MR S5 - Control of Calcium Flashcards
Discuss the diversity of Ca channels
Ca channels have structural diversity
This means a blocker of one channel may not block another channel
They also have different primary locations
This means if one channel is selectively blocked, there can be a localised effect
Describe the sequence of events when an action potential reaches the presynaptic membrane
Arrival of AP causes Ca channels to open
Influx of Ca ions down concentration gradient
Increase of intracellular Ca concentration causes neurotransmitter release
How does fast synaptic transmission occur?
In fast synaptic transmission, the receptor protein is also the ion channel - this means no secondary messenger is necessary
Describe in detail how intracellular Ca concentration causes ACh release
Ca ions enter cell
Bind to “synaptotagmin”, causing snare complex formation
Snare complex causes ACh release
What occurs on the post junctional membrane after ACh release from presynaptic neurone?
The ACh will bind to the nicotinic ACh receptors on the post-junctional membrane
Depolarisation raises the muscle to threshold
End plate potential produced
State the binding site of competitive nicotinic receptor blockers and give an example of a blocker
Bind at the ACh binding site
Eg tubocurarine
Describe how depolarising nicotinic receptor blockers work and give an example of a blocker
Cause maintained depolarisation at the post junctional membrane Therefore Na channels do not activate due to accommodation Eg succinylcholine (used in operations to induce paralysis)
Describe myasthenia gravis
Antibodies destroy ACh receptors on post synaptic membranes
Causes drooping eyelids, profound weakness which worsens upon exertion
Treated with AChe inhibitors
Why is control of intracellular Ca concentration important?
So many processes use small changes in Ca concentration as triggers or use Ca as a catalyst
Ca cannot be metabolised, can only be moved in or out of the cell
What are the benefits and disadvantages of very tightly controlled intracellular Ca concentration
Benefits:
-Changes in concentration can occur rapidly and without active transport
Disadvantages:
-Energy expensive to maintain
-Ca overload causes loss of regulation and cell death
What does the Ca gradient rely on?
- The impermeability of the membrane
- The ability to expel Ca
- Ca buffers
- Intracellular Ca stores
How is membrane permeability controlled?
By the presence of ion channels and their status (open/closed, active/inactive)
How may Ca be expelled from the cell?
By Ca ATPase:
High affinity, low capacity
Intracellular Ca binds to calmodulin then this complex bonds to the channel and Ca is removed from the cell
By Na Ca exchanger
Low affinity, high capacity
Na gradient used as driving force (3Na in, 1Ca out)
Electrogenic and works best at resting membrane potential
How do Ca buffers affect the Ca gradient?
Buffers limit diffusion via binding proteins eg parvalbumin, calreticulin, calsequestin, calbindin
Diffusion depends on binding protein concentration and saturation
How may intracellular Ca be increased?
Ca influx through plasma membrane (altered permeability)
Ca release from rapidly releasable stores
Ca release from non rapidly releasable stores
How does Ca enter the cell via the plasma membrane?
Voltage gated calcium channels open to allow an influx of Ca down it’s concentration gradient
Receptor operated Ca channels open in response to binding of ligands
What are the rapidly releasable Ca stores?
There is a store in the sarcoplasmic reticulum which is set up by the SERCA membrane protein
Ca binds to calsequestrin
How is Ca released from rapidly releasable stores?
G protein coupled receptors (GPCRs)
Calcium induced calcium release (CICR)
How do GPCRs cause Ca to be real eased from rapidly releasable stores?
A ligand binds to the GPCR on the cell membrane
Activates a subunit which binds to membrane phospholipid PIP2
Release of IP3 which binds to a receptor on the sarcoplasmic reticulum
Triggers the release of Ca down it’s concentration gradient
How does CICR or “Ca induced Ca release” cause Ca to be real eased from rapidly releasable stores?
Ca binds to Ryanodine receptor on sarcoplasmic membrane
This triggers the release of Ca down it’s concentration gradient
When is CICRs role especially important physiologically?
In cardiac myocytes, the CICR mechanism is responsible for 85% of the Ca released so is very important for strong contraction of cardiac muscle
Why is Ca concentration returned to basal levels?
Repetative signalling requires a return to basal levels
Too high intracellular [Ca] for too long is toxic to cells
How are Ca stores refilled?
Recycling of cytosolic Ca
SOC (store operated Ca channel) moves mitochondrial Ca to the sarcoplasm
What does a return to basal levels of Ca require?
Termination of signal
Ca removal
Ca store refilling
Describe muscarinic receptors
G protein coupled receptors
Slower than nicotinic
Acts by secondary messengers (multiple subunits)
Describe nicotinic receptors
Ca influx causes release of ACh at presynaptic membrane
ACh binds to a nicotinic receptor on the post synaptic membrane
The receptor is also a Na channel which opens and allows an influx of Na which causes depolarisation
This is fast.
How is Ca released from non rapidly releasable stores?
Mitochondria actively take up Ca to aid buffering, regulatory signalling (micro domains) and stimulation of ATP production via a Ca uni porter
Ca is also taken up as an emergency response when cytoplasmic Ca is high
