M&R S5 - Effects of Electrical Signals, Ligand Gated Channels Flashcards
How does an action potential open Ca2+ channels in a cell membrane?
Where might this happen?
Might happen at a synapse
Action potential arrives at presynaptic axon terminal
Opens voltage gated Ca2+ channels causing an influx of Ca2+ into the cell down the concentration gradient
This increase in Ca2+ leads to the release of neurotransmitter from the axon terminal
Why can influx of Ca2+ into the cell have such a large effect on internal concentration of Ca2+?
Ca2+ concentration in cells is so low that any influx can have a large effect on it
What is the key difference between Na+ and Ca2+ channels?
Explain this difference in terms of channel blockers
Ca2+ channels have structural diversity
This is well shown through the action of channel blockers, a blocker of one type of channel may not block the others
How can calcium channel blockers have a localised effect in the body?
Different types of calcium channel have different primary locations, so selectively blocking one type of channel will have a localised effect
Give an example of a calcium channel type and a blocker of that channel type
L type channels
Blocked by DHPs (Dihydropyridines)
For example, Nifedipine
What is fast synaptic transmission?
The receptor protein is also an ion channel, binding of the transmitter causes it to open
This effect is relatively fast
How does Ca2+ influx into a cell result in ACh release?
Ca2+ enters through Ca2+ channels (found in high density at the axon terminal)
Ca2+ binds to synaptotagmin
This leads tot he formation of a snare complex
The snare complex forms a fusion pore which allows the release of ACh into the synaptic cleft from vesicles that bind to the snare complex
How does the release of ACh lead to an end plate potential being generated in muscle?
ACh crosses the synaptic cleft
Ach binds to Nicitonic Ach receptors (nAChR) (ligand gated ion channels) on the post junctional membrane
End plate potential is produced and the depolarisation will raise the muscle above threshold so that an action potential is produced
What are the two types of blockers for nicitonic receptors?
Explain a bit about each and provide examples
Competitive blockers:
Bind at the ACh binding site
E.g. Tubocurarine
Depolarising blockers:
Cause a maintained depolarisation at the post junctional membrane, adjacent Na+ channels will not be activated due to accommodation
E.g. Succinylcholine (used to induce paralysis)
Describe myasthenia gravis (TOB Semester 1)
Hint: Causes, Symptoms, biochemistry behind the symptoms
Autoimmune disease targeting nAChR
Patients suffer:
Drooping eyelids
Profound weakness (increasing with exercise)
Fatigue
Caused by antibodies directed at nAChR on post-synaptic membranes in skeletal muscle
Leads to loss of functional nAChR by complement mediated lysis and receptor degradation
Endplate potentials reduced in amplitude leading to the muscle weakness and fatigue
Why is control of intracellular Ca2+ important?
In VERY broad terms, how does it do this?
Many cellular process are calcium sensitive
E.g. Fertilisation Secretion Neurotransmission Metabolism Contraction Learning and memory Apoptosis Necrosis
As Ca2+ can’t be metabolised, the cell must regulate Ca2+ concentration by moving Ca2+ in and out of the cell
What is the at rest intra and extracellular Ca2+ concentration?
This gradient means thar movement of calcium out of the cell is…?
Intra - 100nM
Extra - 1-2mM
… Energy expensive
What are the major advantages and disadvantages of a high Ca2+ concentration gradient?
Advantage - Changes in intracellular Ca2+ occur rapidly with little movement
Disadvantage - Rapid Ca2+ overload can lead to loss of regulation and cell death
What does the Ca2+ gradient rely on?
Impermeability of the cell membrane
Ability to expel Ca2+ (Ca2+ ATPase / NCX)
Ca2+ Buffers
Intracellular stores (Rapid and slow release)
What regulates membrane permeability to Ca2+?
The open/closed state of the Ca2+ ion channels
Describe the action of Ca2+ ATPase
High affinity, low capacity
Responds to intracellular [Ca2+] increase
Ca2+ binds to calmodulin - A binding trigger protein
Calmodulin-Ca2+ binds to Ca2+ ATPase
Ca2+ is expelled from the cell
This process requires ATP
Describe the action of Na+/Ca2+ Exchanger (NCX)
Low affinity, high capacity
Na+ gradient used as driving force
Transports 3Na+ out and 1Ca2+ in (Antiport)
Electrogenic
Works best at resting membrane potential
What is the function of Ca2+ buffers?
Give examples of Ca2+ buffers
Ca2+ buffers limit diffusion of Ca2+ through ATP and Ca2+ binding proteins
Example binding proteins are:
Parvalbumin
Calsequestrin
Calbindin
Calreticulin
What does rate of Ca2+ diffusion depend on?
Concentration of binding molecules and their level of saturation
To what level can intracellular [Ca2+] rise when being used to regulate cell activity?
Some intracellular process appear to require even higher concentrations than this, how is this achieved?
From 100nM to ~1uM
Microdomains are areas of localised high [Ca2+] intracellularly (higher than the global concentration of Ca2+ in the cell)
E.g. These might appear around open Ca2+ ion channels
What are the major mechanisms for changing intracellular [Ca2+]?
Ca2+ influx across membrane (altered permeability):
- Voltage gated calcium channels (VGCC)
- Receptor operated ion channels (ionotropic receptors)
Ca2+ release from rapidly-releasable stores:
- G-protein coupled receptors (GPCR)
- Ca2+ induced Ca2+ release (CICR)
Ca2+ release from non-rapidly releasing stores
Briefly explain the action of Voltage gated Ca2+ channels
Open in response to membrane depolarisation allowing calcium to flow into the cell
Briefly explain the action of receptor operated ion channels
Open in response to ligand/agonist binding to the channel allowing Ca2+ to flow into the cell
Describe where the major rapidly releasable store of Ca2+ is found in the cell and how it is
Found in the Sarco/endoplasmic reticulum
Set up by the SERCA protein which moves Ca2+ into the S/ER using ATP where it binds to proteins such as calsequestrin
