Synaptic Transmission Flashcards
What is a neuromuscular junction?
Synapse between a nerve and a skeletal muscle fibre.
What is the main difference between a nerve terminal and the rest of the axon?
High density of voltage-gated calcium channels.
Which ion channels are present in the nerve terminal?
- Voltage-gated Na+ channels
- Voltage-gated K+ channels
- Voltage-gated Ca2+ channels
Describe the structure of voltage-gated calcium channels.
- Structure of alpha-subunit of VOCC is very similar to voltage-gated Na+ channel: 1 peptide with 4 voltage-sensing domains = functional pore-forming subunit.
- Other associated subunits fine tune the properties and enable correct regulation of channel activity.
How can the activity of VOCC be regulated?
- Phosphorylation
- E.g. NA activates beta1 GPCR - Gs - AC - PKA pathway in cardiac ventricles leading to PKA phosphorylating VOOCs to increase calcium entry into myocytes for increase inotropy.
Describe the process of calcium channel inactivation.
- VOCCs inactivate (and activate) more slowly than voltage-gated Na+ channels.
- VOCC inactivation is calcium-dependent: increased intracellular calcium leads to VOCC inactivation through:
- direct binding of Ca2+ to the VOCC-calmodulin complex
- Ca2+ mediated dephosphorylation of VOCC
- Ca2+ dependent disruption of connection between VOCC and cytoskeleton
Describe the process of NT release from the pre-synaptic membrane.
- Nerve membrane depolarisation - calcium entry through VOCC.
- Ca2+ binds to synaptotagmin (involved in synaptic vesicle docking and fusion).
- NT vesicle brought closer to membrane - SNARE complex makes a fusion pore.
- NT released through pore.
How can the amount of NT released be increased?
- Increase frequency of APs - increases amount of nerve terminal Ca2+ entry - increases signal strength.
Describe the generation of an AP by ACh.
- ACh released from the pre-synaptic terminal diffuses across the synaptic cleft.
- 2 ACh bind to nicotinic ACh receptor - conformational change in receptor - causes cation-selective pore opening.
- Na+ enters cell, K+ exits cell through pore at equal rate.
- Membrane depolarisation.
- ACh degraded quickly by ACh esterase.
Why is membrane depolarisation generated by the entry/exit of Na+/K+ through pore at equal rate?
- Membrane is already close to K+ equilibrium - driving force for K+ to exit is smaller than force for Na+ to enter.
How does an AP generate muscle fibre contraction?
- Brief depolarisation initiated close to end plate activates adjacent Na+ channels due to local spread of charge - muscle AP.
- AP propagates along fibre and initiates contraction of skeletal muscle.
How can muscle contraction by blocked?
- By blocking nicotinic ACh receptors - nerve cell cannot pass on electrical signal to muscle cell.
What are the 2 main types of nAChR blockers?
- Competitive blocker
E.g. Tubocurarine - prevents ACh binding (although block by d-TC can be overcome by increasing ACh concentration). - Depolarising blocker
E.g. Succinylcholine - binds and activates nAChR but maintains depolarisation state - initial contraction but will fail to activate adjacent Na+ channels as they will become inactivated.
Name a disease involving nAChRs?
MYASTHENIA GRAVIS
What is myasthenia gravis?
- Autoimmune disease where antibodies are directed against nAChR on post-synaptic membrane of skeletal muscle.
- Leads to loss of functional nAChR by complement-mediated lysis and receptor degradation.
- Endplate potentials are reduced in amplitude and fail to reach threshold - muscle weakness and fatigue.
