Nerve Terminal Excitability Flashcards
What two ions are involved in neurotransmitter release?
Sodium ion influx leads to an upstroke. This then opens voltage gated calcium channels which allows influx of calcium leading to neurotransmitter release.
Where are L type calcium channels found? What can block them?
L type calcium channels are found in nerves, skeletal muscle and lungs. They can be blocked by dihydropyridines.
What clinical problem can we reduced by the action of drugs on L type calcium channels?
Hypertension
By what process are calcium channels generally regulated?
Phosphorylation
In the neurone at the Neuromuscular junction, describe the process by which calcium influx leads to transmitter release.
Calcium binds to synaptotagmin which brings the Vesicle close to the membrane. The snare complex makes a fusion pore through which the neurotransmitter is released.
What type of receptors are found at neuromuscular junctions?
Nicotinic acetylcholine receptors
What ion movement occurs across the junctional folds of a muscle cell at the neuromuscular junction?
Na+ influx and K+ efflux which gives rise to a resting membrane potential between the equilibrium potentials for these two ions.
What happens to end plate potentials when there is a lower Extracellular calcium concentration?
The amplitude of these potentials reduces.
What is a competitive block of a ACh receptor?
This is a molecule which does not cause a conformational change, however it just sits in the receptor. This can be overcome by high ACh concentrations.
What is a depolarising blocker?
This is a molecule which binds to an ion channel and keeps it closed but once they open they become depolarised leading to inactivation of Na+ channels.
What is responsible for miniature end plate potentials?
These are caused by spontaneous vesicle release, however these potentials are not sufficient to stimulate an action potential.
What is myasthenia gravis?
Autoimmune destruction of the nAChR on the junctional folds which leads to weakness which is increased with exercise.
Give an example of a depolarising blocker
Succinylcholine
Name a substance which can cause complete blocking of nAChR channels.
d-tubocurarine
What type of ACh receptor has the fastest response?
Nicotonic as they are ligand gated ion channels. Muscarinic receptors are coupled to G proteins and so there is a cascade before the response.
What are the concentrations for calcium intra and extracellularly?
Intracellularly is about 1 X 10^-7 and extracellularly is 1x 10^ -3
State the advantages of there being a large inward calcium gradient into cells.
Advantage: only small changes in [Ca2+] need to occur for there to be a significant change.
Disadvantage: it is energy expensive and if cells are unable to deal with the calcium then overload occurs leading to cell death.
What feature of the plasma membrane is importance in maintenance of calcium gradient?
The plasma membrane is relatively impermeable to calcium which helps with maintaining the potential as otherwise calcium would flow into the cell down the concentration gradient.
Name the two calcium channels which are responsible for movement of calcium out of the cell, down its concentration gradient.
Ca2+ ATPase and the Na+/Ca2+ exchanger.
Describe the affinity and capacity of Ca2+ ATPase
This is a high affinity but low capacity pump. As intracellular calcium increases, it binds to calmodulin which binds to the pump and then this causes Ca2+ efflux.
What ions does Na+/Ca2+ exchanger pump?
This pumps 3 Na+ into the cell and one Ca2+ ion out of the cell leading to slight depolarisation of the membrane.
When does Na+/Ca2+ exchanger show its highest activity and why?
When the membrane is at its resting potential as movement is down bothe the concentration and electrical gradient.
When expelling lots of calcium from a cell, which pump reduces the most first and then which pump reduces the calcium levels to precise levels at the end?
Na+/Ca2+ exchange first followed by Ca2+ ATPase
How is calcium diffusion limited in cells?
Calcium buffers (calcium binding proteins) which mean that the ions only diffuse a short distance before encountering one of these molecules.
What is a trigger protein?
This is a protein such as calmodulin or synaptotagmin which binds calcium but also alters cellular function.
State two ways in which intracellular calcium increases above basal levels.
Influx across plasma membrane and release from intracellular stores.
What is VOCC?
This is a voltage operated calcium channel which opens when there is depolarisation and calcium moves down the concentration gradient into the cell.
What is an inotropic receptor?
This is a ligand gated ion channel where the ligand can be glutamate or ACh acting on nAChR.
What ion channel is responsible for pumping calcium into intracellular stores?
SERCA
What is found within the ER to allow increased calcium storage?
Calcium binding molecules such as calsequestrin
How can the action of activated G proteins be generalised?
They regulate protein kinases which are responsible for phosphorylation of other complexes
State the cascade associated with aq subunit activation
aq activates Phospholipase C, and this breaks down into diacylglycerol and IP3 leading to increased activation of protein kinase C.
as and ai subunits have different effectors on adenylyl cyclase. What are their actions?
as up regulates adenylyl cyclase while i down regulates. Increased adenylyl cyclase leads to increased cAMP which causes increased protein kinase A activation
Explain the link between Gaq and release of calcium from the ER.
Gaq leads to activation of Phospholipase C which cleaves PIP2 releasing IP3 which binds to receptors on the ER and leads to calcium release.
What is CICR?
This is calcium induced calcium released. After initial influx of calcium, calcium binds to ryanodine receptors and so this leads to increased calcium entry from ER into the cell and increases calcium levels further. This is an example of positive feedback.
Describe calcium changes in a cardiac myocyte which lead to contraction.
The cell is depolarised by the action potential which leads to opening of the voltage gated calcium channels. This leads to calcium influx which then acts on ryanodine receptors further increasing calcium levels in the cell which binds to contractile machinery and leads to contraction.
What mechanism is most responsible for reducing calcium levels in muscle cells following contraction?
SERCA pumping calcium into the ER.
What is the role of mitochondria when intracellular calcium is high?
Mitochondria can take up calcium to protect the cell, stimulate metabolism to meet supply and demand and control cell death.
Describe the mitochondrial role in cell death due to high calcium concentrations.
When a cell has high calcium concentration, this leads to an increased pumping of calcium into the mitochondria. When the mitochondria become overloaded with calcium this triggers apoptosis.
What pump is responsible form movement of calcium into mitochondria?
Mitochondrial Ca2+ uptake uniporter.
What is the fastest method for reduction in intracellular calcium after a signal is removed?
Pumping it across the membrane. A consequence of this is that the store may not be sufficiently refilled.
What happens if the calcium stores in ER of a cell become depleted?
STIM will sense this and the ORAI channel will open to allow replenishment of the store.
