Week 5 - Effects of Electrical Signals Flashcards
What ion channels are present in the nerve terminal?
- Voltage-gated Na+ channels
- Voltage-gated K+ channels
- Voltage-gated Ca2+ channels
Why does the concentration of Ca2+ increase so much?
The concentration of Ca2+ inside is so low, the Ca2+ influx through Ca2+ channels can raise the internal concentration of Ca2+ at the nerve terminal significantly
Describe Ca2+ channels
- Members of the voltage-gated superfamily of ion channels
- Similar in their membrane topology to voltage-gated Na+ channels
- Dihydropyridines are specific blockers of L-type Ca2+ channels
- Consists of: α1, α2, β and δ channels
- Also has phosphorylation sites
How is neurotransmitter released?
- Ca2+ entry through Ca2+ channels
- Ca2+ binds to synaptotagmin
- Vesicle brought close to membrane
- Snare complex makes a fusion pore
- Transmitter released through this pore (exocytosis)
How does ACh have an effect on the post-junctional membrane?
- 2 ACh molecules bind to the nicotinic ACh receptor
- This opens the channel, by causing a conformational change
- Na+ and K+ flow through, causing depolarisation (more Na+)
- This produces an end-plate potential (can activate adjacent Na+ channels due to local spread of charge)
- This depolarisation in turn raises the muscle above threshold potential
- So an action potential is produced in the muscle membrane
How can nicotinic ACh receptors be blocked?
Either a competitive blocker (CB, e.g. tubocurarine) or a depolarising blocker (DB, e.g. succinylcholine)
- CB + receptor CB-R (closed, binds to ACh binding site)
- DB + receptor DB-R (closed) DB-R’ (open, inactivation of Na+ channels so no local spread of current) DB-R* (closed, desensitised)
What are miniature end-plate potentials?
- Spontaneous release of vesicles
- About 1 s-1
- Creates a small end-plate potential
Summarise transmission at the neuromuscular junction
- Action potential arrives at the motorneurone terminal
- Depolarisation occurs
- This opens voltage-gated Ca2+ channels
- Ca2+ entry
- Increases intracellular [Ca2+]
- Ca2+ binds to synaptotagmin
- Acetylcholine-contatining vesicle is brought close to the membrane
- Snare complex makes a fusion pore
- Acetylcholine is released through this pore (exocytosis)
- ACh binds to the nicotinic ACh receptor on the post-junctional membrane
- This causes the receptor to open
- Cations flow in, causing depolarisation (the end-plate potential)
- The end-plate potential depolarises the adjacent muscle membrane
- It activates voltage-gated Na+ channels
- This initiates an action potential in the muscle fibre
- The muscle then contracts due to excitation-contraction coupling
What is calcium responsible for and what does it regulate?
It is critical for normal cellular activity and for pathophysiological changes in cell function
- Strong teeth and bones
- Fertilisation
- Proliferation
- Secretion
- Neurotransmission
- Metabolism
- Contraction
- Learning and memory
- Apoptosis and necrosis
How does Ca2+ act?
- Through ‘trigger’ proteins
- They regulate the activity/function of the trigger proteins either directly by Ca2+ or by altering their cellular distribution/binding partners
How is the calcium gradient set up and maintained?
- Relative impermeability of the plasma membrane (regulated by the open/close state of ion channels)
- Dependent upon the cells ability to expel Ca2+ across the plasma membrane (by Ca2+-ATPase or Na+/Ca2+ exchanger)
- Ca2+ buffers
- Intracellular Ca2+ stores (rapidly or non-rapidly releasable)
Explain the diffusion of Ca2+
- Ca2+ diffuses more slowly than predicted from its ionic or hydrated radius
- Ca2+ buffers limit diffusion, through ATP and Ca2+ binding proteins
- Ca2+ depends on concentration of binding molecules and their level of saturation
- Many other proteins also bind to Ca2+, which alters their function
How can intracellular [Ca2+] be elevated?
- Ca2+ influx across the plasma membrane (altered membrane permeability)
- Ca2+ release from rapidly releasable intracellular stores (Ca2+ was bound to Ca2+ binding proteins)
- Ca2+ release from non-rapidly releasable intracellular stores
How can Ca2+ influx across the plasma membrane elevate intracellular [Ca2+]?
- Voltage-gated Ca2+ channels allow Ca2+ in when depolarisation occurs
- Receptor-operated Ca2+ channels (ligand gated, Ca2+ enters down its concentration gradient)
What are non-rapidly releasable intracellular Ca2+ stores?
- Ca2+ is taken up into mitochondria when [Ca2+]i is high as a protective mechanism
- Mitochondria also participate in normal Ca2+ signalling due to microdomains (areas of cytoplasm with a higher [Ca2+] due to their proximity to a channel)
- They take up Ca2+ to aid in buffering, regulating pattern + extent of Ca2+ signalling and stimulation of mitochondrial metabolism
- Uptake is via a Ca2+ uniporter
