Physiology and Pharmacology 3 - Skeletal Neuromuscular Junction Flashcards
What innervates skeletal muscle?
Motor neurones (aka motoneurones)
What happens to the motor neurone axon near to the muscle?
It divides into unmyelinated branches near to the muscle
What does each unmyelinated branch of a motoneurons do at the muscle?
Innervates an individual skeletal muscle fibre
What is the motoneurone and muscle fibres that it innervates known as?
Motor unit
What is a terminal bouton?
A specialised presynaptic terminal at the end of an axon
What happens to each unmyelinated branch of a motoneurone before it innervates the single muscle fibre?
what do these end in?
It further divides into multiple fine branches
A terminal bouton that forms a chemical synapse with the muscle membrane at the neuromuscular junction
What happens to action potentials arising the in the cell body of a motoneurone?
They are conducted via the icon to the boutons causing the release of the transmitter ACh
What horn of the brainstem/ spinal cord are the cell bodies of motor neurones located?
Ventral horn
What is another name for the presynaptic terminal?
Terminal Bouton
At what region of skeletal muscle fibre does the presynaptic terminal synapse?
Endplate
What is the endplate region of skeletal muscle fibre?
a region of the muscle fibre that contains thousands of receptors
What is the purpose of Schwann cells?
They produce the myelin sheath
What surrounds the terminal bouton?
Schwann cells
What do the synaptic vesicles of the terminal bouton in skeletal muscle fibres contain?
ACh
What is the name of the gap between the 2 neurones at the skeletal neuromuscular junction?
Synaptic cleft
What is the end-plate region of the muscle cell membrane arranged into?
A series of junctional folds
What is the name of the skeletal muscle cell membrane?
Sarcolemma
What do the synaptic vesicles (containing ACh) at the terminal bouton cluster at?
Active zones
What type of receptors are located in the endplate of skeletal muscle fibres?
Nicotonic ACh receptors
Where are the nicotinic ACh receptors of the end plates of skeletal muscle fibres located?
At regions of the junctional folds that face the active zones
What are the 5 major processes involved in the synaptic transmission at the skeletal neuromuscular junction?
1 - synthesis of ACh (choline + acetyl CoA using Choline acetyltransferase)
2 - storage of Ach in synaptic vesicles
3 - release of ACh (due to depolarisation by AP causing Ca2+ influx through voltage activated Ca2+ channels = Ca2+ induced release of ACh)
4 - receptor activation (nicotinic ACh receptors)
5 - transmitter inactivation (acetylcholinesterase - reuptake and reuse of choline)
How is choline transported into the pre-synaptic terminal (terminal bouton)?
Choline transporter (symprot with Na+)
What is the full name of Acetyl CoA?
Acetyl Coenzyme A
What supplies the Acetyl CoA for the production of ACh in the pre-synaptic terminal of motoneurones?
Mitochondria
How is ACh synthesised in the cytosol of the pre-synaptic terminal of motoneruones for skeletal muscle fibres?
Addition of Acetyl Coexyme A and choline by the enzyme choline acetyltransferase (ChAT or CAT)
How is ACh transported into vesicles at the pre-synaptic terminal of motoneruones for muscle fibres?
By the vesicular ACh transporter
What happens when the AP arrives at the pre-synaptic process of motoneurones for skeletal muscle fibres?
Depolarisation and opening of voltage-activated Ca2+ channels occurs
This allows Ca2+ entry into the terminal
Ca2+ causes vesicles “docked” at active zones to fuse with the presynaptic membrane (exocytosis)
ACh diffuses into the synaptic cleft
ACh activates post-synaptic nicotinic ACh receptors in the endplate region
What is the structure of nicotinic ACh receptors?
Pentamer of glycoprotein subunits that surround a central, cation selective, pore (formed by 5 M2 helices)
What are the 5 glycoprotein subunits that make up a nicotinic ACh receptor?
2 X (α1)
β1
δ
ε
What happens to the nicotinic ACh receptor of the post-synaptic process when ACh binds?
the pore contains a fate that is closed in the absence of ACh but opens when 2 molecules of ACh binds to the exterior of the receptor
Permeability of the open Nicotinic ACh receptor to Na+ and K+? What happens to these cations?
Open channel is roughly equally permeable to Na+ and K+ (Does not conduct anions)
When the fate is open Na+ enters the muscle cell whilst K+ exits simultaneously through many receptors at the end plate
At nicotinic ACh receptors, is influx of Na+ greater or less than efflux of K+?
Why?
Influx of Na+ is greater than efflux of K+
The driving force for Na+ is greater than for K+ at resting membrane potential
What does the influx of Na+ and efflux of K+ through the nicotinic ACh receptors at the post-synaptic process of the neuromuscular junction of skeletal muscle cause?
A depolarisation known as the end plate potential (EPP)
What are neurotransmitters released from vesicles in?
A packet of neurotransmitter called a quantum
What one quantum of neurotransmitter generate?
A miniature end plate potential (m.e.p.p.)
What is a miniature end plate potential?
The smallest amount of stimulation that one neurone can send to another neurone (electrical response to one quantum of transmitter, due to activation of nicotinic ACh receptors at the endplate)
What do many miniature end plate potentials summate to produce?
The end-plate potential (a greased (electronic) response)
What happens to an End plate potential that exceeds threshold?
It triggers an “all or none” propagated action potential that initiates contraction
How does an end plate potential that reaches threshold initiate contraction of a muscle cell?
It triggers the opening of voltage-activated Na+ channels around the end plate causing an action potential (all or none response)
Normally one action potential in the motor nerve triggers one action until in the muscle (one to one coupling) and a subsequent “twitch” (contraction) of the muscle
How do some drugs, or toxins, block neuromuscular transmission?
They reduce the amplitude of the e.p.p., such that it does not reach threshold for the opening of voltage-activated Na+ channels, meaning no muscle action potential is generated
What would happen if the muscle fibre did’t have voltage-activated Na+ channels?
the end plate potential would decline as it spreads from the endplate (no muscle action potential = no contraction) - with voltage-activated na+ channels, an action potential propagates fro the endplate over the length of the muscle fibre
What happens to the action potential that propagates over the surface membrane (sarcoma) of skeletal muscle fibre?
It enters transverse (T) tubules triggering release of Ca2+ from the SR which in turn causes contraction by interacting with troponin associated with the myofibrils
What are the transverse (T) tubules?
Invaginations of the sarcolemma that dip deeply into the muscle cell - in close apposition to the sarcoplasmic reticulum (Ca2+ store)
What causes the rapid termination of neuromuscular transmission?
Hydrolysis of ACh by acetylcholinesterase (AChE) - an enzyme associated with the end plate membrane
What does acetylcholinesterase (AChE) hydrolyse ACh to?
What happens to these?
Choline and acetate
Choline is taken up by the choline transporter
Acetate diffuses from the synaptic cleft
what is botulinum toxin?
An extremely potent exotoxin toxin (related to tetanus and diphtheria toxins)
What does botulinum toxin do?
Acts at motor neurone terminals to irreversibly inhibit ACh release by entering presynaptic nerve terminal to enzymatically modify proteins involved in the docking of vesicles containing ACh (therefore preventing exocytosis)
What bacteria releases clostridium botulinum?
Clostridium botulinum
Clinical and cosmetic uses of botulinum toxin?
Low dose botulinum haemaglutin complex can be administered by intramuscular injection to treat overactive muscles (dystonias) e.g. the extra ocular muscles (strabismus) or eyelids (blepharospasm)
Smoothing out age-related wrinkled
What are curate-like compounds?
Compounds that interfere with postsynaptic action of acetylcholine by acting as competitive antagonists of the nicotinic ACh receptor - reduce the amplitdue of the e.p.p. to below the threshold for muscle fibre action potential generation
What are 2 examples of curate like compounds?
Vecuronium
Atracurium
What are the clinical uses of curate like compounds?
induce reversible muscle paralysis in certain types of surgery
