: RECEPTORES NUCLEARES

HVWiVHPG~YLGDGHVPRURQDQGRHPERUDDLQGDIDOWHDOJXP
WHPSRSDUDTXHDVFRPSOH[LGDGHVGDVYLDVVLQDOL]DGRUDV 1
 DGpFDGDGHHVWDYDFODURTXHRVUHFHSWRUHVSDUDKRU
VHMDPLQFRUSRUDGDVIRUPDQGRXPQRYRPRGRGHSHQVDU P{QLRVHVWHURLGHVWDLVFRPRHVWUyJHQRVHJOLFRFRUWLFRLGHV
VREUHDDomRGRVIiUPDFRV &DS¬HVWDYDPSUHVHQWHVQRFLWRSODVPDGDVFpOXODVHHUDP
WUDQVORFDGRVSDUDRQ~FOHRDSyVDOLJDomRFRPVHXOLJDQWH
HVWHURLGH'HVFREULXVHWDPEpPTXHRXWURVKRUP{QLRVFRPR
RKRUP{QLRWLUHRLGLDQR7 & DS¬ HDVYLWDPLQDVOLSRV
Fosforilação de proteínas VRO~YHLV'H$iFLGRUHWLQRLFRDWXDPGHPDQHLUDVLPLODU$
na transdução de sinais FRPSDUDomRHQWUHRVGDGRVGRVHTXHQFLDPHQWRJHQ{PLFRH
SURWHLFROHYRXDRUHFRQKHFLPHQWRGHTXHHUDPPHPEURVGH
• Muitos eventos mediados por receptores envolvem XPDIDPtOLDPXLWRPDLRUGHSURWHtQDVFRUUHODWDV(VWHVVmR
a fosforilação de proteínas, que controlam as DJRUDFRQKHFLGRVFRPRIDPtOLDGRVUHFHSWRUHVQXFOHDUHV15
propriedades funcionais e de ligação das proteínas 215DVVLPFRPRRVUHFHSWRUHVSDUDJOLFRFRUWLFRLGHVH
intracelulares. SDUDRiFLGRUHWLQRLFRFXMRVOLJDQWHVVmREHPFDUDFWHUL]DGRV
• As tirosinas quinases ligadas a receptores, as tirosinas LQFOXLXPDIDPtOLDGHJUDQGHQ~PHURӳGHUHFHSWRUHV
quinases ativadas por nucleotídeos cíclicos e as yUImRV ²UHFHSWRUHVTXHQmRSRVVXHPQHQKXPOLJDQWHEHP
serinas/treoninas quinases intracelulares constituem GHILQLGRFRQKHFLGR'HVWHVRSULPHLURDVHUGHVFULWRQRVDQRV
um mecanismo de “cascata de quinases” que leva à
amplificação dos eventos mediados por receptores.
• Existem muitas quinases com diferentes
especificidades de substrato, proporcionando a
especificidade observada nas vias ativadas por
IRLRUHFHSWRUGHUHWLQRLGH;5;5XPUHFHSWRUFORQDGR
FRPEDVHHPVXDVHPHOKDQoDFRPRUHFHSWRUGHYLWDPLQD$
HTXHYHLRDVHGHVFREULUVHURUHVSRQViYHOSHODOLJDomRGR
iFLGRFLV UHWLQRLFRGHULYDGRGDYLWDPLQD$$RORQJRGRV
DQRVIRUDPFDUDFWHUL]DGRVSDUFHLURVGHOLJDomRHVSHFtILFRV
diferentes hormônios. SDUDPXLWRV15V´yUImRVDGRWDGRVµS¬H[5;5PDVPXLWRV
• A dessensibilização de receptores ligados à proteína RXWURVDLQGDWrPGHVHULGHQWLILFDGRV´yUImRVYHUGDGHLURVµ
G decorre da fosforilação por quinases específicas de ²RXWDOYH]LVVRQmRVHMDSRVVtYHOXPDYH]TXHXPDSRVVtYHO
receptores, o que torna o receptor não funcional e leva IXQomRGHVVHVUHFHSWRUHVpVXDFDSDFLGDGH´SURPtVFXDµGHVH
à sua internalização. OLJDUHPDPXLWRVFRPSRVWRVUHODFLRQDGRVFRPRSRUH[HPSOR
• Existe uma grande família de fosfatases que atuam RVIDWRUHVGLHWpWLFRVFRPEDL[DDILQLGDGH
desfosforilando proteínas e, assim, revertendo os $RFRQWUiULRGHRXWURVUHFHSWRUHVGHVFULWRVQHVWHFDStWXORRV
efeitos das quinases. 15VSRGHPLQWHUDJLUGLUHWDPHQWHFRPR'1$3RUHVVHPRWLYR
42 GHYHPRVWrORVHPFRQWDFRPRIDWRUHVGHWUDQVFULomRDWLYDGRVSRU

C0015.indd 42 04/11/15 1:14 PM

 COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 3
OLJDQWHVTXHWUDQVIRUPDPRVVLQDLVDRPRGLILFDUDWUDQVFULomR $ UHJLmRGHGREUDGLoDDOWDPHQWHIOH[tYHOGDPROpFXODpTXHOKHSHUPLWH
JHQpWLFD2XWUDFDUDFWHUtVWLFD~QLFDpRIDWRGHRV15VQmRHVWD DGLPHUL]DomRFRPRXWURV15V'HVVDIRUPDpSRVVtYHOSURGX]LU
UHPLQFRUSRUDGRVQDVPHPEUDQDVFRPRRV*3&5VRXRVFDQDLV FRPSOH[RVPROHFXODUHVFRPGLYHUVDVFRQILJXUDo}HVFDSD]HVGHLQWH
UDJLUFRPR'1$GHIRUPDGLIHUHQWH)LQDOPHQWHRGRPtQLR&WHUPLQDO
L{QLFRV&DS¬PDVVHHQFRQWUDUHPQDIDVHVRO~YHOGDFpOXOD
$OJXQVFRPRRVUHFHSWRUHVHVWHURLGHVWRUQDPVHPyYHLVQD
SUHVHQoDGHVHXOLJDQWHHSRGHPGHVORFDUVHGRFLWRSODVPD
SDUDRQ~FOHRHQTXDQWRRXWURVFRPRRV5;5SURYDYHOPHQWH
SHUPDQHFHPQRLQWHULRUGRFRPSDUWLPHQWRQXFOHDU
$VXSHUIDPtOLDGRV15GHVHQYROYHXVHVXSRVWDPHQWHD
SDUWLUGHXPJHQHHYROXFLRQiULRDQFHVWUDOGLVWDQWHDWUDYpV
GHGXSOLFDomRHRXWUDVWpFQLFDV1RVHUKXPDQRH[LVWHPSHOR
PHQRVPHPEURVPDVSRGHPVXUJLUPDLVSURWHtQDVDWUDYpV
GHWpFQLFDVGHGLYLVmRDOWHUQDWLYDV(QTXDQWRLVVRUHSUHVHQWD
DSHQDVXPDSHTXHQDSRUomRGHWRGRVRVUHFHSWRUHVPHQRV
FRQWpPDOLJDomRDROLJDQWHHpHVSHFLItFRDFDGDFODVVHGHUHFHSWRU
$UHJLmR$)pLPSRUWDQWHSDUDDDWLYDomRGHSHQGHQWHGROLJDQWHH
GHIRUPDJHUDODOWDPHQWHFRQVHUYDGDHPERUDDXVHQWHGH5HYHUE$
aH5HYHUE$b15VTXHUHJXODPRPHWDEROLVPRFRPRSDUWHGHXP
PHFDQLVPRPROHFXODUGRULWPRFLUFDGLDQR3HUWRGR&WHUPLQDO
WDPEpPHVWmRHOHPHQWRVTXHFRQWrPVLQDLVGHORFDOL]DomRQXFOHDUHV
HRXWURVTXHSRGHPQRFDVRGHDOJXQVUHFHSWRUHVOLJDUDVSURWHtQDV
GHFKRTXHWpUPLFRHRXWUDVSURWHtQDV
CONTROLE DA TRANSCRIÇÃO GENÉTICA
▼2V+5(VmRSHTXHQDVVHTXrQFLDVGH'1$TXDWURRXFLQFRSDUHV
GHGRQ~PHURWRWDOGH*3&5VRV15VVmRDOYRVPXLWR GHEDVHDTXHRV15VVHOLJDPHPRGLILFDPDWUDQVFULomRJHQpWLFD(P
LPSRUWDQWHVGHIiUPDFRV%XUULVHWDOVHQGRUHVSRQVi JHUDOHVWmRSUHVHQWHVVLPHWULFDPHQWHDRVSDUHVHPERUDHVVDHVWUXWXUD
YHLVSHORVHIHLWRVELROyJLFRVGHDSUR[LPDGDPHQWHGH SRVVDYDULDUS¬H[VHTXrQFLDVVLPSOHVRXVHTXrQFLDVLQYHUWLGDV
WRGRVRVIiUPDFRVGHSUHVFULomR(OHVSRGHPUHFRQKHFHUXP &DGD15H[LEHXPDSUHIHUrQFLDSRUGHWHUPLQDGDVHTXrQFLDFRQVHQVXDO
JUXSRH[WUDRUGLQDULDPHQWHGLYHUVLILFDGRGHVXEVWkQFLDVD PDVGHYLGRjKRPRORJLDIDPLOLDUKiXPDJUDQGHVHPHOKDQoDHQWUH
PDLRULDFRPSRVWDSRUPROpFXODVKLGURIyELFDVTXHSRGHPH[L
ELUDWLYLGDGHWRWDORXSDUFLDOFRPRDJRQLVWDVDQWDJRQLVWDVRX
DJRQLVWDVLQYHUVRV$OJXQV15VHVWmRHQYROYLGRVSUHGRPLQDQ
WHPHQWHQDVLQDOL]DomRHQGyFULQDSRUpPPXLWRVDWXDPFRPR
VHQVRUHVGHOLStGHRVHVmRYtQFXORVFUXFLDLVHQWUHQRVVRVVWDWXV
GLHWpWLFRHPHWDEyOLFRHDH[SUHVVmRGHJHQHVTXHUHJXODPR
PHWDEROLVPRHDGLVSRVLomRGHOLStGHRV15VWDPEpPUHJXODP
DH[SUHVVmRGHPXLWDVHQ]LPDVGRPHWDEROLVPRGHIiUPDFRV
HWUDQVSRUWDGRUHV0XLWDVGRHQoDVHVWmRDVVRFLDGDVDRPDX
IXQFLRQDPHQWRGRVLVWHPD15HQWUHHODVLQIODPDomRFkQFHU
GLDEHWHVGRHQoDVFDUGLRYDVFXODUHVREHVLGDGHHGLVW~UELRV
HVVDVVHTXrQFLDV8PDYH]QRQ~FOHRRUHFHSWRUDFRSODGRDROLJDQWH
UHFUXWDJUDQGHVFRPSOH[RVGHRXWUDVSURWHtQDVLQFOXLQGRFRDWLYD
GRUHVRXFRUUHSUHVVRUHVGHPDQHLUDDPRGLILFDUDH[SUHVVmRJHQpWLFD
DWUDYpVGHVHXVGRPtQLRV$)H$)$OJXQVGHVVHVFRDWLYDGRUHVVmR
HQ]LPDVHQYROYLGDVQDGLVUXSomRGHFURPDWLQDWDOFRPRDKLVWRQD
DFHWLODVHGHDFHWLODVHTXHMXQWDPHQWHFRPRXWUDVHQ]LPDVUHJXODP
RGHVHQURODPHQWRGR'1$SDUDIDFLOLWDURDFHVVRGDVHQ]LPDVSROL
PHUDVHHFRQVHTXHQWHPHQWHDWUDQVFULomRGRVJHQHV2VFRPSOH[RV
GHFRUUHSUHVVRUHVVmRUHFUXWDGRVSRUDOJXQVUHFHSWRUHVHHQJOREDP
DKLVWRQDGHDFHWLODVHHRXWURVIDWRUHVTXHSURYRFDPDFRQGHQVDomR
GDFURPDWLQDHYLWDQGRDDWLYDomRDGLFLRQDOGDWUDQVFULomR2FDVR
GR&$5pSDUWLFXODUPHQWHLQWHUHVVDQWHWDOFRPRRFRUUHFRPDOJXQV
QDUHSURGXomR.HUVWHQHWDO¬0XUSK\H+ROGHU¬ WLSRVGHSURWHtQD*GHVFULWRVDQWHULRUPHQWHQHVWHFDStWXORR&$5
SRGHIRUPDUXPFRPSOH[RDWLYRTXHWHUPLQDTXDQGRVHXOLJDQWH
HVWDEHOHFHDOLJDomR2VPHFDQLVPRVGHUHJXODomRQHJDWLYDGRVJHQHV
ESTRUTURA DOS RECEPTORES NUCLEARES SHORV15VVmRSDUWLFXODUPHQWHFRPSOH[RV6DQWRVHWDO¬ SDUD
▼7RGRVRV15VVmRSURWHtQDVPRQRPpULFDVTXHFRPSDUWLOKDPFDUDF XPDERDSHUVSHFWLYDVREUHHVVHIHQ{PHQR
WHUtVWLFDVHVWUXWXUDLVVLPLODUHVFRPSUHHQGHQGRTXDWURPyGXORV
)LJ¬%RXUJXHWHWDO¬SDUDPDLVGHWDOKHV2GRPtQLR1WHUPL CLASSIFICAÇÃO DOS RECEPTORES NUCLEARES
QDOpRTXHDSUHVHQWDPDLRUKHWHURJHQHLGDGHDEULJDQGRRSRQWR$)
IXQomRGHDWLYDomRTXHVHOLJDGHPDQHLUDOLJDQWHLQGHSHQGHQWHD
RXWURVIDWRUHVGHWUDQVFULomRHVSHFtILFRVGDFpOXODHPRGLILFDDOLJDomR
RXDFDSDFLGDGHUHJXODWyULDGRSUySULRUHFHSWRU2VSOLFLQJDOWHUQDWLYR
GRVJHQHVSRGHGDURULJHPDGLYHUVDVLVRIRUPDVGRUHFHSWRUFDGD
2V15VVmRQRUPDOPHQWHFODVVLILFDGRVHPVXEIDPtOLDVGH
DFRUGRFRPVHXGHVHQYROYLPHQWRILORJHQpWLFR1RHQWDQWR
HSDUDQRVVRVREMHWLYRVpPDLV~WLODGLVWLQomRWRPDQGRSRU
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AF1 AF2

N-teminal Domínio central de ligação DNA Região de Domínio de ligação-ligante Extensão

Região coativadora AF1 com “dedos de zinco” “dobradiça” Região coativadora AF2 C-terminal
Ligação HSP

Fig. 3.19 Diagrama esquemático de um receptor nuclear. O domínio heterogêneo N-terminal engloba o local AF1 (função de ativação 1).
Isso liga fatores de transcrição específicos das células que modificam as propriedades do receptor. O domínio central altamente conservado
engloba dois “dedos de zinco”; alças ricas em cistina (ou cisteína/histidina) na cadeia de aminoácidos que são mantidas em determinada
conformação pelos íons de zinco e que são responsáveis pelo reconhecimento e a ligação do DNA. A região de “dobradiça” flexível na
molécula permite que o receptor dimerize com outros NRs, e o domínio C-terminal, que contém o módulo de ligação-ligante, é específico de
cada classe de receptor (ver texto para mais detalhes).
43

C0015.indd 43 04/11/15 1:14 PM

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Tabela 3.4 Alguns receptores nucleares farmacologicamente significativos

Nome do Ligação- Mecanismo

receptor Abreviatura Ligante Fármacos Localização ligante de ação

Tipo I
Androgênio AR Testosterona Todos os glicocorticoides
Translocação
Estrogênio ERa, b 17b-oestradiol naturais e sintéticos (Cap. 33),
para o núcleo.
mineralocorticoides (Cap. 29)
Ligação aos
Glicocorticoide GRa Cortisol, e esteroides sexuais (Cap. 35)
Citosólico Homodímeros HREs com dois
corticosterona juntamente com os seus
semipontos
antagonistas (p. ex., raloxifina,
Progesterona PR Progesterona em sequência
4-hidroxi-tamoxifen e
invertida
Mineralocorticoide MR Aldosterona mifepristona)

Tipo II
Retinoide X RXR a, b, g Ácido
9-cis-retinoico Fármacos retinoides
Complexados
(Cap. 27)
Ácido retinoico RAR a, b, g Vitamina A com
correpressores,
Hormônio tireoide TR a, b T3, T4 Fármacos hormônio tireoide que são
Heterodímeros
deslocados
Proliferador PPAR a, b, Ácidos graxos, Nuclear frequentemente
Rosiglitazona, pioglitazona após ligação
eroxissoma g,d prostaglandinas com RXR
ao ligante e
Androstano CAR Androstano permitindo
Estimulação da síntese de a ligação de
constitutivo
CYP e alteração metabolismo transativadores
Pregnano X PXR Xenobióticos do fármaco

Apenas estão apresentados exemplos das Classes I e II.

44

C0015.indd 44 04/11/15 1:14 PM

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• Uma família de 48 receptores solúveis que podem
detectar lipídeos e sinais hormonais, além de modular a
transcrição gênica.
• Seus ligantes são muitos e variados, incluindo
fármacos esteroides e hormonais, hormônios tireoides,
vitaminas A e D, vários lipídeos e xenobióticos.
• Duas categorias principais:
– Os RN de classe I estão presentes no citoplasma
e formam homodímeros na presença de seu
ligante, migrando até o núcleo. Seus ligantes são
principalmente de natureza endócrina (p. ex.,
hormônios esteroides).
– Os RN de classe II estão, em geral, constitutivamente
presentes no núcleo e formam heterodímeros com o
receptor retinoide X. Seus ligantes são, via de regra,
lipídeos (p. ex., os ácidos graxos).
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• A família dos receptores é o alvo de cerca de 10%
dos fármacos prescritos, e as enzimas que regulam
afetam a farmacocinética de cerca de 60% de todos os
fármacos prescritos.
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CANAIS DE
CÁTIONS (4
subunidades)
N C N C N C

Exemplos: Canais de Exemplos: Canais de K+ Exemplo: Canais de

K+ controlados retificadores de entrada, P2XR, K+ em repouso
por voltagem, canais TRP ASIC, ENaC, degenerinas

CANAIS DE SÓDIO
E CÁLCIO
CONTROLADOS
POR VOLTAGEM
N C

Fig. 3.20 Arquitetura molecular dos canais iônicos. Os retângulos vermelhos e azuis representam as a hélices que atravessam
a membrana. Os grampos azuis são domínios em alça do poro (P), presentes em muitos canais, sendo os retângulos azuis as regiões
formadoras dos poros das a hélices que atravessam a membrana. Os retângulos listrados representam as regiões sensoras de voltagem
dos canais controlados por voltagem. O símbolo verde representa a partícula inativadora dos canais de sódio controlados por voltagem.
A nomenclatura do canal de potássio se baseia no número de hélices transmembrana (T) e das alças formadoras de poro (P) em cada
subunidade. Mais informações sobre canais iônicos são dadas no Capítulo 4. ASIC, canal iônico sensível a ácido; ENaC, canal epitelial de
sódio; TRP, canal de receptor de potencial transitório.
46

C0015.indd 46 04/11/15 1:14 PM

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