11ª AULA

Prévia do material em texto

•  Equação de Goldman-Hodgkin-Katz – significado. Potencial de acção: canais 
iónicos envolvidos e significado. Mecanismo de neurotransmissão química. Tipos 
de sinapses. 
Bibliografia 
•  Lodish H., Baltimore D., Berk A., Zipursky S.L., Matsudaira P., and Darnell J., Molecular Cell 
Biology (4ª Ed.), Freeman W.H. and Company (USA), Cap 15 (2000). 
•  Campbell N.A., Reece J.B., and Mitchell L.G., BIOLOGY (5ª Ed.), Addison-Wesley, 1999. 
•  Nelson D.L., and Cox M.M., Lehninger – Principles of Biochemistry (4ª Ed.), Freeman W.H. 
and Company (USA), pp 406-408 (2005). 
Dedução da Equação de Nernst:
–
+
+
Equação de Nernst: dedução
+
+
+
–
–
–
–
+
K+f
K+d
∆Ψm= –70 mV
Potencial de repouso
Non-gated channels 
Permeabilidade selectiva da membrana 
∆ΨK+ = 60 log [K+e]/ [K+i] = – 78 mV
∆Ψm= –70 mV
O potencial de equilíbrio para K+ aproxima-se do potencial medido experimentalmente
Cálculo do ∆Ψm a partir das concentrações dos diferentes iões e das suas P (Ctes de 
permeabilidade) utilizando uma versão mais complexa da equação de Nernst (Equação de 
Goldman-Hodgkin-Katz). 
No caso do axónio da lula os únicos iões que contribuem significativamente para o ∆Ψm são o 
K+, o Na+ e o Cl-. Inserindo na equação acima os valores de P e das concentações para estes 
iões encontra-se um valor idêntico ao valor de ∆Ψm medido experimentalmente.
Equação de Goldman-Hodgkin-Katz descreve o potencial de repouso 
potencial de acção possui um limiar de disparo 
p.a. – resposta tipo tudo-ou-nada 
Limiar: é o valor do potencial de membrana a partir do qual é inevitável a geração de um 
potencial de acção. Este potencial é menos negativo que o potencial de repouso. 
POTENCIAL DE ACÇÃO 
  é um fenómeno das células excitáveis 
  despolarização rápida 
  repolarização da membrana até pot. de repouso 
  representa o mecanismo básico para transmissão da informação, no sistema 
nervoso e em todos os tipos de músculos. 
  Despolarização: é o processo pelo qual o potencial de membrana fica menos 
negativo. 
POTENCIAL DE ACÇÃO
Mecanismos usados para sinalização por longas distâncias, tanto no sistema nervoso qt no músculo. 
São fenómenos tudo-ou-nada; 
Não sofrem variação com a distância. 
POTENCIAL DE ACÇÃO 
1)  No estado de repouso quer o canal de Na+ quer o canal de K+ estão fechados, mantendo-se o 
potencial de repouso. 
2)  Durante a fase de despolarização, o potencial de acção gera-se á medida que os portões de 
activação dos canais de Na+ abrem, e os canais de K+ permanecem fechados. Iões Na+ 
precipitam-se para o interior da célula ocorrendo despolarização. 
3)  Durante a fase de repolarização, portões de inactivação fecham os canais de Na+ e canais de K+ 
abrem. Iões de K+ saiem da célula ficando o interior da célula mais negativo; 
4)  Durante a hiperpolarização, ambos os portões dos canais de Na+ estão fechados, mas os canais 
de K+ permanecem abertos porque são canais lentos a responder à repolarização da membrana. 
A abertura e o fecho de “portões” sensíveis à 
voltagem são responsáveis pelas alterações no 
potencial membranar que ocorrem quando um 
estímulo acciona um potencial de acção. 
Propagação do potencial de acção – Transmissão sináptica 
Propagação Unidireccional 
Células excitáveis
Potencial elétrico de membranas existe em todas as células; contudo apenas 
determinado tipo de células, incluindo os neurónios e células musculares têm a 
capacidade para gerarem alterações nos seus potenciais membranares. 
Chemical Synapse 
Events at a chemical synapse 
1. Arrival of nerve impulse opens 
 volage-gated calcium channels. 
2. Ca++ influx into presynaptic terminal. 
3. Ca++ acts as intracellular messenger 
 stimulating synaptic vesicles to fuse with 
 membrane and release NT via exocytosis. 
4. NT diffuses across synaptic cleft and 
 binds to receptor on postsynaptic memb 
5. Receptor changes shape of ion channel 
 opening it and changing membrane potential 
6. NT is quickly destroyed by enzymes or 
 taken back up by presynaptic membrane. 
Note: For each nerve impulse reaching the 
presynaptic terminal, about 300 vesicles are 
emptied into the cleft. 
MECANISMO DA NEUROTRANSMISSÃO QUÍMICA 
1.  Chegada do impulso nervoso ao terminal; 
2.  Abertura de Canais de Ca Voltagem 
dependentes; 
3.  Influxo de Ca (2o mensageiro); 
4.  Exocitose dos NT; 
5.  Interação NT- receptor pós-sinaptico 
causando abertura de canais iônicos NT 
dependente; 
6.  Os NT são degradados por enzimas (6); 
Remoção dos Neurotransmissores 
Remoção dos Neurotransmissores 
Destruição enzimática
Recaptação
  Neurotransmissores são químicos que 
permitem a transmissão de sinais entre 
neurónios através de sinapses. 
  Também se localizam nos terminais de axónios 
de neurónios motores, onde estimulam as fibras 
musculares. 
  São produzidos por algumas glândulas, tais 
como a PITUITÁRIA e as GLÂNDULAS ADRENAIS. 
Neurotransmissores 
  They are chemicals that communicate information throughout 
our brain and body. 
  The brain uses neurotransmitters to tell your heart to beat, your 
lungs to breathe, and your stomach to digest. 
  They can also affect mood, sleep, concentration, weight, and 
can cause adverse symptoms when they are out of balance. 
Neurotransmitters 
Classes de Neurotransmissores 
Small
molecule
neurotransmitters

Type
 Neurotransmitter
 Postsynaptic
effect

Acetylcholine
 Excitatory

Amino
acids
 Gamma
aminobutyric
acid

GABA
 Inhibitory

Glycine
 Inhibitory

Glutamate
 Excitatory

Aspartate
 Excitatory

Biogenic
amines
 Dopamine
 Inhibitory

Nor
adrenaline
 Excitatory

Serotonin
 Inhibitory

Histamine
 Excitatory

GABA - neurotransmissor inibitório (canal de Cl –) 
BENZODIAZEPINAS 
Excitatory and Inhibitory Postsynaptic Potentials: 
•  EPSP:Transient postsynaptic membrane depolarization 
by presynaptic release of neurotransmitter 
•  IPSP: Transient hyperpolarization of postsynaptic 
membrane potential caused by presynaptic release of 
neurotransmitter 
Principles of Chemical Synaptic Transmission 
Junção Neuromuscular – Placa Motora 
a)   Sinapse Eléctrica 
Presença de mediadores químicos 
Controle e modulação da transmissão 
Lenta 
Sem mediadores químicos 
Nenhuma modulação 
Rápida 
TIPOS DE SINAPSE 
b) Sinapse Química 
Acetilcolinesterase 
Sinapses colinérgicas 
•  Organophosphate intoxicants include 
insecticides (malathione, parathione) and 
“nerve gases” (Soman, sarin, tabun, VX) 
•  Protection from the toxic effects of 
organophosphates requires covering all the 
potential access sites of the chemical: 
1.  Lungs 
2.  Mouth 
3.  Mucosal surfaces (eyes, nasal) 
4.  Skin 
Chemical Warfare Suit 
•  The autoinjector cartridge delivers both 
atropine and 2-PAM via IM injection 
Autoinjector kit 
Cholinesterase Inhibitors 
iPrO
P
O
FiPrO
P
Me F
OiPrO
N
S
P
O
O
VX Nerve Agent
The VX nerve agent is the most well-known of the V-series of nerve agents. Its chemical name 
is O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothiolate and its molecular formula is 
C11H26NO2PS.
The only countries known to possess VX are the United States and Russia. VX agent is 
considered an area denial weapon due to its physical properties.
With its high viscosity and low volatility VX has the texture and feel of high-grade motor oil. This 
makes it especially dangerous, as it has a high persistence in the environment. It is odorless 
and tasteless, and can be distributed as a liquid or, through evaporation, into small amounts of 
vapor. It works as a nerve agent by blocking the functionof the enzyme acetylcholinesterase. 
Normally, an electric nerve pulse would cause the release of acetylcholine over a synapse that 
would stimulate muscle contraction. The acetylcholine is then broken down to non-reactive 
substances (acetic acid and choline) by the acetylcholinesterase enzyme. If more muscle 
tension is needed the nerve must release more acetylcholine. VX blocks the action of 
acetylcholinesterase, thus resulting in sustained contractions of all the muscles in the body. 
Sustained contraction of the diaphragm muscle causes death by asphyxiation.
The chemist Ranajit Ghosh discovered the V-series nerve agents at the government 
research establishment at Porton Down, England in 1952; VX was passed over in 
favour of continuing with sarin as their chemical weapon of choice. The United 
Kingdom unilaterally renounced chemical and biological weapons in 1956. In 1958 
the British government traded their research on VX technology with the United 
States of America in exchange for information on thermonuclear weapons. The US 
then went into production of large amounts of VX in 1961.
The US later destroyed all of its stockpiles of the deadly nerve agent (by 
incineration at Johnston Island in the South Pacific), as mandated by the US 
accession to the Chemical Weapons Convention. Earlier, pre-treaty disposal 
included the US Army's CHASE (Cut Holes And Sink 'Em) program, in which old 
ships were filled with chemical weapons stockpiles and then scuttled. CHASE 8 was 
conducted on June 15, 1967, in which the S.S. Cpl. Eric G. Gibson was filled with 
7,380 VX rockets and scuttled in 7,200 feet of water, off the coast of Atlantic City, 
New Jersey. The long-term environmental ramifications of exposing large quantities 
of VX to seawater and marine life could pose a grave danger, but are ultimately 
unknown.
The US is also destroying chemical weapons stockpiles containing VX in nine other locations, one of which 
is in Russia. On June 12, 2005, it was reported that more than 250,000 US gallons (950 m³) of the chemical 
weapon are stored at the Newport Chemical Depot in Newport, Indiana, about 30 miles (50 km) north of 
Terre Haute, Indiana. The VX is in the process of being hydrolyzed to much less toxic byproducts using 
concentrated caustic solution. The VX hydrolysate produced will contain mainly a phosphonate ester and a 
thiolamine, with 20 parts per billion or less of residual VX. (Interestingly, 20 ppb is the level of VX in water 
that is considered permissible for drinking by US combat troops.) 
A plan was developed to truck the hydrolysate from Indiana to the DuPont Chambers Works Secure 
Environmental Facility at Deepwater, NJ where it was to be further treated to destroy the phosphonate ester 
and the thiolamine, and dumped into the Delaware River. The governors of Delaware, New Jersey, 
Pennsylvania, and New York have opposed this plan and the New Jersey Governor Codey instructed the 
New Jersey Department of Transportation to deny entry to any trucks carrying the hydrolysate to the 
Deepwater facility. Prior to the current plan, it had been proposed that the hydrolysate be dumped into the 
Great Miami River, a tributary of the Ohio River, near Dayton, Ohio but the community there successfully 
defeated the proposal.
VX hydrolysis began on May 5 2005 and as of June 12 the facility had destroyed 2,894 US gallons (11 m³) 
of VX. A contained spill of 30 US gallons (100 L) drew attention to the disposal process, but authorities said 
no agent was released and no one was injured in the spill.
Iraq under Saddam Hussein admitted to UNSCOM that it had researched VX, but denied weaponizing the 
agent due to production failure. Subsequent investigation after the 2003 Invasion of Iraq indicates that Iraq 
had indeed weaponized VX in 1988 and had dropped three VX-filled bombs on Iran.
receptores colinérgicos
Abordagem terapêutica – 
inibição da acetilcolinestase 
corrige parcialmente o deficit 
de acetilcolina na fenda 
sináptica
Alzheimer's disease
(AD)
Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative 
disease characterized by progressive cognitive deterioration together with declining 
activities of daily living and neuropsychiatric symptoms or behavioral changes. It is 
the most common type of dementia.
The most striking early symptom is loss of short term memory (amnesia), which 
usually manifests as minor forgetfulness that becomes steadily more pronounced 
with illness progression, with relative preservation of older memories. As the disorder 
progresses, cognitive (intellectual) impairment extends to the domains of language 
(aphasia), skilled movements (apraxia), recognition (agnosia), and those functions 
(such as decision-making and planning) closely related to the frontal and temporal 
lobes of the brain as they become disconnected from the limbic system, reflecting 
extension of the underlying pathological process. These changes make up the 
essential human qualities, and thus AD is sometimes described as a disease where 
the victims suffer the loss of qualities that define human existence.
This pathological process consists principally of neuronal loss or atrophy, principally 
in the temporoparietal cortex, but also in the frontal cortex, together with an 
inflammatory response to the deposition of amyloid plaques and neurofibrillary 
tangles.
Alzheimer's disease (AD)
Ainda o equilibrio nernsteniano...
K+
K+ 
+
+
+
+
–
–
–
–
A ocorrência do transporte activo de um ião pode deduzir-se a 
partir do conhecimento das concentrações intra e extracelulares 
do ião e do valor de ∆Ψm 
∆Ψião = +(-)60 log Ce / Ci
∆Ψm= –70 mV
60 = RT / ZF
O Na+ não se distribui de acordo com o potencial eléctrico 
medido (∆Ψm = -70 mV). 
 Conclusão: 
 O Na+ é transportado activamente !!!!!!! 
Se o Na+ se distribuisse de acordo com o ∆Ψm medido 
(∆Ψm = -70 mV) qual seria a Ci esperada? 
Conclusão: 
O Na+ é transportado activamente para o exterior da célula! 
∆Ψm= –70 mV
Conclusão? 
Conclusão? 
Potássio 
∆Ψm = -70 mV