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22 SEÇÃO 1� � PRINCÍPIOS GERAIS Como agem os fármacos: aspectos moleculares 3 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 clonagem e estudos estruturais. Por fi m, discutire- mos as várias formas de conexão receptor-efetor (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 superfi cialmente esses capítulos sem perder o fi o 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. 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de composto anômalo Transporte bloqueado Inibidor Falso substrato Transporte normal RECEPTORES CANAIS IÔNICOS ENZIMAS TRANSPORTADORES Produto anômaloAgonista/substrato Antagonista/inibidor Pró-fármaco Direto Sem efeito Mediadores endógenos bloqueados Antagonista Agonista/ agonista inverso Transcrição do DNA Modulação de canais iônicos Ativação/inibição enzimática Abertura/fechamento de canais iônicos Mecanismos de transdução Aumento ou diminuição da probabilidade de abertura Moduladores Bloqueio da permeação Bloqueadores Produção de fármaco ativo Produção de metabólito anômalo Inibição da reação normal Inibidor Pró-fármaco Falso substrato ou A B C D Fig. 3.1 Tipos de alvos para a ação de fármacos. 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GH�OLJDomR�GLVWLQWDV�H�GLIHUHQWHV�PHFDQLVPRV�GH�WUDQVGXomR�GH�VLQDO�� HPERUD�VXD�UHOHYkQFLD�IDUPDFROyJLFD�DLQGD�HVWHMD�SRU�VHU�HVFODUHFLGD�� 2XWUR�SURFHVVR�TXH�SRGH�SURGX]LU�UHFHSWRUHV�GLIHUHQWHV��PDV�YLQGRV�GR� PHVPR�JHQH��p�D�HGLomR�GR�51$P��TXH�HQYROYH�D�VXEVWLWXLomR�DQ{PDOD� GH�XPD�EDVH�QR�51$P�SRU�RXWUD��GH�RQGH�VXUJH�XPD�SHTXHQD�YDULDomR� QD�VHTXrQFLD�GH�DPLQRiFLGRV�GR�UHFHSWRU������� �(VVD�KHWHURJHQHLGDGH�PROHFXODU�p�XPD�FDUDFWHUtVWLFD�GH�WRGRV� RV�WLSRV�GH�UHFHSWRUHV�²�QD�YHUGDGH��GDV�SURWHtQDV�IXQFLRQDLV��� 1.Canais iônicos controlados por ligantes (receptores ionotrópicos) 2.Receptores acoplados à proteína G (metabotrópicos) 3.Receptores ligados a quinases 4.Receptores nucleares NÚCLEO Transcrição de gene Transcrição de gene Efeitos celularesEfeitos celulares Fosforilação de proteína Efeitos celulares Fosforilação de proteína Outro Liberação de Ca 2+ Alteração da excitabilidade Efeitos celulares Hiperpolarização ou despolarização HorasHorasSegundosMilissegundos Escala de tempo Segundos mensageiros R R/E R E G G ou ou Íons Íons Síntese de proteína Síntese de proteína Receptor de estrógenos Receptores de citocinas Receptor muscarínico da ACh Receptor nicotínico da ACh Exemplos R R Fig. 3.2 Tipos de relação entre receptor e efetor. ACh, acetilcolina; E, enzima; G, proteína G; R, receptor. ����2�WHUPR��UHFHSWRU�QXFOHDU��QmR�p�PXLWR�DGHTXDGR�SRUTXH�DOJXQV�HVWmR�� QD�YHUGDGH��ORFDOL]DGRV�QR�FLWRVRO�H�GHVORFDP�VH�SDUD�R�FRPSDUWLPHQWR� QXFOHDU�QD�SUHVHQoD�GH�XP�OLJDQWH������2V�UHFHSWRUHV�SDUD���+7���&DS�¬�����VmR�DWXDOPHQWH�RV�FDPSH}HV�GH� GLYHUVLGDGH��FRP����VXEWLSRV�FORQDGRV�� C0015.indd 25 04/11/15 1:13 PM SEÇÃO 1 PRINCÍPIOS GERAIS3 26 HP�JHUDO��1RYRV�VXEWLSRV�H�LVRIRUPDV�GH�UHFHSWRUHV�FRQWLQXDP� VHQGR�GHVFREHUWRV��H�DWXDOL]Do}HV�UHJXODUHV�GR�FDWiORJR�VmR� GLVSRQLELOL]DGDV���ZZZ�JXLGHWRSKDUPDFRORJ\�RUJ����2V�SUR� EOHPDV�GH�FODVVLILFDomR��QRPHQFODWXUD�H�WD[RQRPLD�UHVXOWDQWHV� GHVVH�DF~PXOR�GH�GDGRV�IRUDP�PHQFLRQDGRV�DQWHULRUPHQWH�� 'R�SRQWR�GH�YLVWD�IDUPDFROyJLFR��QR�TXDO�QRVVR�SURSyVLWR�p� HQWHQGHU�RV�IiUPDFRV�LQGLYLGXDLV�H�VHXV�HIHLWRV�QRV�RUJDQLVPRV� YLYRV��EHP�FRPR�GHVHQYROYHU�IiUPDFRV�PHOKRUHV�TXH�RV�H[LV� WHQWHV��p�LPSRUWDQWH�PDQWHUPRV�D�IDUPDFRORJLD�PROHFXODU�HP� IRFR��2�´QRYR�ULWRµ�SURYRX�VH�UHYHODGRU�GH�PXLWDV�PDQHLUDV�� PDV�D�JUDQGH�FRPSOH[LGDGH�GH�FRPSRUWDPHQWRV�GDV�PROpFX� ODV�VLJQLILFD�TXH�WHPRV�XP�ORQJR�FDPLQKR�DWp�DWLQJLU�D�XWRSLD� UHGXFLRQLVWD�TXH�D�ELRORJLD�PROHFXODU�SURPHWLD��4XDQGR�FKH� JDUPRV�Oi��HVWH�OLYUR�VHUi�PXLWR�PHQRU��3RU�HQTXDQWR��WHQWDPRV� VHOHFLRQDU�RV�SULQFtSLRV�JHUDLV��VHP�QRV�SHUGHUPRV�HP�XP� DSURIXQGDPHQWR�H[FHVVLYR�QRV�GHWDOKHV�� �$�VHJXLU��GHVFUHYHPRV�DV�FDUDFWHUtVWLFDV�GH�FDGD�XPD�GDV� TXDWUR�VXSHUIDPtOLDV�GH�UHFHSWRUHV���� TIPO 1: CANAIS IÔNICOS ATIVADOS POR LIGANTES �1HVWD�GHVFULomR�JHUDO�GD�HVWUXWXUD�GRV�FDQDLV�L{QLFRV�DWLYD� GRV�SRU�OLJDQWHV��YDPRV�QRV�GHEUXoDU�LQLFLDOPHQWH�VREUH�R� UHFHSWRU�QLFRWtQLFR�GH�DFHWLOFROLQD��TXH�VH�HQFRQWUD�QD�MXQomR� QHXURPXVFXODU���&DS�¬������7UDWD�VH�GH�XP�GRV�UHFHSWRUHV�PDLV� FRQKHFLGRV��FRP�HVWUXWXUD�H�IXQomR�VHPHOKDQWHV�D�RXWURV� UHFHSWRUHV��FLV�ORRS���DVVLP�FKDPDGRV�SRUTXH�SRVVXHP�XP�ODUJR� GRPtQLR�LQWUDFHOXODU�HQWUH�RV�GRPtQLRV�WUDQVPHPEUDQDUHV��� H����TXH�FRQWrP�YiULRV�UHVtGXRV�GH�FLVWLQD�>�)LJ�¬����$@���TXH� WDPEpP�LQFOXHP�R�*$%$�$��H�RV�UHFHSWRUHV�GH�JOLFLQD���&DS�¬������EHP�FRPR�RV¬UHFHSWRUHV���+7�����&DSV�¬���H¬�����������������([LVWHP�RXWURV� WLSRV�GH�FDQDLV�L{QLFRV�DWLYDGRV�SRU�OLJDQWHV�²�QRWDGDPHQWH�� RV¬UHFHSWRUHV�LRQRWUySLFRV�GH�JOXWDPDWR���&DS�¬�����H�RV�UHFHS� WRUHV�SXULQpUJLFRV�3�;����&DSV�¬���H¬����������������²�TXH�GLIHUHP�HP�YiULRV� DVSHFWRV�GR�UHFHSWRU�QLFRWtQLFR�GH�DFHWLOFROLQD�� ESTRUTURA MOLECULAR �2V�FDQDLV�L{QLFRV�DWLYDGRV�SRU�OLJDQWHV�WrP�WUDoRV�HVWUXWXUDLV� HP�FRPXP�FRP�RXWURV�FDQDLV�L{QLFRV��GHVFULWRV�QD�SiJLQD����� 2�UHFHSWRU�QLFRWtQLFR�GD�DFHWLOFROLQD���)LJ�¬��������IRL�R�SULPHLUR�D� VHU�FORQDGR��FRQVLVWLQGR�HP�XPD�PRQWDJHP�HP�IRUPD�GH�SHQ� WkPHUR�GH�GLIHUHQWHV�VXEXQLGDGHV��GDV�TXDLV�H[LVWHP�TXDWUR� WLSRV��GHQRPLQDGRV��a����b����g��H��d���FDGD�TXDO�FRP�SHVR�PROHFXODU� ��0��U���HQWUH������¬N'D��$V�VXEXQLGDGHV�DSRQWDP�XPD�PDUFDQWH�KRPRORJLD�QD�VHTXrQFLD��H�FDGD�XPD�GHODV�FRQWpP�TXDWUR� 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EUDQD��0�����GH�FDGD�XPD�GDV�FLQFR�VXEXQLGDGHV�IRUPD�R�UHYHVWLPHQWR�GR�FDQDO�L{QLFR���)LJ�¬�������$V�FLQFR�KpOLFHV�0����TXH�IRUPDP�R�SRUR�VmR�GHIRUPDGDV�SDUD�GHQWUR��D�PHLR�FDPLQKR�GD�HVSHVVXUD�GD�PHPEUDQD�� IRUPDQGR�XPD�FRQVWULomR��4XDQGR�DV�PROpFXODV�GH�DFHWLOFROLQD�VH�OLJDP�� RFRUUH�XPD�DOWHUDomR�FRQIRUPDFLRQDO�QD�SDUWH�H[WUDFHOXODU�GR�UHFHSWRU� �UHYLVmR�SRU��*D\�H�<DNHO�¬�������TXH�WRUFH�DV�VXEXQLGDGHV��a���ID]HQGR�FRP� TXH�RV�VHJPHQWRV�0����DEDXODGRV�VH�DIDVWHP�XQV�GRV�RXWURV��SURPRYHQGR��DVVLP��D�DEHUWXUD�GR�FDQDO���0L\D]DZD��HW�DO���¬��������$�ERUGD�GR�FDQDO�FRQ� WpP�XPD�VpULH�GH�UHVtGXRV�DQL{QLFRV��R�TXH�WRUQD�R�FDQDO�VHOHWLYDPHQWH� SHUPHiYHO�D�FiWLRQV��LQLFLDOPHQWH��1$����H�.�����HPERUD�DOJXQV�WLSRV�GH� UHFHSWRUHV�QLFRWtQLFRV�WDPEpP�VHMDP�SHUPHiYHLV�DR�&D������� �2�XVR�GH�PXWDJrQHVH�GLUHFLRQDGD�DR�ORFDO��TXH�SHUPLWH�TXH�SHTXH� QDV�UHJL}HV�RX�UHVtGXRV�~QLFRV�GD�VHTXrQFLD�GH�DPLQRiFLGRV�VHMDP� DOWHUDGRV��PRVWURX�TXH�D�PXWDomR�GH�XP�UHVtGXR�FUtWLFR�QD�KpOLFH��� Domínio de ligação ao DNA (“dedos de zinco”) Domínio catalítico Domínios de ligação Revestimento do canal x 4 ou 5 Domínio de ligação Domínio de acoplamento à proteína G Domínio de ligação Domínio de ligação A B C D Tipo 3 Receptores ligados a quinases Tipo 4 Receptores nucleares Tipo 1 Canais iônicos controlados por ligantes (receptores ionotrópicos) Tipo 2 Receptores acoplados à proteína G (receptores metabotrópicos) N C N C N C N C 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 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 acoplados à proteína G. [ C ] Tipo 3: receptores ligados a quinases. A maior parte dos receptores de fatores de crescimento incorpora o domínio de ligação ao ligante e o domínio enzimático (quinase) na mesma molécula, como aqui mostrado, enquanto os receptores de citocinas não possuem um domínio de quinase intracelular, mas se relacionam com moléculas de quinases citosólicas. Outras variantes estruturais também existem. [ D ] Tipo 4: receptores nucleares que controlam a transcrição de genes. 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PDLV�FRPSOLFDGD��SRLV�DJRQLVWDV�GLIHUHQWHV�SRGHP�FDXVDU�D�DEHUWXUD� GH�FDQDLV�HVSHFtILFRV�D�XP�RX�PDLV�QtYHLV�GH�FRQGXWkQFLD�GLVWLQWRV� ��)LJ�¬�������,VVR�LPSOLFD�D�H[LVWrQFLD�GH�PDLV�GR�TXH�XPD�FRQIRUPDomR� 5 ��3DUD�DOpP�GLVVR��D�GHVVHQVLELOL]DomR�GRV�FDQDLV�L{QLFRV�RSHUDGRV�SRU� OLJDQWHV���&DS�¬����WDPEpP�LPSOLFD�XP�RX�PDLV�HVWDGRV�FRQIRUPDFLRQDLV� DGLFLRQDLV�LQGX]LGRV�SRU�DJRQLVWDV��(VVDV�GHVFREHUWDV�H[LJHP�PDLV� DSHUIHLoRDPHQWR�GR�PRGHOR�VLPSOHV�HP�TXH�XP�~QLFR�HVWDGR��5 ��p� UHSUHVHQWDGR��H�VmR�XP�ERP�H[HPSOR�GD�IRUPD�FRPR�R�FRPSRUWDPHQWR� DWXDO�GRV�UHFHSWRUHV�WRUQD�QRVVRV�PRGHORV�WHyULFRV�XP�SRXFR�HVJRWDGRV��������� TIPO 2: RECEPTORES ACOPLADOS À PROTEÍNA G �$�JUDQGH�IDPtOLD�*3&5�HQJORED�PXLWRV�GRV�UHFHSWRUHV�TXH� VmR�IDPLOLDUHV�DRV�IDUPDFRORJLVWDV��FRPR�$&K5�PXVFDUtQLFRV�� DGUHQRFHSWRUHV��UHFHSWRUHV�GH�GRSDPLQD��UHFHSWRUHV���+7�� UHFHSWRUHV�RSLRLGHV��UHFHSWRUHV�SDUD�PXLWRV�SHSWtGHRV��UHFHSWR� UHV�GH�SXULQDV�H�PXLWRV�RXWURV��LQFOXLQGR�RV�TXLPLRUUHFHSWRUHV� HQYROYLGRV�QR�ROIDWR�H�QD�GHWHFomR�GH�IHURP{QLRV��H�WDPEpP� PXLWRV�UHFHSWRUHV�´ yUImRVµ���)UHGULNVVRQ�H�6FKL|WK�¬��������3DUD� D�PDLRULD�GHOHV��RV�HVWXGRV�IDUPDFROyJLFRV�H�PROHFXODUHV�UHYH� ODUDP�D�H[LVWrQFLD�GH�YiULRV�VXEWLSRV��7RGRV�DSUHVHQWDP�XPD� HVWUXWXUD�KHSWD�KHOLFRLGDO������ Tabela 3.1 Os quatro tipos principais de receptores Tipo 1: canais iônicos controlados por ligantes Tipo 2: receptores acoplados à proteína G Tipo 3: receptores ligados a quinases Tipo 4: receptores 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 acetilcolina, receptor GABA A Receptor muscarínico da acetilcolina, adrenoceptores Insulina, fatores de crescimento, receptores de citocinas Receptores de esteroides Estrutura Organização oligomérica de subunidades circundando um poro central Estrutura monomérica ou oligomérica compreendendo sete hélices transmembrana com um domínio intracelular acoplador de proteína G Hélice transmembrana única ligando o domínio extracelular do receptor ao domínio da quinase Estrutura monomérica com domínios de ligação ao receptor e domínios de ligação ao DNA C0015.indd 27 04/11/15 1:13 PM SEÇÃO 1 PRINCÍPIOS GERAIS3 28 �0XLWRV�QHXURWUDQVPLVVRUHV��H[FHWR�RV�SHSWtGLRV��SRGHP� LQWHUDJLU�WDQWR�FRP�RV�*3&5V�FRPR�FRP�RV�FDQDLV�DWLYDGRV� SRU�OLJDQWHV��SHUPLWLQGR�TXH�D�PHVPD�PROpFXOD�SURGX]D� �DWUDYpV�GRV�FDQDLV�L{QLFRV�DWLYDGRV�SRU�OLJDQWHV��HIHLWRV�UiSL� GRV�PDV�WDPEpP�OHQWRV��DWUDYpV�GRV�*3&5V���3RU�RXWUR�ODGR�� RV�KRUP{QLRV�SHSWtGHRV�LQGLYLGXDLV�JHUDOPHQWH�DJHP�VREUH� RV�*3&5V�RX�VREUH�RV�UHFHSWRUHV�OLJDGRV�D�TXLQDVHV��DGLDQWH��� SRUpP�UDUDPHQWH�VREUH�DPERV��H�XPD�HVFROKD�VHPHOKDQWH� VH�DSOLFD�D�YiULRV�OLJDQWHV�TXH�DWXDP�VREUH�RV�UHFHSWRUHV� QXFOHDUHV�������� �2�JHQRPD�KXPDQR��LQFOXLQGR�RV�JHQHV�TXH�FRGLILFDP�FHUFD� GH�����*3&5V��H[FOXLQGR�RV�UHFHSWRUHV�GH�RGRU���FRQVWLWXL�D� FODVVH�~QLFD�PDLV�FRPXP�GH�DOYRV�SDUD�IiUPDFRV�WHUDSrXWLFRV�� H�DFUHGLWD�VH�TXH�YiULRV�DOYRV�SURPLVVRUHV�SDUD�WDLV�IiUPDFRV� DLQGD�GHYDP�VHU�LGHQWLILFDGRV��3DUD�XPD�EUHYH�UHYLVmR��FRQ� VXOWDU��+LOO���������� ESTRUTURA MOLECULAR �2�SULPHLUR�*3&5�D�VHU�WRWDOPHQWH�FDUDFWHUL]DGR�IRL�R�UHFHSWRU� �b��DGUHQpUJLFR���&DS�¬������TXH�IRL�FORQDGR�HP�������5DSLGDPHQ� WH��D�ELRORJLD�PROHFXODU�DOFDQoRX�D�IDUPDFRORJLD��H�D�PDLRULD� GRV�UHFHSWRUHV�TXH�IRUDP�LGHQWLILFDGRV�SRU�VXDV�SURSULHGDGHV� IDUPDFROyJLFDV�HVWi�DJRUD�FORQDGD��2�TXH�SDUHFLD�VHU�UHYROXFLR� QiULR�HP������p�DJRUD�FRQVLGHUDGR�OXJDU�FRPXP��5HFHQWHPHQ� WH��D�GLILFXOGDGH�GD�FULVWDOL]DomR�GRV�*3&5V�IRL�XOWUDSDVVDGD� ��:HLV�H�.RELOND�¬��������SRVVLELOLWDQGR�R�HPSUHJR�GH�WpFQLFDV� SRWHQWHV�GH�FULVWDORJUDILD�FRP�UDLRV�;�QR�HVWXGR�GHWDOKDGR� GD�HVWUXWXUD�PROHFXODU�GHVVHV�UHFHSWRUHV���)LJ�¬���������3DUD�DOpP� GLVVR��IRUDP�GHVHQYROYLGRV�PpWRGRV�GH�IOXRUHVFrQFLD�SDUD� HVWXGDU�D�FLQpWLFD�GD�OLJDomR�GRV�OLJDQWHV�H�DV�PXGDQoDV�FRQ� IRUPDFLRQDLV�VXEVHTXHQWHV�DVVRFLDGDV�j�DWLYDomR���/RKVH��HW� DO���¬������%RFNHQKDXHU��HW�DO���¬��������(VVH�IDWR�WHP�OHYDGR�DR� FRQKHFLPHQWR�GH�LQIRUPDo}HV�LPSRUWDQWHV�VREUH�DV�FRQIRUPD� o}HV�GD�OLJDomR�GRV�DQWDJRQLVWD�DJRQLVWDV�DRV�UHFHSWRUHV��EHP� FRPR�VREUH�DV�LQWHUDo}HV�GRV�UHFHSWRUHV�DFRSODGRV�j�SURWHtQD� *��$�SDUWLU�GHVVHV�HVWXGRV��p�SRVVtYHO�DIHULU��FRP�PDLRU�FODUH]D�� R�PHFDQLVPR�GH�DWLYDomR�GRV�*3&5V�H�RV�IDWRUHV�GHWHUPLQDQ�WHV�QD�HILFiFLD�GRV�DJRQLVWDV��EHP�FRPR�REWHU�PHOKRUHV�EDVHV� SDUD�D�FRQFHSomR�GH�QRYRV�OLJDQWHV�*3&5�� �2V�UHFHSWRUHV�DFRSODGRV�j�SURWHtQD�*�FRQVLVWHP�QXPD�~QLFD� FDGHLD�GH�SROLSHSWtGHRV��QRUPDOPHQWH�GH���������UHVtGXRV�� PDV��HP�DOJXQV�FDVRV��DWLQJLQGR�������UHVtGXRV��$�DQDWRPLD� JHUDO�p�DSUHVHQWDGD�QD��)LJXUD¬����%��6XD�HVWUXWXUD�HQJORED��� Canais iônicos regulados por ligantes • São chamados às vezes de receptores ionotrópicos. • Estão envolvidos principalmente na transmissão sináptica rápida. • Existem várias famílias estruturais, sendo a mais comum a organização heteromérica de quatro ou cinco subunidades, com hélices transmembrana dispostas em torno de um canal central aquoso. • A ligação do ligante e a abertura do canal ocorrem em uma escala de tempo de milissegundos. • Os exemplos incluem os receptores nicotínicos da acetilcolina, do GABA tipo A (GABA A ), receptores de glutamato (NMDA) e de ATP (P2X). ����(QWUHWDQWR��RV�H[HPSORV�GH�SURPLVFXLGDGH�HVWmR�DXPHQWDQGR��2V� KRUP{QLRV�HVWHURLGHV��QRUPDOPHQWH�ILpLV�DRV�UHFHSWRUHV�QXFOHDUHV�� LQWHUDJHP�RFDVLRQDOPHQWH�FRP�FDQDLV�L{QLFRV�H�RXWURV�DOYRV���)DONHQVWHLQ� �HW�DO���¬��������H�DOJXQV�HLFRVDQRLGHV�DJHP�QRV�UHFHSWRUHV�QXFOHDUHV��EHP� FRPR�QRV�*3&5V��$�QDWXUH]D�WHP�D�PHQWH�PXLWR�DEHUWD��HPERUD�WDLV� H[HPSORV�VHMDP�UHVSRQViYHLV�SRU�GHL[DU�RV�IDUPDFRORJLVWDV�DERUUHFLGRV� H�RV�HVWXGDQWHV�HP�GHVHVSHUR�� A ACh ACh ACh ACh α α γ α β δ α β δ Exterior Membrana Citosol α-Hélices formando a comporta 6 nm 3 nm 2 nm Poro de ~0,7 nm de diâmetro B Fig. 3.4 Estrutura do receptor nicotínico da acetilcolina (um típico canal iônico controlado por ligante). [ A ] Diagrama esquemático em visão lateral (acima) e transversal (abaixo). As cinco subunidades do receptor ( a 2 , b , g , d ) formam um agregado que circunda um poro transmembrana central, cujo revestimento é formado pelos segmentos helicoidais M 2 de 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 Refi ned structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346(4), 967-989.) C0015.indd 28 04/11/15 1:13 PM 3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 29 VHWH�KpOLFHV��a��WUDQVPHPEUDQDUHV��VHPHOKDQWHV�jV�GRV�FDQDLV� L{QLFRV�DQWHULRUPHQWH�GLVFXWLGRV��FRP�XP�GRPtQLR�WHUPLQDO�1� H[WUDFHOXODU�GH�FRPSULPHQWR�YDULiYHO�H�XP�GRPtQLR�WHUPLQDO� &�LQWUDFHOXODU�� �2V�*3&5V�VmR�GLYLGLGRV�HP�WUrV�JUXSRV�GLVWLQWRV��([LVWH� FHUWD�KRPRORJLD�GH�VXDV�VHTXrQFLDV�GHQWUR�GR�PHVPR�JUXSR�� PDV�SRXFD�HQWUH�RV�GLIHUHQWHV�JUXSRV��3DUWLOKDP�D�PHVPD� HVWUXWXUD�GH�VHWH�VHJPHQWRV�WUDQVPHPEUDQDUHV�HP�KpOLFH��KHS� WD�KHOLFRLGDO���PDV�GLIHUHP�HP�RXWURV�DVSHFWRV��SULQFLSDOPHQWH� QR�FRPSULPHQWR�GR�WHUPLQDO�²1�H[WUDFHOXODU�H�QD�ORFDOL]DomR� GR�GRPtQLR�GH�OLJDomR�GR�DJRQLVWD���7DEHOD¬���������$�IDPtOLD�$�p�� GH�ORQJH��D�PDLRU��FRPSUHHQGHQGR�D�PDLRU�SDUWH�GRV�UHFHS� WRUHV�SDUD�PRQRDPLQDV��QHXURSHSWtGHRV�H�TXLPLRFLQDV��$� IDPtOLD�%�LQFOXL�UHFHSWRUHV�SDUD�DOJXQV�RXWURV�SHSWtGHRV��FRPR� FDOFLWRQLQD�H�JOXFDJRQ��$�IDPtOLD�&�p�D�PHQRU��VHXV�SULQFLSDLV� PHPEURV�VmR�RV�UHFHSWRUHV�PHWDERWUySLFRV�SDUD�JOXWDPDWR�H� *$%$���&DS�¬�����H�RV�UHFHSWRUHV�VHQVtYHLV�DR�&D�������&DS�¬����������� �����▼�$�FRPSUHHQVmR�GD�IXQomR�GHVVH�WLSR�GH�UHFHSWRU�GHYH�PXLWR�DR� HVWXGR�GH�XPD�SURWHtQD�HVWUHLWDPHQWH�UHODFLRQDGD��D��URGRSVLQD���TXH�p� UHVSRQViYHO�SHOD�WUDQVGXomR�QRV�EDVWRQHWHV�UHWLQLDQRV��(VVD�SURWHtQD� p�DEXQGDQWH�QD�UHWLQD��H�VHX�HVWXGR�p�PXLWR�PDLV�IiFLO�GR�TXH�R�GDV� SURWHtQDV�UHFHSWRUDV��TXH�QmR�VmR�DEXQGDQWHV���p�FRQVWUXtGD�HP�XP� SODQR�LGrQWLFR�DR�PRVWUDGR�QD��)LJXUD¬�����H�WDPEpP�SURGX]�UHVSRVWD� QR�EDVWRQHWH��KLSHUSRODUL]DomR��DVVRFLDGD�j�LQLELomR�GD�FRQGXWkQFLD� DR�1D�����DWUDYpV�GH�XP�PHFDQLVPR�HQYROYHQGR�XPD�SURWHtQD�*��SiJ�� �����)LJ�¬�������$�GLIHUHQoD�PDLV�yEYLD�p�TXH�D�UHVSRVWD�p�SURGX]LGD�SRU� XP�IyWRQ��H�QmR�SRU�XPD�PROpFXOD�GH�DJRQLVWD��&RP�HIHLWR��D�URGRS� VLQD�SRGH�VHU�FRQVLGHUDGD�XPD�SURWHtQD�TXH�LQFRUSRUD�VXD�SUySULD� PROpFXOD�GH�DJRQLVWD��FKDPDGD��UHWLQDO���D�TXDO�VRIUH�LVRPHUL]DomR�GD� IRUPD��WUDQV���LQDWLYD��SDUD�D�IRUPD��FLV���DWLYD��TXDQGR�DEVRUYH�XP�IyWRQ������� �([SHULPHQWRV�GH�PXWDJrQHVH�GLUHFLRQDGD�D�ORFDLV�PRVWUDP� TXH�D�WHUFHLUD�DOoD�FLWRSODVPiWLFD�p�D�UHJLmR�GD�PROpFXOD�TXH� VH�DFRSOD�j�SURWHtQD�*��SRLV�D�GHOHomR�RX�D�PRGLILFDomR�GHVVD� SRUomR�UHVXOWDP�HP�UHFHSWRUHV�TXH�DWp�VH�OLJDP�D�OLJDQWHV�� PDV�TXH�VmR�LQFDSD]HV�GH�VH�DVVRFLDU�jV�SURWHtQDV�*�RX�GH� SURGX]LU�UHVSRVWDV��(P�JHUDO��GHWHUPLQDGR�VXEWLSR�GH�UHFHS� WRU�DFRSOD�VH�VHOHWLYDPHQWH�D�XPD�SURWHtQD�*�HP�SDUWLFXODU� H��DR�WURFDU�SDUWHV�GD�DOoD�FLWRSODVPiWLFD�HQWUH�GLIHUHQWHV� UHFHSWRUHV��DOWHUD�VXD�VHOHWLYLGDGH�SHOD�SURWHtQD�*��$�IRV� IRULODomR�GRV�UHVtGXRV�GH�VHULQD�H�GH�WUHRQLQD�QR�ILQDO�GR� WHUPLQDO²&�H�GH�RXWURV�GRPtQLRV�LQWUDFHOXODUHV�DWUDYpV�GH� TXLQDVHV�LQWUDFHOXODUHV�SRGH�UHVXOWDU�HP�GHVVHQVLELOL]DomR� GR�UHFHSWRU��SiJ������� �1DV�PROpFXODV�PHQRUHV��WDO�FRPR�QRUDGUHQDOLQD��QRUHSLQH� IULQD��H�DFHWLOFROLQD��R�GRPtQLR�GD�OLJDomR�DR�OLJDQWH�QRV�UHFHS� WRUHV�GH�FODVVH�$�HVWi�LQVHULGR�QD�IHQGD�HQWUH�RV�VHJPHQWRV� ��a����KHOLFRLGDLV�GHQWUR�GD�PHPEUDQD���)LJV�¬���%�H¬�������VLPLODU� DR�HVSDoR�RFXSDGR�SHOR�UHWLQDO�QD�PROpFXOD�GH�URGRSVLQD��2V��� Tabela 3.2 Famílias de receptores acoplados à proteína G a Família Receptores b Características estruturais A: família da rodopsina O maior grupo. Receptores para a maioria dos neurotransmissores aminados, muitos neuropeptídeos, purinas, prostanoides, canabinoides etc. Cauda extracelular (N terminal) curta. O ligante liga-se a hélices transmembrana (aminas) ou a alças extracelulares (peptídeos) B: família dos receptores de secretina/glucagon Receptores para hormônios peptídicos, incluindo secretina, glucagon, calcitonina Cauda extracelular intermediária incorporando o domínio de ligação ao ligante C: família do receptor metabotrópico de glutamato/ sensor de cálcio Grupo pequeno. Receptores metabotrópicos de glutamato, receptores GABA B , receptores sensíveis ao Ca 2+ Cauda extracelular longa incorporando o domínio de ligação ao ligante a Uma quarta família distinta inclui muitos receptores para feromônios, mas nenhum receptor farmacológico. b Para listas completas, consulte www.guidetopharmacology.org . ����2�UHFHSWRU�VHQVRU�GH�&D�������&RQLJUDYH��HW�DO���¬�������p�XP�*3&5�LQFRPXP� TXH�p�DWLYDGR�QmR�SHORV�PHGLDGRUHV�FRQYHQFLRQDLV��PDV�VLP�SHOR�&D����� H[WUDFHOXODU��QD�IDL[D�GH���D���¬PPRO�O�²�XPD�DILQLGDGH�H[WUHPDPHQWH� EDL[D��HP�FRPSDUDomR�FRP�RXWURV�DJRQLVWDV�GH�*3&5V��(VVH�UHFHSWRU�p� H[SUHVVR�HP�FpOXODV�GD�JOkQGXOD�SDUDWLUHRLGH�H�WHP�SRU�IXQomR�UHJXODU� D�FRQFHQWUDomR�GH�&D�����H[WUDFHOXODU�DWUDYpV�GR�FRQWUROH�GD�VHFUHomR�GR� SDUDWRUP{QLR���&DS�¬������(VVH�PHFDQLVPR�KRPHRVWiWLFR�p�EDVWDQWH�GLVWLQWR� GRV�PHFDQLVPRV�GH�UHJXODomR�GR�&D�����LQWUDFHOXODU�GLVFXWLGRV�QR��&DStWXOR¬���� N C N CCANAIS ATIVADOS POR LIGANTES (5, 4 ou 3 subunidades) Receptores de NMDA Exemplos: NMDAExemplos: nAChR, GABA A ,5-HT 3 , IP 3 R, RyR Receptores de cistina (cys-loop) Exemplo: P2XR Receptores P2X 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-HT 3 , 5-hydroxitriptamina tipo 3; receptor GABA A , GABA tipo A; IP 3 R, receptor do inositol trifosfato; nAChR, receptor nicotínico de acetilcolina; NMDA, N -metil D-Aspartato; P2XR, receptor de purina P2X; RyR, receptor de rianodina. C0015.indd 29 04/11/15 1:14 PM SEÇÃO 1 PRINCÍPIOS GERAIS3 30 OLJDQWHV�SHSWtGLFRV��FRPR�D�VXEVWkQFLD�3���&DS�¬������OLJDP�VH� PDLV�VXSHUILFLDOPHQWH�jV�DOoDV�H[WUDFHOXODUHV��FRPR�PRVWUDGR� QD��)LJXUD¬����%��$�SDUWLU�GH�HVWUXWXUDV�FULVWDOLQDV�H�H[SHULPHQWRV� GH�PXWDJrQHVH�HP�ORFDO�~QLFR��p�SRVVtYHO�PDSHDU�R�GRPtQLR�GH� OLJDomR�DR�OLJDQWH�GHVVHV�UHFHSWRUHV��FRP�D�H[SHFWDWLYD�GH�TXH�� HP�EUHYH��VHMD�SRVVtYHO�SURMHWDU�OLJDQWHV�VLQWpWLFRV�FRP�EDVH�QR� FRQKHFLPHQWR�GD�HVWUXWXUD�GR�ORFDO�UHFHSWRU�²�XP�LPSRUWDQWH� PDUFR�SDUD�D�LQG~VWULD�IDUPDFrXWLFD��TXH��DWp�HQWmR��WHP�FRQWD� GR�SULQFLSDOPHQWH�FRP�D�HVWUXWXUD�GH�PHGLDGRUHV�HQGyJHQRV� �FRPR�D�KLVWDPLQD��RX�GH�DOFDORLGHV�YHJHWDLV��FRPR�D�PRUILQD�� FRPR�IRQWH�GH�LQVSLUDomR�TXtPLFD��������� RECEPTORES ATIVADOS POR PROTEASES ������▼�(PERUD�D�DWLYDomR�GRV�*3&5V�VHMD�QRUPDOPHQWH�D�FRQVHTXrQFLD� GD�OLJDomR�GH�XP�DJRQLVWD�GLIXVR��WDPEpP�SRGH�VHU�UHVXOWDQWH�GD� DWLYDomR�SRU�XPD�SURWHDVH��-i�IRUDP�LGHQWLILFDGRV�TXDWUR�WLSRV�GH� UHFHSWRUHV�DWLYDGRV�SRU�SURWHDVH��3$5V����GR�LQJOrV��SURWHDVH�DFWLYDWHG� UHFHSWRUV���UHYLVDGRV�SRU��5DPDFKDQGUDQ�H�+ROOHQEHUJ�¬��������0XLWDV� SURWHDVHV��FRPR�D�WURPELQD��XPD�SURWHDVH�HQYROYLGD�QD�FDVFDWD�GD� FRDJXODomR�VDQJXtQHD���&DS�¬������DWLYDP�RV�3$5V�DR�UHPRYHUHP�D� H[WUHPLGDGH�GD�FDXGD�1�WHUPLQDO�H[WUDFHOXODU�GR�UHFHSWRU���)LJ�¬�������� SDUD�H[SRU�FLQFR�RX�VHLV�UHVtGXRV�1�WHUPLQDLV�TXH�VH�OLJDP�DRV�GRPt� QLRV�GR�UHFHSWRU�QDV�DOoDV�H[WUDFHOXODUHV��IXQFLRQDQGR�FRPR�XP� ´DJRQLVWD�DSULVLRQDGRµ��5HFHSWRUHV�GHVVH�WLSR�RFRUUHP�HP�YiULRV� WHFLGRV���5DPDFKDQGUDQ�H�+ROOHQEHUJ�¬�������H�SDUHFHP�GHVHPSHQKDU� XP�SDSHO�QD�LQIODPDomR�H�HP�RXWUDV�UHVSRVWDV�D�OHV}HV�GH�WHFLGR��QDV� TXDLV�VmR�OLEHUDGDV�SURWHDVHV�WHFLGXDLV��8P�UHFHSWRU�GD�IDPtOLD�GRV� 3$5V��R�3$5����p�DWLYDGR�SRU�XPD�SURWHDVH�OLEHUDGD�GH�PDVWyFLWRV� H�p�H[SUHVVR�HP�QHXU{QLRV�VHQVRULDLV��$FUHGLWD�VH�TXH�HVVH�UHFHSWRU� GHVHPSHQKH�SDSHO�UHOHYDQWH�QD�GRU�GD�LQIODPDomR���&DS�¬������8PD� PROpFXOD�3$5�SRGH�VHU�DWLYDGD�VRPHQWH�XPD�YH]��SRUTXH�QmR�Ki� FRPR�D�FOLYDJHP�VHU�UHYHUWLGD��GH�PRGR�TXH�p�SUHFLVR�RFRUUHU�UHV� VtQWHVH�FRQWtQXD�GD�SURWHtQD�UHFHSWRUD��$�LQDWLYDomR�VH�Gi�DWUDYpV�GH� XPD�FOLYDJHP�SURWHROtWLFD�TXH�DWD�R�OLJDQWH��RX�DWUDYpV�GD�GHVVHQVLEL� OL]DomR��HQYROYHQGR�IRVIRULODomR���)LJ�¬�������TXDQGR�R�UHFHSWRU��HQWmR�� p�LQWHUQDOL]DGR�H�GHJUDGDGR��VHQGR�VXEVWLWXtGR�SRU�XPD�SURWHtQD� UHFpP�VLQWHWL]DGD�������� PROTEÍNAS G E SUA FUNÇÃO �$V�SURWHtQDV�*�HQJOREDP�XPD�IDPtOLD�GH�SURWHtQDV�UHVLGHQWHV� QD�PHPEUDQD�FXMD�IXQomR�p�UHFRQKHFHU�RV�*3&5V�DWLYDGRV�H� WUDQVPLWLU�D�PHQVDJHP�DRV�VLVWHPDV�HIHWRUHV�TXH�JHUDP�XPD� UHVSRVWD�FHOXODU��5HSUHVHQWDP�R�QtYHO�GH�FRRUGHQDomR�LQWHU� PHGLiULD�QD�KLHUDUTXLD�RUJDQL]DFLRQDO��LQWHUYLQGR�HQWUH�RV� UHFHSWRUHV�²�FRPR�GLOLJHQWHV�RILFLDLV�DWHQWRV�DR�PtQLPR�VLQDO� GH�VHX�DJHQWH�TXtPLFR�SUHIHUHQFLDO�²�H�DV�HQ]LPDV�HIHWRUDV�RX� FDQDLV�L{QLFRV�²�D�EULJDGD�GH�VROGDGRV�UDVRV�TXH�H[HFXWDP� R�WUDEDOKR�VHP�SUHFLVDU�VDEHU�TXDO�KRUP{QLR�DXWRUL]RX�R� SURFHVVR��6mR�DV�SURWHtQDV�´GH�PHLR�FDPSRµ��TXH��QD�UHDOLGD� GH��IRUDP�GHQRPLQDGDV�SURWHtQDV�*��GHYLGR�j�VXD�LQWHUDomR� FRP�RV�QXFOHRWtGHRV�JXDQLQD��*73�H�*'3��3DUD�LQIRUPDo}HV� PDLV�GHWDOKDGDV�VREUH�D�HVWUXWXUD�H�DV�IXQo}HV�GDV�SURWHtQDV� *��YHU�DV�UHYLV}HV�GH��0LOOLJDQ�H�.RVWHQLV���������H��2OGKDP�H� ����0XLWRV�FRPSRVWRV�LPSRUWDQWHV�QRV�~OWLPRV�DQRV�WLYHUDP�RULJHP�QD� WULDJHP�GH�HQRUPHV�ELEOLRWHFDV�TXtPLFDV���&DS�¬������1HQKXPD�LQVSLUDomR� p�QHFHVViULD��DSHQDV�HQVDLRV�FRQVLVWHQWHV��JUDQGHV�FRPSXWDGRUHV�H�XPD� UREyWLFD�HILFLHQWH��$JRUD��FRP�DV�HVWUXWXUDV�GH�FULVWDO��SRGHUHPRV�HVWDU�D� FDPLQKR�GH�XPD�HUD�PDLV�VRILVWLFDGD�QD�GHVFREHUWD�GH�IiUPDFRV�� Exterior da célula Modulador alostérico positivo Agonista Membrana Interior da célula Fig. 3.7 Estrutura do receptor muscarínico M 4 . Imagem de alta resolução que apresenta a conformação do receptor muscarínico M 4 ligado a um agonista (ortostérico) e também a um modulador alostérico positivo. Os cilindros em amarelo representam os domínios transmembranares. A extensão total dos domínios N- e C- terminal e o terceiro circuito intracelular não estão representados. (Cortesia de A Christopoulos.) 10 ms 3 pA 20 ms 2 pA 0 1 2 18 pS 38 pS N ú m e r o d e c a n a i s a b e r t o s E s t a d o s d e c o n d u t i v i d a d e Aberturas do canal nicotínico de acetilcolina Aberturas do canal NMDA A B Fig. 3.6 Aberturas de canais registradas através da técnica de Patch-clamp . [ A ] Canais iônicos ativados por acetilcolina na placa motora terminal da rã. A pipeta é pressionada contra a superfície da membrana com 10 m mol/l ACh. Os desvios abaixo apresentam o fl uxo da corrente através dos canais iônicos na zona da membrana em que foi aplicada a pipeta. No fi nal do registro, é possível ver a abertura discreta entre os dois canais. [ B ] Correntes num único canal receptor de NMDA registradas nos neurônios cerebrais na conformação exterior da parte da 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 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; painel [B] reproduzido com autorização de Cull-Candy SG & Usowicz MM 1987 Nature 325, 525-528.) C0015.indd 30 04/11/15 1:14 PM 3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 31 �+DPP����������$V�SURWHtQDV�*�VH�FODVVLILFDP�HP�WUrV�VXEXQL� GDGHV���a����b��H��g����)LJ�¬�����������2V�QXFOHRWtGHRV�JXDQLQD�OLJDP�VH� j�VXEXQLGDGH��a���TXH�WHP�DWLYLGDGH�HQ]LPiWLFD��*73DVH��� FDWDOLVDQGR�D�FRQYHUVmR�GR�*73�D�*'3��$V�VXEXQLGDGHV��b�� H��g��SHUPDQHFHP�XQLGDV�QD�IRUPD�GH�XP�FRPSOH[R��b���g���$� VXEXQLGDGH�´�g�µ�HVWi�OLJDGD�j�PHPEUDQD�DWUDYpV�GH�XPD� FDGHLD�GH�iFLGRV�JUD[RV�DFRSODGD�j�SURWHtQD�*�SRU�PHLR�GH� XPD�UHDomR�FRQKHFLGD�FRPR��SUHQLODomR���$V�SURWHtQDV�*�SDUH� FHP�VHU�OLYUHPHQWH�GLIXVtYHLV�QR�SODQR�GD�PHPEUDQD��GH� PRGR�TXH�XP�~QLFR�FRQMXQWR�GH�SURWHtQDV�*�HP�XPD�FpOXOD� SRGH�LQWHUDJLU�FRP�YiULRV�UHFHSWRUHV�H�HIHWRUHV�GLIHUHQWHV��GH� PDQHLUD�HVVHQFLDOPHQWH�SURPtVFXD��1R�HVWDGR�GH�´UHSRXVRµ� ��)LJ�¬�������D�SURWHtQD�*�SHUPDQHFH�FRPR�XP�WUtPHUR��a��b��g��TXH� SRGH��RX�QmR��VHU�SUHYLDPHQWH�DFRSODGR�DR�UHFHSWRU��FRP�R� *'3�D�RFXSDU�R�ORFDO�QD�VXEXQLGDGH��a���4XDQGR�R�*3&5�p�DWL� YDGR�SRU�XP�DJRQLVWD��RFRUUH�XPD�PXGDQoD�FRQIRUPDFLRQDO�� HQYROYHQGR�R�GRPtQLR�FLWRSODVPiWLFR�GR�UHFHSWRU���)LJ�¬����%�� H�LQGX]LQGR�XPD�LQWHUDomR�GH�JUDQGH�DILQLGDGH�HQWUH��a��b��g��H� R�UHFHSWRU��(VVD�LQWHUDomR�RFRUUH�GHQWUR�GH����PV��FDXVDQGR�D� GLVVRFLDomR�GR�*'3�OLJDGR�H�VXD�VXEVWLWXLomR�SRU�*73��SHU� PXWD�*'3�*73���R�TXH��SRU�VXD�YH]��OHYD�j�GLVVRFLDomR�GR� WUtPHUR�GD�SURWHtQD�*��OLEHUDQGR�DV�VXEXQLGDGHV��a��*73�H��b��g��� HVWDV�VmR�DV�IRUPDV�´DWLYDVµ�GD�SURWHtQD�*��TXH�VH�GLIXQGHP�QD�PHPEUDQD�H�SRGHP�DVVRFLDU�VH�D�GLYHUVDV�HQ]LPDV�H�FDQDLV� L{QLFRV��FDXVDQGR�D�DWLYDomR�GR�DOYR���)LJ�¬�������2ULJLQDOPHQWH�� DFUHGLWDYD�VH�TXH�DSHQDV�D�VXEXQLGDGH��a��WLQKD�IXQomR�VLQDOL� ]DGRUD��H�R�FRPSOH[R��b��g��VHUYLULD�DSHQDV�FRPR�XP�´DFRPSD� QKDQWHµ���FKDSHURQH���TXH�PDQWHULD�DV�VXEXQLGDGHV��a��VROWDV�H� IRUD�GR�DOFDQFH�GDV�YiULDV�SURWHtQDV�HIHWXDGRUDV��TXH��GH�RXWUR� PRGR��VHULDP�SRU�HODV�H[FLWDGDV��1R�HQWDQWR��RV�FRPSOH[RV� �b��g��WrP�VXDV�SUySULDV�DWULEXLo}HV�H�FRQWURODP�RV�HIHWRUHV�GH� PRGR�PXLWR�VHPHOKDQWH�DR�GDV�VXEXQLGDGHV��a���$�DVVRFLDomR� GDV�VXEXQLGDGHV��a��RX��b��g��FRP�DV�HQ]LPDV�DOYR�RX�RV�FDQDLV� SRGH�FDXVDU�DWLYDomR�RX�LQLELomR��GHSHQGHQGR�GH�TXH�SURWHtQD� *�HVWi�HQYROYLGD���7DEHOD¬���������$�DWLYDomR�GD�SURWHtQD�*�UHVXOWD� HP�DPSOLILFDomR�SRUTXH�XP�~QLFR�FRPSOH[R�DJRQLVWD�UHFHSWRU� SRGH�DWLYDU��SRU�VXD�YH]��YiULDV�SURWHtQDV�*��H�FDGD�XPD�GHODV� SRGH�SHUPDQHFHU�DVVRFLDGD�jV�HQ]LPDV�HIHWRUDV�SRU�WHPSR� VXILFLHQWH�SDUD�SURGX]LU�PXLWDV�PROpFXODV�GR�FRPSRVWR��2� FRPSRVWR��D�VHJXLU��p�IUHTXHQWHPHQWH�XP�´PHQVDJHLUR� VHFXQGiULRµ�H�RFRUUH�XPD�DPSOLILFDomR�SRVWHULRU�DQWHV�GH�VHU� SURGX]LGD�D�UHVSRVWD�FHOXODU�ILQDO��$�VLQDOL]DomR�p�FRQFOXtGD� TXDQGR�RFRUUH�D�KLGUyOLVH�GH�*73�SDUD�*'3�SHOD�DWLYLGDGH� GH�*73DVH�GD�VXEXQLGDGH��a���2��a��*'3�UHVXOWDQWH��HQWmR��VH� GLVVRFLD�GR�HIHWRU�H�VH�UHOLJD�FRP��b��g���FRPSOHWDQGR�R�FLFOR� �����▼�2�TXH�D�OLJDomR�GD�VXEXQLGDGH��a��D�XPD�PROpFXOD�HIHWRUD�ID]�p� DXPHQWDU�VXD�DWLYLGDGH�GH�*73DVH��$�PDJQLWXGH�GHVVH�DXPHQWR�p� GLIHUHQWH�SDUD�WLSRV�GLVWLQWRV�GH�HIHWRU��3RU�VHU�D�KLGUyOLVH�GH�*73�D� HWDSD�TXH�DEROH�D�FDSDFLGDGH�GD�VXEXQLGDGH��a��GH�SURGX]LU�VHX�HIHLWR�� D�UHJXODomR�GH�VXD�DWLYLGDGH�GH�*73DVH�SHOD�SURWHtQD�HIHWRUD�VLJQLILFD� TXH�D�DWLYDomR�GR�HIHWRU�WHQGH�D�VHU�DXWROLPLWDQWH��3DUD�DOpP�GLVVR�� H[LVWH�XP�JUXSR�GH�FHUFD�GH�YLQWH�SURWHtQDV�FHOXODUHV��UHJXODGRUDV�GH� VLQDOL]DomR�GD�SURWHtQD�*��5*6���UHYLVmR�GH��;LH�H�3DOPHU�¬��������TXH� SRVVXHP�XPD�VHTXrQFLD�TXH�OLJD�HVSHFLILFDPHQWH�DV�VXEXQLGDGHV� �a���GH�IRUPD�D�DXPHQWDU�VLJQLILFDWLYDPHQWH�D�DWLYLGDGH�GH�*73DVH� H��GHVVD�IRUPD��DFHOHUDU�D�KLGUyOLVH�GH�*73�H�LQDWLYDU�R�FRPSRVWR�� $V�SURWHtQDV�5*6�H[HUFHP��DVVLP��HIHLWR�LQLELWyULR�QD�VLQDOL]DomR�GH� SURWHtQD�*��XP�PHFDQLVPR�TXH�VH�DFUHGLWD�WHU�XPD�IXQomR�UHJXODGRUD� HP�PXLWDV�VLWXDo}HV������� �&RPR�D�HVSHFLILFLGDGH�GD�IXQomR�GR�*3&5�p�DOFDQoDGD�GH� PRGR�TXH�FDGD�WLSR�GH�UHFHSWRU�SURGX]D�XP�SDGUmR�GLVWLQWR� GH�UHVSRVWDV�FHOXODUHV"�+DYHQGR�XP�FRQMXQWR�FRPXP�GH� SURWHtQDV�*�SURPtVFXDV�TXH�VH�OLJDP�DRV�YiULRV�UHFHSWRUHV� H�VLVWHPDV�HIHWRUHV�HP�XPD�FpOXOD��SRGH�SDUHFHU�TXH�WRGD� D�HVSHFLILFLGDGH�VHULD�SHUGLGD��PDV�FODUDPHQWH�DV�FRLVDV� QmR�VmR�DVVLP��3RU�H[HPSOR��P$&K5V�H��b��DGUHQRFHSWRUHV�� DPERV�RFRUUHQGR�QDV�FpOXODV�PXVFXODUHV�FDUGtDFDV��SURGX]HP����� Receptores acoplados à proteína G • São denominados algumas vezes receptores metabotrópicos ou receptores com sete domínios transmembrana (7-TDM). • As estruturas compreendem sete a -hélices que atravessam a membrana, em geral ligadas, formando estruturas diméricas. • 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, fi ca livre para ativar um efetor (p. ex., uma enzima de membrana). Em alguns casos, a subunidade b g 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 b g . • 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. ATIVO DESSENSIBILIZADO N Clivagem pela trombina INATIVO N N Agonista preso Fosforilação Fragmento liberado P N 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. C0015.indd 31 04/11/15 1:14 PM SEÇÃO 1 PRINCÍPIOS GERAIS3 32 Tabela 3.3 Os principais subtipos de proteína G e suas funções a Subtipos Receptores associados Efetores principais Notas Subunidades G a G a s Muitos receptores para aminas e outros (p. ex., catecolaminas, histamina, serotonina) Estimula a adenililciclase, aumentando a formação de AMPc Ativadas pela toxina do cólera, que bloqueia a atividade GTPase, impedindo, assim, a inativação G a i Como para Ga S , e também receptores opioides e canabinoides Inibe a adenililciclase, diminuindo a formação de AMPc Bloqueadas pela toxina pertússis, que impede a dissociação do complexo a b g G a o Como para Ga S , e também receptores opioides e canabinoides ? Efeitos limitados da subunidade a (os efeitos devem-se principalmente às subunidades b g ) Bloqueada pela toxina pertússis. Ocorre principalmente no sistema nervoso G a q Receptores de aminas, peptídeos e prostanoides Ativa a fosfolipase C, aumentando a produção dos segundos mensageiros inositol trisfosfato e diacilglicerol (págs. 34 e 35) — Subunidades G b g Todos os GPCRs Ativam canais de potássio Inibem canais de cálcio controlados por voltagem Ativam as GPCR quinases (GRKs, pág. 36) Ativam a cascata de proteínas quinases ativadas por mitógenos Interage com algumas formas de adenil-ciclase e com fosfolipase C b Muitas isoformas de b g identifi cadas, mas as funções específi cas ainda não são conhecidas. GPCR, receptor acoplado à proteína G ( G-protein-coupled receptor ). a Esta tabela lista apenas as isoformas de maior signifi cância farmacológica. Muitas outras foram identifi cadas, algumas, inclusive, têm funções no olfato, paladar, transdução visual e em outras funções fi siológicas ( Offermanns, 2003 ). Receptor GDP GDP GDP P + GTP GTP Estado de repouso Proteínas-alvo ativadas βγα βγ βγα βγα Alvo 1 Alvo 2 Alvo 2 Receptor ocupado por um agonista InativoInativo AtivoAtivoAtivoAtivo InativoInativo GTP hidrolisado Target 1 Alvo 2 Alvo 1 Alvo 2 α Alvo 1 Fig. 3.9 A função da proteína G. A proteína G consiste em três subunidades ( a , b , g ) que fi cam ancoradas à membrana através de resíduos de lipídeos fi xos. 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 b g , interagindo com uma proteína-alvo (alvo 1, que pode ser uma enzima, como adenil-ciclase ou fosfolipase C). O complexo b g 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 b g . C0015.indd 32 04/11/15 1:14 PM 3COMO AGEM OS FÁRMACOS: ASPECTOS MOLECULARES 33 HIHLWRV�IXQFLRQDLV�RSRVWRV����&DSV�¬���H¬�����������������$�UD]mR�SULQFLSDO�p�D� YDULDomR�PROHFXODU�GHQWUR�GDV�VXEXQLGDGHV��a���GDV�TXDLV�PDLV� GH�YLQWH�VXEWLSRV�IRUDP�LGHQWLILFDGRV����������7DEHOD¬�������4XDWUR� FODVVHV�SULQFLSDLV�GH�SURWHtQD�*��*�V���*�L���*�R��H�*�T���WrP�LPSRUWkQ�FLD�IDUPDFROyJLFD��&RPR�UHVXPLGR�QD��7DEHOD¬������RV�VXEWLSRV� PRVWUDP�VHOHWLYLGDGH�QR�TXH�GL]�UHVSHLWR�DRV�UHFHSWRUHV�H�DRV�HIHWRUHV�FRP�RV�TXDLV�VH�DFRSODP��WHQGR�GRPtQLRV�GH�UHFR� QKHFLPHQWR�HVSHFtILFR�HP�VXD�HVWUXWXUD�FRPSOHPHQWDU�SDUD� GRPtQLRV�GH�OLJDomR�GH�SURWHtQD�*�HVSHFtILFRV�QDV�PROpFXODV� UHFHSWRUDV�H�HIHWRUDV��$�*�V��H�D�*�L��SURGX]HP��UHVSHFWLYDPHQWH��HVWLPXODomR�H�LQLELomR�GD�HQ]LPD��DGHQLOLO�FLFODVH����)LJ�¬���������� �$V�VXEXQLGDGHV��a��GHVVDV�SURWHtQDV�*�DSUHVHQWDP�GLIHUHQoDV� HVWUXWXUDLV��8PD�GLIHUHQoD�IXQFLRQDO�TXH�VH�PRVWURX�~WLO�FRPR� IHUUDPHQWD�H[SHULPHQWDO�SDUD�GLVWLQJXLU�TXDO�WLSR�GH�SURWHtQD� 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GH�FDGHLD�OHYH���TXH�p�QHFHVViULD�j�FRQWUDomR��,VVR�H[SOLFD�R� UHOD[DPHQWR�GR�P~VFXOR�OLVR�SURGX]LGR�SRU�PXLWRV�IiUPD� FRV�TXH�DXPHQWDP�D�SURGXomR�GH�$03F�QR�P~VFXOR�OLVR� ��&DS�¬����� �&RPR�Mi�PHQFLRQDGR��RV�UHFHSWRUHV�OLJDGRV�j�*�L���PDLV�GR�TXH�j�*�V���LQLEHP�D�DGHQLOLO�FLFODVH�H��DVVLP��UHGX]HP�D�IRUPDomR�GH�$03F��2V�H[HPSORV�LQFOXHP�FHUWRV�WLSRV�GH�P$&K5��S�¬H[���R� UHFHSWRU�0����GR�P~VFXOR�FDUGtDFR���&DS�¬������RV��a�����DGUHQRFHSWR�UHV�QR�P~VFXOR�OLVR���&DS�¬�����H�RV�UHFHSWRUHV�RSLRLGHV���&DS�¬������ $�DGHQLODWR�FLFODVH�SRGH�VHU�GLUHWDPHQWH�DWLYDGD�SRU�IiUPDFRV� FRPR�R��IRUVNROLQ���TXH�HVWi�VHQGR�XWLOL]DGR�H[SHULPHQWDOPHQWH� QR�HVWXGR�GR�SDSHO�GR�VLVWHPD�$03F�� �2�$03�FtFOLFR�p�KLGUROLVDGR�GHQWUR�GDV�FpOXODV�SHODV��IRV� IRGLHVWHUDVHV���3'(V���XPD�LPSRUWDQWH�H�XEtTXD�IDPtOLD�GH� HQ]LPDV��([LVWHP����VXEWLSRV�GH�3'(��GRV�TXDLV�DOJXQV� �S�¬H[���3'(����H�3'(�����VmR�VHOHWLYRV�SDUD�$03F��HQTXDQWR�RXWURV��S�¬H[���3'(�����VmR�VHOHWLYRV�SDUD�*03F��$�PDLRU�SDUWH��� �����(P�KXPDQRV��Ki����VXEWLSRV�FRQKHFLGRV�GH�*�a���H[LVWHP�VHLV�GH�*�b��H� ���GH�*�g���IRUPDQGR��HP�WHVH��FHUFD�GH�������YDULDQWHV�GR�WUtPHUR��3RXFR� VH�VDEH�VREUH�R�SDSHO�GRV�GLIHUHQWHV�VXEWLSRV��a����b��H��g���PDV�VHULD�OHYLDQR� SHQVDU�TXH�DV�YDULDo}HV�VmR�IXQFLRQDOPHQWH�LUUHOHYDQWHV��3RU�RUD��YRFr� QmR�ILFDUi�VXUSUHVR��DLQGD�TXH�ILTXH�XP�SRXFR�FRQIXVR��FRP�HVVH�JUDX� GH�KHWHURJHQHLGDGH�PROHFXODU��Mi�TXH�HVVH�p�R�FDPLQKR�GD�HYROXomR�� Enzima- alvo Receptor inibitório Receptor estimulatório G i G s R i R s βγ βγαi αs Fig. 3.10 Controle bidirecional de uma enzima-alvo como a adenilato ciclase, por G s e G i . A heterogeneidade das proteínas G permite que receptores diferentes exerçam efeitos opostos em uma mesma enzima-alvo. C0015.indd 33 04/11/15 1:14 PM SEÇÃO 1 PRINCÍPIOS GERAIS3 34 p�PRGHUDGDPHQWH�LQLELGD�SRU�IiUPDFRV�FRPR�DV�PHWLO[DQWLQDV� �S�¬H[����WHRILOLQD��H��FDIHtQD�����&DSV�¬���H¬�����������������2��UROLSUDP���XVDGR� QR�WUDWDPHQWR�GD�DVPD���&DS�¬�����p�VHOHWLYR�SDUD�3'(����H[SUHVVD�QDV�FpOXODV�LQIODPDWyULDV���PLOULQRQD���XVDGD�QR�WUDWDPHQWR� GD�LQVXILFLrQFLD�FDUGtDFD���&DS�¬�����p�VHOHWLYD�SDUD�3'(�����D�TXDO�p�H[SUHVVD�QR�P~VFXOR�FDUGtDFR��D��VLOGHQDILOD���PDLV� FRQKHFLGD�FRPR�9LDJUD�����&DS�¬�����p�VHOHWLYD�SDUD�3'(����H��FRQVHTXHQWHPHQWH��UHIRUoD�RV�HIHLWRV�YDVRGLODWDGRUHV�GR�y[LGR� QLWURVR��12��H�GH�IiUPDFRV�TXH�OLEHUDP�12��FXMRV�HIHLWRV�VmR� PHGLDGRV�SHOR�*03F���&DS�¬������$�VLPLODULGDGH�HQWUH�DOJXPDV� Do}HV�GHVVHV�IiUPDFRV�FRP�DV�GDV�DPLQDV�VLPSDWRPLPpWLFDV� ��&DS�¬�����SURYDYHOPHQWH�UHIOHWH�VXD�SURSULHGDGH�FRPXP��TXH� p�D�GH�DXPHQWDU�D�FRQFHQWUDomR�LQWUDFHOXODU�GH�$03F��(VWmR� HP�GHVHQYROYLPHQWR�LQLELGRUHV�VHOHWLYRV�GDV�YiULDV�3'(V�� SULQFLSDOPHQWH�SDUD�R�WUDWDPHQWR�GH�GRHQoDV�FDUGLRYDVFXOD� UHV�H�UHVSLUDWyULDV��� O sistema fosfolipase C/fosfato de inositol �2�VLVWHPD��IRVIRLQRVLWtGHR���XP�LPSRUWDQWH�VLVWHPD�LQWUDFHOXODU� GH�VHJXQGRV�PHQVDJHLURV��IRL�GHVFREHUWR�QD�GpFDGD�GH������ SRU�+RNLQ�H�+RNLQ��TXH�HVWDYDP�LQWHUHVVDGRV�SULQFLSDOPHQWH� QR�PHFDQLVPR�GH�VHFUHomR�GH�VDLV�SHODV�JOkQGXODV�QDVDLV�GDV� DYHV�PDULQKDV��(OHV�FRQVWDWDUDP�TXH�D�VHFUHomR�HUD�DFRPSD� QKDGD�GH�DXPHQWR�GD�UHQRYDomR�GH�XPD�FODVVH�PHQRU�GH� IRVIROLStGHRV�GH�PHPEUDQD��FRQKHFLGRV�FRPR�IRVIRLQRVLWtGHRV� �FROHWLYDPHQWH�GHVLJQDGRV�GH�3,V���)LJ�¬����������3RVWHULRUPHQWH�� 0LFKHOO�H�%HUULGJH�GHVFREULUDP�TXH�PXLWRV�KRUP{QLRV�TXH� SURGX]HP�HOHYDomR�QD�FRQFHQWUDomR�LQWUDFHOXODU�GH�&D�����OLYUH��LQFOXLQGR��SRU�H[HPSOR��DJRQLVWDV�PXVFDUtQLFRV�H�DJRQLVWDV�GH� �a��DGUHQRFHSWRUHV�TXH�DJHP�QR�P~VFXOR�OLVR�H�QDV�JOkQGXODV� VDOLYDUHV��H��YDVRSUHVVLQD���TXH�DWXD�VREUH�DV�FpOXODV�KHSiWLFDV�� WDPEpP�DXPHQWDP�D�UHQRYDomR�GH�3,��3RVWHULRUPHQWH��GHV� FREULX�VH�TXH�XP�PHPEUR�HP�SDUWLFXODU�GD�IDPtOLD�3,��FKDPD� GR�IRVIDWLGLOLQRVLWRO��������ELVIRVIDWR��3,3������TXH�SRVVXL�JUXSRV�DGLFLRQDLV�GH�IRVIDWR�OLJDGRV�DR�DQHO�LQRVLWRO��GHVHPSHQKD� SDSHO�FKDYH��2�3,3����p�R�VXEVWUDWR�GH�XPD�HQ]LPD�OLJDGD�j�PHPEUDQD��D�IRVIROLSDVH�&�b���3/&�b����TXH�HIHWXD�VXD�FOLYDJHP� HP��GLDFLOJOLFHURO���'$*��H��LQRVLWRO�����������WULIRVIDWR���,3������)LJ�¬����������RV�TXDLV�DWXDP�FRPR�VHJXQGRV�PHQVDJHLURV��FRQIRUPH�GLV� FXWLGR�PDLV�DGLDQWH��SiJ�������$�DWLYDomR�GD�3/&�b��SRU�YiULRV� DJRQLVWDV�p�PHGLDGD�SRU�XPD�SURWHtQD�*��*�T����7DEHOD¬�������$SyV�D�FOLYDJHP�GR�3,3�����R��VWDWXV�TXR��p�UHVWDEHOHFLGR��FRPR�PRVWUD�D��)LJXUD¬�������VHQGR�R�'$*�IRVIRULODGR�GHVWLQDGR�D�IRUPDU�iFLGR� IRVIDWtGLFR��3$���HQTXDQWR�R�,3����p�GHVIRVIRULODGR�H��D�VHJXLU���� Lipase (ativa) ATP ADP Aumento da lipólise ATP ADP Redução da síntese de glicogênio ATP ADP ATP ADP Fosforilase quinase (ativa) Fosforilase a (ativa) ATP ADP Aumento da quebra de glicogênio Glicogênio Glicose-1-fosfato Glicogênio sintase (inativa) G Proteína quinase (ativa) Proteína quinase (inativa) Lipase (inativa) Glicogênio sintase (ativa) Fosforilase quinase (inativa) Fosforilase b (inativa) AC ATP AMPc Agonista R Fig. 3.11 Regulação do metabolismo energético pelo AMPc. AC, adenilil ciclase. 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