ACETILCOLINA - University of São Paulo
Transcript of ACETILCOLINA - University of São Paulo
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ACETILCOLINA
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ACETILCOLINA (ACh)
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• Bactérias, fungos, protozoários e plantas
• Córnea, alguns epitélios ciliados, baço e placenta humana
• Junção Neuromuscular
• Sistema Neurovegetativo
• Sistema Nervoso Central
DISTRIBUIÇÃO DA ACh
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Estudos e usos de agentes colinérgicos
• Toxinas
• Terapia colinérgica: Alzheimer e miastenias
• Pesticidas e armas químicas (organofosfatos)
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O 1º registro: chefe indígena Opechankanough (VA, EUA, 1550 e 1644)
Clínico inglês Thomas Willis descreve pacientes com uma fraqueza mus-
cular flutuante que ele denominou "paralysia spuria non habitualis" (1672)
Forma auto-imune: 50-125 pacientes/milhão
Forma congênita e hereditária: - de 100 casos
HISTÓRICO
Miastenia grave
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♀ de 30 anos: sintomas começaram por uma fadiga após leitura em
voz alta e progrediram para fraqueza muscular generalizada, com
queda das pálpebras, alterações da voz, da deglutição e dificuldade
respiratória. A paciente faleceu oito anos após o início dos sintomas
(Paris, 1868)
A descrição mais completa ??: o neurologista alemão Heinrich Erb
(1840-1921), na época denominada doença de Erb-Goldflam-
Oppenheim ou Samuel Wilks (1877)
HISTÓRICO
Miastenia grave
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“Vagusstoff”
HISTÓRICO
Metade da década de 30: Henry Dale e a transmissão sináptica
neuromuscular (ACh) e Mary Walker e o uso de inibidores da
acetilcolinesterase (fisostigmina e neostigmina) para reverter os
sintomas da doença
1921 – Otto Loewi demonstra a sinapse química no SNV
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Harvey e col. descobrem que na miastenia a amplitude do potencial
composto diminui rapidamente parecido com o padrão
induzido pelo curare (1945-1960)
Na década de 50, a timectomia como trata-
mento
Changeux (Paris) e Miledi e Potter (Londres)
usam a a-BGT para isolar os receptores (1971)
HISTÓRICO
Miastenia grave
1936 – Otto Loewi e Henry Dale dividem o prêmio Nobel de
Medicina e Fisiologia
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Fambrough e Drachman usam a a-BGT radioativa para marcar recepto-
res em placas motoras humanas (1973)
Patrick e Lindstrom injetam receptores pu-
rificados em coelhos e observam os mês-
mos sintomas (1973)
HISTÓRICO
Miastenia grave
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O CONHECIMENTO ATUAL
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Colina
Faz parte do complexo B de vitaminas
Encontrada nos lipídeos de membrana
Encontrada nos ovos, peixes, legumes (soja),
grãos (trigo), nozes, carnes e verduras
Acetil Coenzima A
Sintetizada a partir do piruvato (glicólise)
Acetilcolina
SÍNTESE
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Acetilcolina
SÍNTESE e DEGRADAÇÃO
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ChT1- família dos transporta- dores de glicose dependente de Na+)
TERMINAL COLINÉRGICO
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TERMINAL COLINÉRGICO
VAChT- antiporte, H+
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SINAPSE COLINÉRGICA
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ACETILCOLINESTERASE
Inibidores: Glaucoma Miastenia grave Atonias Inseticidas Arma química
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5 subtipos: M1-M5
Muscarínicos
Acetilcolina
Várias subunidades (a, b, g, d, e)
e subtipos
Nicotínicos
RECEPTORES
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ACh
RECEPTORES
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TM1 TM2 TM3 TM4
COOH NH2
Extracelular
Intracelular
Receptores Nicotínicos de Acetilcolina (nAChRs)
RECEPTORES
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nAChRs neuronais
Hetero/Homoméricos
Subunidades: a7-a10
(a7)5
Subtipos de nAChRs
nAChRs
musculares
Subunidades: a1, b1, g, d, e
(a1)2b1gd
nAChRs neuronais
Heteroméricos
Subunidades: a2-a6, b2-b4
(a4)2(b2)3 (a4)2(b2)2a5
(a3)2b2b4a5 (a3)2(b4)2a5 (a3)2(b4)3
RECEPTORES
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nAChRs
RECEPTORES
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RECEPTORES
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Junção Neuromuscular
Subunidades: a1, b1, g, d, e
(a1)2b1gd
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Junção Neuromuscular
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Miastenia grave (Myasthenia gravis)
Junção Neuromuscular
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Desenvolvimento do SNC
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TeO
SpM
SpL
SLu
nBOR
MPv
MN
Ipc
IP
Imc
Hb
GT
DT
GC
G
ADULT E18 E16 E14 E12 E10 E8 E6 E4 ChAT
TeO
SpL
SLu
nBOR
MPv
MN
Ipc
IP
Imc
Hb
G
Cb
AVT
ADULT E18 E16 E14 E12 E10 E8 E6 E4 AChE
ChAT
AChE
Torrão et al., 2000
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E3,5
E8
Ganglia
0
1
2
3
4
E4
E6
E8
E10
E12
E14
E16
E18
Adul
tInte
ns
ity o
f la
be
llin
g
a2
a3
a5
a8
b2
Torrão et al., 2000
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E8
E8
E8
E12
E18
Optic tectum
0
1
2
3
4
E4
E6
E8
E10
E12
E14
E16
E18
Adul
tInte
ns
ity o
f la
be
llin
g
a2
a3
a5
a8
b2
Torrão et al., 2000
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E16
E17
Cerebellum
0
1
2
3
4
E4
E6
E8
E10
E12
E14
E16
E18
Adul
tInte
ns
ity o
f la
be
llin
g
a2
a3
a5
a8
b2
Torrão et al., 2000
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b2 X AChE
Britto et al., 2001
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nAChRs X GABA
Torrão & Britto 2001
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Transporte axônico
Lesão da retina
Lesão do núcleo espiriforme lateral
(SpL)
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Tecto óptico
Retina
SpL
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Efeito da lesão retiniana sobre a expressão
da subunidade b2 dos nAChR
Britto et al., 1994
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Efeito da lesão retiniana sobre a expressão das
subunidades a7 e a8 dos nAChR
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Efeito da lesão do SpL sobre a expressão das
subunidades b2 e a5 dos nAChR no TeO
Torrão et al., 1996
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Retina - TeO
SpL - TeO
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Regulação da expressão dos nAChRs
Desaferentação colinérgica
Tratamento com agonistas e antagonistas
Aplicação de KCl
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Desaferentação colinérgica
Lesão do núcleo semilunar (SLu)
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Lesão do (SLu)
Torrão et al., 2000
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Efeito da lesão do SLu sobre a expressão
da subunidade a2 dos nAChR
Torrão et al., 2000
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Tratamento com agonistas e
antagonistas nicotínicos
In ovo e in vitro
Nicotina e a-Bgt
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Efeito do tratamento in ovo com nicotina e a-Bgt sobre o
desenvolvimento de neurônios colinoceptivos
Expressão de
a2 no SpL
Expressão de
a8 no TeO
Torrão et al., 2003
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Efeito do tratamento in vitro com
nicotina e a-Bgt sobre a extensão
de neuritos em células do tecto
óptico em cultura
Neuritic length (micrometers)
*
**
NS
0
20
40
60
80
100
Control NIC BGT NIC+BGT
Torrão et al., 2003
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Efeito da aplicação de KCl sobre a expressão
da subunidade a7 dos nAChR no córtex de rato
Torrão et al., 2002
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Subtipo M1
Receptor Muscarínico de Acetilcolina (mAChRs)
RECEPTORES
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Vias de Sinalização de mAChRs
RECEPTORES
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RECEPTORES
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mAChRs
RECEPTORES
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Sistema Neurovegetativo
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Simpático Parassimpático
Sistema Neurovegetativo
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Sistema Neurovegetativo
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Sistema Nervoso Central
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Sistema Nervoso Central
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Doença de Alzheimer
Sistema Nervoso Central
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Doença de Alzheimer
Sistema Nervoso Central
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Vício em drogas
Sistema Nervoso Central