Lecture 10 - Skeletal Muscle Neurophysiology 2 Flashcards
List the steps associated with initiation of skeletal muscle contraction at the neuromuscular junction
1) Action potential in axon - Voluntary control, high order signal from the brain relayed to the spinal cord to the motor neural and the action potential then propagates all the way down the axon
2) Voltage gated Ca2+ channels open and Ca2+ enters
- Just like a normal synapse
- The action potential when it invades the synaptic terminal it depolarises it, there are voltage gated sodium channels out in. The axon responsible for propagating the action potential and the depolarisation of the action potential spreads into the nerve terminal and opens the voltage gates calcium channels that are located throughout the terminal and many are at the same location as the vesicles, want the calcium channels very close to vesicles to allow for tight coupling of calcium entry and exocytosis
3) Ca2+ triggers vesicle fusion, ACh released and diffuses in cleft - Cleft is a small space which allows for very fast diffusion of ACh
4) ACh binds nAchR on muscle fibre
5) nAchR channel opens, Na+ enters
6) Local depolarisation spreads to exntrajunctional membrane
7) Depolarisation opens voltage-gated Na+ channels, muscle action potential triggered
8) Action potential propagates along fiber - Propagates out from either side of the synapse (in both directions), propagates/spreads very quickly and it allows even very long muscle cells to be depolarised relatively instantaneously
9) ACh degraded by AchE
Other notes
Similar to neurons, muscle cells maintain a hyper polarised resting membrane potential whereby the inside of the cell is more negative relative to the outside
1 to 1 relationship of action potentials because an action potential in the neuron is likely to trigger an action potential in the muscle cell and this is because of so much ACh being released which causes the depolarisation to be so large that it is always going to trigger a spike, this is what happens in a healthy NMJ
Single motor neuron branches out to 100s of muscle fibres
What happens in a healthy NMJ
1 to 1 relationship of action potentials because an action potential in the neuron is likely to trigger an action potential in the muscle cell and this is because of so much ACh being released which causes the depolarisation to be so large that it is always going to trigger a spike, this is what happens in a healthy NMJ
Nicotinic acetylcholine receptor
5 subunits, each subunit has 4 transmembrane domains (crosses the membrane 4 times),
Muscle nAchR subunits slightly different to neuronal
Subunits surround pore in the membrane
Pore is ‘gated’, normal closed but has the ability to open or close
Pore of the ion channel is due to the second transmembrane domain (M2) so all these M2s when you put these subunits together line up in the centre and forms a pore
Sequence of amino acids in the pore determines what ions can pass through it
5 subunits form a complete channel receptor complex
Subunits and transmembrane domains of nicotinic acetylcholine receptors
5 subunits, each subunit has 4 transmembrane domains (crosses the membrane 4 times),
What can nicotinic AchR be activated by
Receptor can be activated by Ach but also nicotine, the amount of nicotine required to activate varies with composition of the receptor
what type of receptor is nicotinic AchR
Ionotropic receptor as the ion channel is part of the receptor
Chemically gated- opens when two Ach molecule bind
Selectivity of nicotinic AchR
Non-selectrice cation channel permeable to both Na+ and K+
States of nicotinic AchR
Opening —> depolarisation due to Na+ entry
3 states = resting (gates closed), activated (gate open), desensitised (gate closed)
Binding causes change in the shape of the receptor such that it opens the pore/gate and this allows sodium flux into the cell and down its concentration gradient and allows potassium to exit from the cell down its concentration gradient. The overall net flux is positive charge into the cell and overall effect is depolarisation
When ACh unbinds, the nicotinic AchR goes back into the resting closed state and in a state where it can bind ACh again
Go from resting to activated state when two acetylcholine molecules bind and if these two molecules stay bound for a long period of time then the channel with desensitise which is a mechanism to ensure that the depolarisation from this channel is relatively short lived.
Muscarinic acetylcholine receptor
CNS, ANS (autonomic), smooth muscle - not really found in the skeletal muscle
Indirect gating via G-protein
Metabotropic receptors - not ion channels themselves but signal by using the activation of GPCR pathways which regulate intracellular signalling and regulate the opening of the ion channel
Binding causes a conformation change in the receptor which relays to the G proteins and this changes the affinity of the G alpha subunit and it exchanges GDP for GTP
G alpha can have indirect effects but can also directly react with ion channels
Nicotinic receptor agonist
Agonist = Nicotine
Causes opening of receptor
Different types of nicotinic receptors are due to different subunits, the subunits in the brain are much more sensitive to nicotine than subunits in the skeletal muscle meaning the effects of smoking has more effects on the central nervous system rather than skeletal muscle until you get very high levels of nicotine
Nicotinic receptor anatagonist
Antagonist (blocks receptor)
Tubocurarine - poisoned arrow tips, if shot at animal then it will paralyse it due to blocking the nicotinic receptors
Alpha-neurotoxins
Location of muscarinic receptors
Muscarinic receptor (not in skeletal muscle but in CNS, ANS and smooth muscle)
Muscarinic receptor agonist
Agonist = Muscarine (can be found in mushrooms)
Muscarinic receptor anatagonist
Antagonist = atropine
Inhibition of AChE
Edrophonium
Pyridostigmine
