Lecture 5 Flashcards
Name key features of an action potential
- Change in voltage across membrane
- Depends on ionic gradients and relative permeability of the membrane
- Only occurs if a threshold level is reached
- All or nothing
- Propagated without loss of amplitude
Action potentials and times recorded in the following tissues:
- Axon
- Skeletal muscle
- Sino-atrial node
- Cardiac ventricle
Much longer action potentails in sino-atrial node and cardiac ventricles
How can you experimentally show that Na+ influx is responsible for AP depolarisation?
- Remove EC Na+ - Electrochemical gradient for Na+ into the cell decreases - Peak of AP is reduced
What is conductance? (in terms of an AP) Which channels are responsible for each phase in the AP?
- Conductance is the number of open ion channels for a particular ion
- Na+ responsible for upstroke/DP, K+ efflux responsible for repolarisation
- Na+ channels are activated then inactivated rapidly, K+ channels also activated by DP, but remain open longer allowing for repolarisation of membrane,
Three channels:
- Na+ ligand gated channels (to reach threshold)
- Na+ voltage gated channels (responsible for depolarisation)
- K+ voltage gated channels (responsible for repolarisation)
What happens to the membrane potential, when conductance to a particular ion increases?
• If the conductance (g) to any ion is increased, the membrane potential (Vm) will move closer to the equilibrium potential (EION) for that ion.
• The conductance of the membrane to a particular ion is dependent on the number of channels for the ion that are open
What 2 factors determine how much an ion moves when the channel is open?
Electrical gradient
Chemical gradient
Explain why the Na+ and K+ move in the particular directions at each stage in the action potential.
- Na+ channels open, Na+ will move into the membrane, along it’s electrical gradient and it’s chemical gradient.
- Na+ entering the cell will depolarise the membrane potential, moving it closer to the ENa
- Na+ movement winto the cell then slows, this is because the electrical graident is resisting Na+ entering as the Na+ is now entering a postiively charged cell.
- K+ channels open along K+ to move out because it’s chemical gradient exceed it’s electrical gradient. K+ is moving out, so membrane potential becomes more negative
Explain the following diagram:
How is Na+-K+-ATPase involved in the action potential
IT IS NOT! The role it has to to set up the correct concentration gradient either side of the cell (i.e. set’s up the concentration gradients for the resting potential, i.e. allowing K+ to then diffuse out)
What are the 2 recovery periods that occur after an AP has been triggered?
1) Absolute refractory period - where all Na+ channels are in inactive state and an AP cannot be triggered. 2) Relative refractory period - where Na+ channels are recovering from inactive period - only large stimuli can generate an AP here.
Describe the basic structure of voltage-gated Na+, Ca2+ and K+ channels.
- Na+ and Ca2+ channels are structurally similar. Both only need 1 a subunit to be functional. Each alpha subunit consists of 4 units each with 6 TM domains. Within each TM domain is an S4 voltage sensor that allows for channel opening and an inactivation particle which plugs the pore when the channel is open.
- K+ channels require 4 x a-subunits, similarly have an S4 voltage sensor, but are lacking an inactivation particle.
Explain the three states Na+ and Ca+ channels can be in
- After being open, thye go into the inactive state.
- When inactivated, they cannot open until the membrane potential has undergone hyperpolarisation to make them recover.
- In the closed state, they are ready to open again
Why is it important that Na+ channels become inactivated?
What is the consequences of the delayed closing of voltage-gated K+ channels?
- This allows the polarisation of the membrane to OCCUR QUICKLY. Refractory period is also very important in enabling the action potential to move in the forward direction only
- Ensures that hyperpolarisation reaches a fairly negative value, this is important with the recovery of the inactive sodium channels. More hyperpolarisation = quicker Na+ channels will recover from inactivation
Name a local anaesthetic
Lidocaine (also called lignocaine)
How do the charges work with local anaethetics? How do local anaesthetics work?
- Can exist in the unprotonated (B) form which is lipophilic, or the protonated (BH+) form which is hydrophillic and membrane impermeable
- Two pathways of blocking:
- – Hydrophilic pathway - in BH+ form, it blocks the pore of the Na+ channel, stops the Na+ entering
- – Hydrophobic pathway - in B form, it moves from the membrane laterally, then blocking the Na+ channel
When channels are open = increase susceptibility of being blocked
Order that local anaethetics block…
- small myelinated axons
- un-myelinated axons
- large myelinated axons
Summary of action potential generation
- depolarization to threshold triggers the opening of many voltage-gated Na+ channels
- Na+ influx produces the upstroke of the action potential (membrane potential moves towards ENa)
- this depolarization causes inactivation of Na+ channels and opening of voltage-gated K+ channels
- Na+ influx stops and K+ efflux leads to repolarization (membrane potential moves towards EK )
- relatively little ions move and the Na/K ATPase is NOT involved in action potential repolarization
How is conduction velocity measured?
Conduction velocity = distance
time
How is conduction velocity of an AP measured?
- Electrodes placed over nerve cell
- Measure time it takes for AP to reach a certain point (X)
- Use x/time to work out velocity in meters per second.
Explain the local current theory of membrane depolarisation.
Injection of current into an axon causes the resulting charge (depolarisation) to spread along the axon and cause an immediate local change in the membrane potential. Depolarisation causes AP to be trigger in adjacent areas of the axon in a wave like fashion.
Local current theory and length constant: What is the length constant?
Length constant = the distance is takes for the potential to fall to 37% of its original value (get further away from the point of Na+ moving into the cell = the less depolarised the cell gets further from this point)
Explain ‘membrane resistance’ in more depth - how does this affect the length constant (the local current spread)
Higher membrane resistance = less ion channels open = longer length constant
The membrane resistance depends on the number of ion channels open. The lower the resistance, the more ion channels are open and the more loss of the local current occurs across the membrane, thus limiting the spread of the local current effect.
Explain ‘capacitance’ in more depth
Capacitance = ability to store charge = higher capacitance = more charge is stored = shorter the length constant
Capacitance, C, is the ability to store charge. This is a property of the lipid bilayer. A high capacitance takes more current to charge (or a longer time for a given current) and can cause a decrease in spread of the local current, especially with brief current pulses
Myelinated vs non-myelinated axon - where the Na+ channels are?
Myelinated - Na+ channels are focused in the nod of Ranvier and either side of the node of Ranvier (paranode and juxtaparanoid). Underneath the myelin, there are very few ion channels.
Unmyelinated - Even distribution of Na+ channels.
Where are Na+ and K+ channels in a myelinated axon?
Explain saltatory conduction, how does the myelin sheath improve conduction?
- The myelin sheath acts as a good insulator thereby increasing the length constant
- This enables the local circuit currents to depolarize the next node above threshold and initiate an action potential.
- The action potential “jumps” from node to node allowing a much faster conduction velocity. An action potential occurs only at the nodes (as there are no channels in the internode)
How does myelin sheath improve conduction?
• large increase in membrane resistance (Rm) (means it spreads further along the axon)
• large decrease in membrane capacitance (Cm) (allows change to voltage to occur more quickly)
-> these increase length constant
• slight decrease in time constant, so will occur more quickly too
Why does demyelination in disease slow conduction velocity? Name a demyelination disease in the CNS and PNS.
- removal of myelin
- the length constant for this part of the axon is decreased
- this part of the axon doesn’t have any ion channels as it should have a myelin sheath around it
- This means as the length constant is reduced, the voltage can’t reach the next node = failure to reach threshold = action potential stops
The following disease result from breakdown or damage to the myelin sheath:
- CNS = Multiple sclerosis (all CNS nerves)
- PNS = Charcot-Marie-Tooth disease and Landry-Guillain-Barre
What does a neuromuscular junction look like?
Draw out a diagram of the neuromuscular junction, include: nerve terminal and motor end plate
Pic showing neurotransmitter release
What are the sequence of events at a nerve terminal that lead to neurotransmitter being released
- AP arrives
- Open’s voltage-gated Ca2+ channels
- Ca2+ entry, increasing IC Ca2+
- Ca2+ bind to synaptagmin
- Vesicles containing neurotransmitter are brought close to the membrane
- Snare complex (set of proteins) make a fusion pore
- Transmitter released through this pore and into the synaptic cleft
Increasing the frequency of an action potential at the nerve terminal, leads to…
How is skeletal muscle depolarised after ACh is released from the synapse at the neuromuscular junction? What only movement of one cation?
nAChR is the nicotinic acetylcholine receptor (ligand gated ion channel), in skeletal muscles end plates
- ACh binds to nAChR on the muscle end plate
- This is a ligand gated ion channel with integral ion channel
- Binding opens its non-specific cation channel
- Influx of cations cause DP
It is equally permeable to Na+ and K+, why do only Na+ move in, why doesn’t K+ move out at the start?
- Electrical and chemical gradient makes Na+ move in
- K+ can’t move out because it would be going against it’s electrical gradient
End-plate potential initiates a muscle action potential - how does this occur?
- The ACh bound to the nAChR receptors is quickly by ACh esterase (an enzyme)
- Local current produced by the localised depolarisation of the end plate will riase the adjacent part of the muscle above it’s threshold value, meaning the action potential travels along the axon (local current model - lecture 2)
- Spreading action potential along the muscle will initiate contraction via a mechanism called excitation contraction coupling (covered in another lecture)
Competitive block of nAChR (what is this, example of a drug)
- *1) Competitive block:**
- competes with ACh for binding to the receptor, when the competitive block is bound, ACh can’t be bound. When the competive block is bound to the receptor, the receptor can’t open. Therefore get much smaller depolarisation as less ACh can bind at one time.
- e.g. d-tubocurarine (d-TC)
- this can be overcome by increasing the concentration of ACh
Depolarising block of nAChR - what is this, give an example of a drug
- *2) Depolarising block**
- Continuous activation of receptors so a maintained depolarisation occurs (as not broken down by ACh esterase)
- therefore Na+ channels became inactivated and stay this way, this means that AP’s cannot fire.
- E.g.: succinylcholine
What is myasthenia gravis and why does it cause significant muscle weakness?
- Autoimmune disease that targets nAChR’s
- Antibodies directed against these receptors leads to loss of functional nAChR by mediated lysis and receptor degradation (therefore, fewer functioning nAChR receptors)
- Endplate potentials are reduced in amplitude (same amoint of neurotransmitter release in a healthy person compared to myethenia gravis, in myasthenia gravis, the size of depolarisation of end plate is smaller, therefore may not reach threshold… muscle weakness…)
- Leads to muscle weakness and fatigue that increases with exercise
How is myasthenia gravis diagnosed? What is the test called?
- Edrophonium test
- Edrophonium chloride is a short acting anticholinesterase, which alleviates facial weakness rapidly. If this occurs, it is a positive test for MG.
- It alleviates facial weakness as it has ‘overcome’ some of the weakness, by increasing the amplitude of the end plate potential as more ACh around to combine with as many functioning ACh as possible
Where are nAChR (nicotinic ACh receptor) found? Where are mAChR (muscarinic ACh receptor) found?
nAChR is found between:
- motor neurones and skeletal muscles
- pre-ganglionic neurone and post-ganglionic neurones (in the parasympathetic branch of th autonomic nervous system)
mAChR is found between:
- post-ganglionic neurone (parasympathetic, autonomic nervous system) and target tissue
What type of receptors are nAChR and mAChR?
- nAChR: ligand gated ion channel (produce fast depolarisation because it is this type of channel)
- mAChR: G-protein (produce a slower response, trigger a cascade of events in the cell)
