Electrical Signals And Control Of [Ca] Flashcards
Describe the diversity of Ca channels
Structural diversity means a blocker that blocks one Ca channel will not necessarily block another.
Different Ca channels have different locations so selectively blocking can have a localised effect.
Describe how an action potentials cause the release of ACh
AP arrives at presynaptic membrane, VG Ca channels open, influx of Ca, binds to synaptotagmin leading to the formation of snare complexes.
Synaptotagmin brings vesicle of ACh close to membrane and snare comes makes fusion pore, ACh released through pore.
Describe how an action potential is produced in the post synaptic membrane
The released ACh binds to nicotinic ACh receptors on the post junctional membrane, this causes conformational change, Na channels open, producing an end-plate potential.
What is a miniature end plate potential?
A small depolarisation caused by the spontaneous release of vesicles of ACh (approx 1 per second)
Occurs randomly and doesn’t reach threshold so no AP fired.
What are the 2 types of blockers of nicotinic receptors?
Competitive blockers
Depolarising blockers
Describe the difference between competitive and depolarising blockers of nicotinic receptors
Competitive blockers bind at the molecular recognition site for ACh
Depolarising blockers cause a maintained depolarisation at post junctional membranes, adjacent Na channels are not activated due to accommodation.
Give an example of a nicotinic ACh receptor competitive blocker
Tubocurarine
Give an example of a nicotinic ACh receptor depolarising blocker
Succinylcholine- used to induce paralysis in operations
Describe myasthenia gravis
Autoimmune disease targeting nicotinic ACh receptors.
Antibodies cause lysis and degradation of nAChR on post synaptic membranes in skeletal muscle, reduced end plate potentials lead to muscle weakness and fatigue.
Droopy eyelids and profound weakness which increases with exercise.
Treat with AChesterase inhibitors to increase the time that ACh is in the synaptic effect
Why is it important to control intracellular Ca concentration?
Many cellular processes are Ca sensitive eg fertilisation, secretion, neurotransmission, metabolism, contraction, apoptosis, necrosis etc
Since Ca cannot be metabolised the cell must regulate its conc by moving it in and out of cytoplasm.
Describe the Ca conc gradient and its advantages and disadvantages
At rest intracellular Ca = 100nM (10^-7M)
extracellular Ca = 1-2mM (10^-3M)
Advantage of large gradient is that changes in Ca conc can occur rapidly with movement of few ions
Disadvantages are that large gradient is energy expensive, and Ca overload leads to loss of regulation and cell death
What does the Ca gradient rely on?
- The relative impermeability of the plasma membrane
- The ability to expel Ca across the membrane
- Ca buffers
- Intracellular Ca stores
How does membrane impermeability contribute to the Ca gradient?
Membrane permeability is regulated by the open/closed state of ion channels. Closed ion channels make the membrane relatively impermeable so Ca ions cannot leak back across the membrane into the cell.
How does the ability to expel Ca contribute to the Ca gradient?
Using Ca-ATPase and the Na/Ca Exchanger.
Ca-ATPase is high affinity, low capacity. Binds to calmodulin bound Ca (calmodulin is a binding trigger protein) to remove Ca from the cell when intracellular Ca increases
Na/Ca exchanger is low affinity, high capacity. Uses Na gradient as a driving force to transport 3Na in per 1Ca out. Works best at resting membrane potential.
How do Ca buffers contribute to the Ca gradient?
They limit diffusion of Ca, through ATP and Ca binding proteins eg parvalbumin, calbindin
Diffusion depends on the conc of binding molecules and the level of saturation.
How do intracellular Ca stores contribute to the Ca gradient?
Stores of Ca are set up in sarco/endoplasmic reticulum by the SERCA protein
Ca is taken up into mitochondria as a protective mechanism in high Ca concs
How are changes in intracellular Ca conc brought about?
- Ca influx across plasma membrane due to altered permeability
- Ca release from rapidly releasable stores
- Ca release from non-rapidly releasable stores
How can membrane permeability for Ca ions be altered?
Membrane depolarisation triggers Voltage Gated calcium channels to open and allow an influx of Ca.
Ligands/agonists bind to Receptor Operated calcium channels, open the channels and allow an influx of Ca.
How is Ca released from rapidly releasable stores?
Ligand binds to GPCR on cell membrane, activates the G-alpha subunit, leads to the release of IP3. This binds to receptors on the SR/ER which triggers Ca release into the cell.
Ca binds to Ryanodine receptors on the SR/ER which triggers Calcium Induced Calcium Release into the cell.
How does Ca uptake by mitochondria contribute to Ca conc?
When Ca conc is high it is taken up by mitochondria as a protective mechanism.
Mitochondria also participate in normal Ca signalling due to micro domains (areas of cytoplasm with higher conc of Ca) to aid in buffering, regulating signalling, and stimulation of ATP production. They do this via a Ca uniporter driven using respiration.
How is intracellular Ca concentration returned to basal levels?
Requires:
Termination of signal
Ca removal (by Ca-ATPase, Ca/Na-Exchanger)
Ca store refilling
How are Ca stores refilled?
Recycling of cytosolic Ca (eg in cardiac myocytes)
Mitochondrial Ca is used to replenish SR stores via the store-operated Ca channel (SOC)
