M&R 5.1 Effects of electical signals - ligand gated ion channels Flashcards
Name 3 types of voltage-gated ion channels located in an axon membrane
Voltage gated Na+ & K+ channels (along the axonal membrane)
Voltage-gated Ca2+ channels (concentrated at the nerve terminal)
Describe the general effects of depolarisation on voltage-gated Ca2+ channels and the consequences
Depolarisation opens VGCCs
Ca2+ enters the nerve terminal
Increased [Ca2+]i triggers the release of neurotransmitters
What are the intracellular and extracellular concentrations of Ca2+ in an axon?
What is ECa ?
Intracellular = 1x10-7M Extracellular = 1x10-3M
ECa = +122mV
is the structure of VGCCs most similar to that of VGNCs or VGKCs?
VG Na+ channels
Both have a single alpha subunit with 4 ‘quarters’
Where are L-type Ca2+ channels found?
Muscle (skeletal, smooth, cardiac) , neurones and lung
Which group are specific blockers of L-type Ca2+ channels?
Dihydropiridines (e.g. nifedipine)
What does phosphorylation of Ca2+ channels do?
Makes the channel open more at any given voltage - therefore increases permeability to Ca2+
In the NMJ, where are the Ca2+ channels located? Why?
Close to vesicle release sites
So an increase in [Ca2+]i following an AP reaching the terminal can activate proteins associated with vesicles, to promote exocytosis of ACh
Describe the process (and proteins involved) in transmitter release at the NMJ
Ca2+ enters via VGCCs
Ca2+ binds to synaptotagmin, which brings the vesicle close to the membrane
SNARE complex makes a fusion pore between vesicle and membrane
ACh released via fusion pore into synaptic cleft
In the NMJ, what receptor does ACh bind to on the post-junctional membrane? What type of receptor is this?
Nicotinic ACh receptor (nAChR)
= a ligand-gated ion channel
How do nAChRs work?
Each nAChR has 2 binding sites for ACh (on the 2 alpha subunits)
When both have bound ACh, a conformational change causes the ion channel to open
The channel is a non-specific cation channel - allows Na+ and K+ through [Na+ enters, K+ leaves]
If NMJ nAChRs let both Na+ and K+ through, then why does their activation result in depolarisation?
The RMP of skeletal muscles is ~85-90mV
Therefore RMP is close to Ek, so there is little driving force for K+ to leave
RMP is far from ENa, so there is a big driving force for Na+ to enter
Therefore Na+ entry will overcome K+ exit = net inward flow of positively charged ions = depolarisation
What is the depolarisation produced by the nAChR after ACh binding called?
What does it do?
An end-plate potential (EPP)
It in turn raises the muscle above threshold so that VGNCs are activated and an AP is produced in the muscle membrane
What is the ‘reversal potential’ of an ion channel?
The point at which there is no net movement across the membrane
How is the amplitude of an EPP related to calcium concentration? What does this prove?
The EPP amplitude decreases as Ca2+ concentration is decreased
Proves that Ca2+ release is a necessary step for transmitter release
How is synaptic transmission terminated in the NMJ?
Degradation of ACh by acetylcholinesterase (AChE)
Name a competitive blocker of nAChRs
d-Tubocurarine
Name a depolarising blocker of nAChRs
succinylcholine
How does d-tubocurarine block nAChRs?
Competitive block - it sits in ACh’s binding sites which prevents ACh from binding.
It doesn’t cause the conformational change, so the channel remains closed and no EPP is produced.
How does succinylcholine block nAChRs?
Depolarising block:
(normally brief depolarisation at the post-junctional membrane activates adjacent Na+ channels by local spread of charge, causing a muscle AP)
Succinylcholine causes a prolonged depolarisation. This causes adjacent Na+ channels to become inactivated, so they can no longer be activated to cause a muscle AP
Can competitive block by tubocurarine be overcome?
Yes - block can be overcome if lots of ACh around - displaces curare
Can depolarising block by succinylcholine be overcome?
No
Even if some ACh came along and managed to bind with some free receptors & depolarise further, this would not be able to trigger the AP because of inactivated Na+ channels
What is a miniature end-plate potential (MEPP)?
A small depolarisation , due to the spontaneous release of a vesicle resulting in its package of ACh being released
Always similar size (~1mV) because vesicles are similar sizes
don’t reach threshold or activate AP
What is Myasthenia Gravis?
An autoimmune disease where patients suffer profound muscle weakness, which increases with exercise
Which receptors are affected in Myasthenia gravis? How?
Antibodies are directed at the nAChRs on the post-synaptic membrane of skeletal muscle
This leads to loss of functional nAChR by complement-mediated lysis and receptor degradation
How are EPPs affected in Myasthenia gravis? Why?
EPPs are reduced in amplitude
Because although the same amount of ACh is released per vesicle, the response is smaller because nAChRs have been damaged
What class of drug can be used to treat both Myasthenia gravis and d-tubocurarine toxicity? Why?
Acetylcholinesterase inhibitors
Because in both conditions the availability of functioning nAChR receptors is reduced. The AChE inhibitor blocks ACh degradation, therefore raising the amount in the NMJ. The extra ACh which collects can then correct for the lack of functioning nAChRs by activating the remaining normal receptors at a higher rate.
__________ - __________ ________ is the mechanism by which an AP in a muscle fibre leads to contraction of the fibre
Excitation-contraction coupling
