M&R - Calcium Flashcards
How is the internal concentration of Ca2+ significantly raised?
Ca2+ influx through Ca2+ channels
How is the structure of the alpha subunit of voltage gated Ca2+ channels similar to the voltage gated Na+ channels?
How do they differ?
Similar - split into repeats, voltage sensor, cause conformational change. Pore region which dictates permeability
Differs - slightly different as otherwise Na+ would flow through
What is an important type of alpha subunit of voltage gated Ca2+ channels?
How are they blocked?
L type
Blocked by DHP
What is necessary for a functional channel?
What is the role of associated subunits?
Pore forming subunit
Fine tune the properties and enable correct regulation of channel activity
What is the name of the synapse between a nerve and skeletal muscle fibre?
Neuromuscular junction
How is a signal passed from nerve to muscle?
Axon hillock has been raised to threshold
AP travels along axon
Gets to nerve terminal and release of transmitter causes contraction of skeletal muscle
What enzyme breaks down ACh?
Acetylcholine esterase
What is the importance of mitochondria in nerve terminals?
Reduce Ca2+ concentration for AP
Once AP has arrived, AP needs to decrease again for next AP. Ca2+ needs to be taken out of cytoplasm into store.
How is the transmitter released?
Ca2+ entry through Ca2+ channels Ca2+ binds to snaptotgamin Vesicle brought close to membrane Snare complex make a fusion pore Transmitter released through this pore
How many binding sites does a nicotinic receptor have?
When does it open?
What type of channel is it?
What molecules does it allow through?
Two.
Once two molecules of ACh are bound –> channel opens
Action channel - allows Na+ and K+ through in equal measures
Why does Na+ influx rather than K+ at the nicotinic receptor?
Channel opens
As the membrane potential is close to Ek, Na+ will influx and predominate to depolarise the cell causing an action potential
Where on the nicotinic receptor does ACh bind? How many alpha subunits are in the receptor?
What does the binding cause?
To each alpha subunit. 5 alpha subunit
Conformational change in the receptor causing the pore to open
What is transmitter release dependent on?
What happens to the end plate potentials in amplitude as external Ca2+ is lowered
Ca2+ entry
End plate potentials decrease in amplitude
What does curare cause?
And how?
Paralysis - by blocking the transmission between nerve and muscle
What are the two types of blockers of nicotinic receptors?
Competitive blockers
Depolarising blockers
How does a competitive blocker work?
Give an example
Binds at the nicotinic recognition site for ACh and closes channel
Tubocurarine
How does a depolarising blocker work?
Give an example.
Binds with nicotinic receptor and causes them to activate –> maintained depolarisation.
Area of membrane adjacent to NMJ are in Accomodation (Na+ channels inactivated. Small depolarisation has caused accumulation of inactivated NA+ channels
What are miniature end plate potentials?
Very small end plate potentials can still be recorded in response to single vesicle releasing its ACh.
How is an action potential generated in a muscle fibre?
ACh binding to nicotinic ACh receptors on muscle end plate, causing them to open and flow of cations causes depolarisation (end plate potential)
End plate potential depolarises the adjacent muscle membrane and activates voltage gated Na+ channels
AP travels along post synaptic nerve fibre and initiating an AP in the muscle
What type of disease is myasthenia gravis?
What are the symptoms?
How is it treated? And why?
Autoimmune disease targeting ACh receptors.
Drooping eyelids, profound weakened which increases with exercise.
ACh-esterase inhibitors - increase the amount of time ACh is in the synaptic cleft
How do nicotinic and muscarinic ACh receptors operate differently?
Nicotinic - produces a fast depolarisation because it is ligand gated ion channel
Muscarinic - does not have an ion channel. Produces a slower response because they are coupled to G proteins which trigger a cascade of events
How do action potentials cause Ca2+ channels to open in cell membranes?
AP arrives at the presynaptic membrane. The depolarisation causes voltage gated Ca2+ channels to open and the subsequent influx of Ca2+ down their concentration gradient
Why is calcium regulated by moving Ca2+ into and out of cytoplasm?
As it cannot be metabolised, that’s the way to cell regulates it
What are the advantages of a large inward gradient?
Changes in Ca2+ occur rapidly with movement of little Ca2+
Little has to be removed to re-establish resting conditions
What are the disadvantages of a large inward Ca2+ gradient?
Energy expensive
Inability to deal with Ca2+ easily leads to Ca2+ overload, loss of regulation and cell death.
What does the Ca2+ gradient rely on?
Relative impermeability of plasma membrane
The ability to expel Ca2+ across plasma membrane using Ca2+ATPase and Na+/Ca2+ exchanger
Ca2+ buffers
Intracellular Ca2+ stores - rapidly releasable and non rapidly releasable
What is the membrane permeability regulated by?
Open/close state of ion channels
How is Ca2+ expelled across the plasma membrane?
Describe what happens
Ca2+ATPase - as intracellular Ca2+ increases,
Ca2+ binds to calmodulin which binds to Ca2+ATPase and Ca2+ is removed from the cell
High affinity, low capacity
Na+/Ca2+ exchanger
Na+ gradient used as a driving force.. Transports 3Na+ into the cell and one Ca2+ out. Antiporter is Electrogenic = works best at resting membrane potential
Low affinity, high capacity
How do Ca2+ buffers work?
What is diffusion dependent upon?
Ca2+ diffuses more slowly than predicted from ionic or hydrated radius
Ca2+ buffers limit diffusion through ATP and Ca2+ binding proteins
Diffusion dependent on concentration of binding molecules and level of saturation
What are the two types of intracellular Ca2+ stores?
Rapidly releasable
Non-rapidly releasable
What are trigger proteins?
Proteins that bind to Ca2+ not to buffer changes but to regulate activity
How is Ca2+ elevated and returned to basal levels in cells?
Ca2+ influx across plasma membrane - voltage gated Ca2+ channels or receptor gated ion channels
Ca2+ release from rapidly releasable stores - GPCR, Ca2+ induced Ca2+ release.
Non rapidly releasable stores = mitochondria
How can Ca2+ influx across a membrane?
Voltage gated Ca2+ channels
Receptor-operated ion channels
What two ways can Ca2+ be rapidly released from stores?
G protein coupled receptors
Ca2+ induced Ca2+ release
Why does Ca2+ store require ATP?
Ca2+ store is greater than the cytoplasm so a SERCA pump is needed.
What regulates release from Ca2+ stores?
Ion channel - as there will be a large outward driving force when the store is full
What are the two types of release channels that are activated to release Ca2+?
IP3 receptors or ryanodine receptors
How does a GPCR release Ca2+?
A ligand binds to the GPCR on the cell membrane, activating Gq subunit. The subunit binds to phospholipid PIP2 releasing IP3 which in turn binds to its receptor on the Sarcoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell
How does Ca2+ induced Ca2+ release Ca2+?
Where does the initial Ca2+ come from?
Ca2+ binds to the ryanodine receptor on the side of the sarcoplasmic recticulum, triggering the release of Ca2+ down its concentration gradient
Voltage gated Ca2+ channels, ionotropic receptors, intracellular stores
What happens to Ca2+ at the very early part of the action potential?
Conditions will favour the reversal of Na+/Ca2+ exchanger (NCX) which will result in a small amount of Ca2+ entry.
As Ca2+ increases and membrane repolarisation starts, NCX will revert to Ca2+ extrusion and lower Ca2+.
Ca2+ will be pumped back into SR by SERCA in preparation for another AP
What is the similarity Ca2+ channels have to Na+ channels in terms of activation and inactivation?
What allows prolongation of the depolarisation in cardiac cells?
Activation and inactivation occur but much slower
The above along with low K+ conductance at depolarised potentials
What is the functional role of Ca2+ in muscle contraction?
Increase in cytoplasmic Ca2+ results in contraction
Ca2+ binds to troponin which undergoes conformational change, causing tropomyosin to move and reveal binding sites on actin for myosin head groups.
In the presence of ATP, myosin undergoes cycles of attachment and detachment, that, coupled with the movement of the head group results in sliding of the actin along myosin bundles and a shortening (contraction) of the myoctyes
What is the role of the. Mitochondrial Ca2+ uptake?
Ca2+ buffering - regulate pattern and extent of Ca2+ signalling
Stimulation of mitochondria metabolism - match energy demand and supply
Role in cell death - apoptosis
What within mitochondria do ca2+ use to signal?
Microdomains - areas of cytoplasm with a higher concentration of Ca2+ due to their proximity to a channel
How does the cell return to basal Ca2+ levels?
Termination of signal
Ca2+ removal
Ca2+ store refilling
Why is calcium regulated by moving Ca2+ into and out of cytoplasm?
As it cannot be metabolised, that’s the way to cell regulates it
What are the advantages of a large inward gradient?
Changes in Ca2+ occur rapidly with movement of little Ca2+
Little has to be removed to re-establish resting conditions
What are the disadvantages of a large inward Ca2+ gradient?
Energy expensive
Inability to deal with Ca2+ easily leads to Ca2+ overload, loss of regulation and cell death.
What does the Ca2+ gradient rely on?
Relative impermeability of plasma membrane
The ability to expel Ca2+ across plasma membrane using Ca2+ATPase and Na+/Ca2+ exchanger
Ca2+ buffers
Intracellular Ca2+ stores - rapidly releasable and non rapidly releasable
What is the membrane permeability regulated by?
Open/close state of ion channels
How is Ca2+ expelled across the plasma membrane?
Describe what happens
Ca2+ATPase - as intracellular Ca2+ increases,
Ca2+ binds to calmodulin which binds to Ca2+ATPase and Ca2+ is removed from the cell
High affinity, low capacity
Na+/Ca2+ exchanger
Na+ gradient used as a driving force.. Transports 3Na+ into the cell and one Ca2+ out. Antiporter is Electrogenic = works best at resting membrane potential
Low affinity, high capacity
How do Ca2+ buffers work?
What is diffusion dependent upon?
Ca2+ diffuses more slowly than predicted from ionic or hydrated radius
Ca2+ buffers limit diffusion through ATP and Ca2+ binding proteins
Diffusion dependent on concentration of binding molecules and level of saturation
What are the two types of intracellular Ca2+ stores?
Rapidly releasable
Non-rapidly releasable
What are trigger proteins?
Proteins that bind to Ca2+ not to buffer changes but to regulate activity
How is Ca2+ elevated and returned to basal levels in cells?
Ca2+ influx across plasma membrane - voltage gated Ca2+ channels or receptor gated ion channels
Ca2+ release from rapidly releasable stores - GPCR, Ca2+ induced Ca2+ release.
Non rapidly releasable stores = mitochondria
How can Ca2+ influx across a membrane?
Voltage gated Ca2+ channels
Receptor-operated ion channels
What two ways can Ca2+ be rapidly released from stores?
G protein coupled receptors
Ca2+ induced Ca2+ release
Why does Ca2+ store require ATP?
Ca2+ store is greater than the cytoplasm so a SERCA pump is needed.
What regulates release from Ca2+ stores?
Ion channel - as there will be a large outward driving force when the store is full
What are the two types of release channels that are activated to release Ca2+?
IP3 receptors or ryanodine receptors
How does a GPCR release Ca2+?
A ligand binds to the GPCR on the cell membrane, activating Gq subunit. The subunit binds to phospholipid PIP2 releasing IP3 which in turn binds to its receptor on the Sarcoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell
How does Ca2+ induced Ca2+ release Ca2+?
Where does the initial Ca2+ come from?
Ca2+ binds to the ryanodine receptor on the side of the sarcoplasmic recticulum, triggering the release of Ca2+ down its concentration gradient
Voltage gated Ca2+ channels, ionotropic receptors, intracellular stores
What happens to Ca2+ at the very early part of the action potential?
Conditions will favour the reversal of Na+/Ca2+ exchanger (NCX) which will result in a small amount of Ca2+ entry.
As Ca2+ increases and membrane repolarisation starts, NCX will revert to Ca2+ extrusion and lower Ca2+.
Ca2+ will be pumped back into SR by SERCA in preparation for another AP
What is the similarity Ca2+ channels have to Na+ channels in terms of activation and inactivation?
What allows prolongation of the depolarisation in cardiac cells?
Activation and inactivation occur but much slower
The above along with low K+ conductance at depolarised potentials
What is the functional role of Ca2+ in muscle contraction?
Increase in cytoplasmic Ca2+ results in contraction
Ca2+ binds to troponin which undergoes conformational change, causing tropomyosin to move and reveal binding sites on actin for myosin head groups.
In the presence of ATP, myosin undergoes cycles of attachment and detachment, that, coupled with the movement of the head group results in sliding of the actin along myosin bundles and a shortening (contraction) of the myoctyes
What is the role of the. Mitochondrial Ca2+ uptake?
Ca2+ buffering - regulate pattern and extent of Ca2+ signalling
Stimulation of mitochondria metabolism - match energy demand and supply
Role in cell death - apoptosis
What within mitochondria do ca2+ use to signal?
Microdomains - areas of cytoplasm with a higher concentration of Ca2+ due to their proximity to a channel
How does the cell return to basal Ca2+ levels?
Termination of signal
Ca2+ removal
Ca2+ store refilling
