Ligand gated ion channels as mediators of synaptic transmission
Learning objectives
1. Knowledge and understanding of mechanisms of excitatory and inhibitory transmission
2. Knowledge and understanding of relationships between molecular structure and function in ligand-gated ion channels
and their roles as mediators of excitatory (nicotinic receptors) and inhibitory (GABA & glycine receptors)
neurotransmission.
3. Familiarity with some disorders caused by mutations in ligand-gated ion channels.
4. Knowledge of the phylogenetic distribution and evolution of ligand-gated ion channels.
1st example of ligand-gated ion channels is nicotinic acetylcholine receptors
• Nicotinic acetylcholine receptors are the most well characterised ligand-gated ion channel
• Looking at proteins involved primarily with neuromuscular transmission
• Nicotinic acetylcholine receptors are located on the muscle membrane opposite the colarneraic
• Image showing:
- A vertebrate neuromuscular junction (part 1)
• Postsynaptic nicotinic acetylcholine receptors are involved in converting chemical signal into electrical signal.
• In the previous lecture looking at how electrical signal is converted into chemical signal in the presynaptic neuron.
- Acetylcholine containing vesicles arrive at the AP and release content from vesicle by exocytosis
- Content enters the synaptic cleft, where then bind to the receptor proteins for acetylcholine
- This will create a EPSP in the postsynaptic cell, which will lead to the activation of voltage-gated sodium
channel to generate an AP and pass down the muscle fibre and eventually lead to muscle contraction.
• Nicotinic Ach receptors are located postsynaptically.
• Voltage-gated sodium channels in the membrane of muscles trigger the generation of an AP in a muscle membrane
following the depolarization by the activation of ligand-gated ion channel nicotinic acetylcholine receptor causes
activation of Na channels and an AP occurs along the muscle triggering muscle contraction.
• Motor neurons release acetylcholine presynaptically, which then bind to the nicotinic acetylcholine receptor.
• muscle membranes have Na channels
• AP occurs in the muscle
• Image showing:
, - A vertebrate neuromuscular junction (part 2)
Structure of neuromuscular synapse
• Electron micrograph of neuromuscular synapse
• Force colour
• Realistically black and white.
• Nicotinic acetylcholine receptors are so abundant that they can be visualised under an EM.
Summary of events in chemical synaptic transmission at the vertebrate neuromuscular junction
• Begin at step 1 and ends at step 8.
• The voltage-gated calcium channels are located presynaptically and they mediate the influx of calcium
• The calcium ions lead to the fusion of the vesicles containing acetylcholine with the presynaptic membrane
• Release of the acetylcholine content into the synaptic cleft by exocytosis
• Acetylcholine bind to acetylcholine receptors leasing to depolarisation or an end plate potential
- EPP is the depolarisation of skeletal muscle fibers caused by neurotransmitter binding to the postsynaptic
membrane in the neuromuscular junction. This small response (~0.4mV) is called a miniature end plate
potential (MEPP) and is generated by one acetylcholine-containing vesicle
• Conversion of an electrical signal into a chemical signal
• The calcium is an intracellular chemical signal
• Acetylcholine is an intercellular chemical signal
• By the process of excitation secretion coupling, convert an electrical signal presynaptically to an electrical signal
postsynaptically.
• It is possible for electrical signals to pass across synapsis by gap junctions, where there is no need to change electrical
signal into a chemical signal. Instead, the electrical signal ca pass directly through the connexion.
, • However, in most cases, syntactical transmission requires the conversion of electrical to chemical signals and then back
to electrical signal.
Why are nicotinic ACh receptors of particular interest?
• There are 2 types of acetylcholine receptors:
1. Nicotinic acetylcholine receptor
- Important in excitatory transmission
- Nicotinic acetylcholine receptor binds to nicotine
- Nicotinic acetylcholine receptors mediate fast excitatory neuromuscular transmission in vertebrate skeletal
muscle. These receptors are accessible for biochemical and physiological studies.
- Nicotinic acetylcholine receptors are also expressed in the brain and mediate the effects of nicotine (from
tabacco) in the brain.
- This is why smoking effects us as affects our brain due to the nicotinic Ach receptors in our brains
- Ach receptors are peripheral (on the muscle) therefore accessible for experimental study, and, therefore know
a lot about nicotinic Ach receptors.
- There are Ach in our brain but more difficult to obtain as barried in brain.
2. Muscarinic acetylcholine receptor
- Important in the heart
- Slows down the heart rate
- Not ion channels, work in a different way
- Will not mention this type of acetylcholine receptor in this module
Patch-clamp recording of acetylcholine receptor-channel currents
• Patch clamping
- Is a micro version of voltage clamping that enables you to record the current
• If apply patch-clamping technique to muscle fibers, will observe inward currents when acetylcholine applied.
• Patch of membrane revealing individual opening and closing of ion channels
• Patch clamp recording of acetylcholine receptors Inward current (downward deflection), downward deflection, and
transients opening of nicotinic receptors. Summating to give rise to excitation of muscle
• At the molecular level, it is noisy but at the cellular level all, the receptors average out.
Learning objectives
1. Knowledge and understanding of mechanisms of excitatory and inhibitory transmission
2. Knowledge and understanding of relationships between molecular structure and function in ligand-gated ion channels
and their roles as mediators of excitatory (nicotinic receptors) and inhibitory (GABA & glycine receptors)
neurotransmission.
3. Familiarity with some disorders caused by mutations in ligand-gated ion channels.
4. Knowledge of the phylogenetic distribution and evolution of ligand-gated ion channels.
1st example of ligand-gated ion channels is nicotinic acetylcholine receptors
• Nicotinic acetylcholine receptors are the most well characterised ligand-gated ion channel
• Looking at proteins involved primarily with neuromuscular transmission
• Nicotinic acetylcholine receptors are located on the muscle membrane opposite the colarneraic
• Image showing:
- A vertebrate neuromuscular junction (part 1)
• Postsynaptic nicotinic acetylcholine receptors are involved in converting chemical signal into electrical signal.
• In the previous lecture looking at how electrical signal is converted into chemical signal in the presynaptic neuron.
- Acetylcholine containing vesicles arrive at the AP and release content from vesicle by exocytosis
- Content enters the synaptic cleft, where then bind to the receptor proteins for acetylcholine
- This will create a EPSP in the postsynaptic cell, which will lead to the activation of voltage-gated sodium
channel to generate an AP and pass down the muscle fibre and eventually lead to muscle contraction.
• Nicotinic Ach receptors are located postsynaptically.
• Voltage-gated sodium channels in the membrane of muscles trigger the generation of an AP in a muscle membrane
following the depolarization by the activation of ligand-gated ion channel nicotinic acetylcholine receptor causes
activation of Na channels and an AP occurs along the muscle triggering muscle contraction.
• Motor neurons release acetylcholine presynaptically, which then bind to the nicotinic acetylcholine receptor.
• muscle membranes have Na channels
• AP occurs in the muscle
• Image showing:
, - A vertebrate neuromuscular junction (part 2)
Structure of neuromuscular synapse
• Electron micrograph of neuromuscular synapse
• Force colour
• Realistically black and white.
• Nicotinic acetylcholine receptors are so abundant that they can be visualised under an EM.
Summary of events in chemical synaptic transmission at the vertebrate neuromuscular junction
• Begin at step 1 and ends at step 8.
• The voltage-gated calcium channels are located presynaptically and they mediate the influx of calcium
• The calcium ions lead to the fusion of the vesicles containing acetylcholine with the presynaptic membrane
• Release of the acetylcholine content into the synaptic cleft by exocytosis
• Acetylcholine bind to acetylcholine receptors leasing to depolarisation or an end plate potential
- EPP is the depolarisation of skeletal muscle fibers caused by neurotransmitter binding to the postsynaptic
membrane in the neuromuscular junction. This small response (~0.4mV) is called a miniature end plate
potential (MEPP) and is generated by one acetylcholine-containing vesicle
• Conversion of an electrical signal into a chemical signal
• The calcium is an intracellular chemical signal
• Acetylcholine is an intercellular chemical signal
• By the process of excitation secretion coupling, convert an electrical signal presynaptically to an electrical signal
postsynaptically.
• It is possible for electrical signals to pass across synapsis by gap junctions, where there is no need to change electrical
signal into a chemical signal. Instead, the electrical signal ca pass directly through the connexion.
, • However, in most cases, syntactical transmission requires the conversion of electrical to chemical signals and then back
to electrical signal.
Why are nicotinic ACh receptors of particular interest?
• There are 2 types of acetylcholine receptors:
1. Nicotinic acetylcholine receptor
- Important in excitatory transmission
- Nicotinic acetylcholine receptor binds to nicotine
- Nicotinic acetylcholine receptors mediate fast excitatory neuromuscular transmission in vertebrate skeletal
muscle. These receptors are accessible for biochemical and physiological studies.
- Nicotinic acetylcholine receptors are also expressed in the brain and mediate the effects of nicotine (from
tabacco) in the brain.
- This is why smoking effects us as affects our brain due to the nicotinic Ach receptors in our brains
- Ach receptors are peripheral (on the muscle) therefore accessible for experimental study, and, therefore know
a lot about nicotinic Ach receptors.
- There are Ach in our brain but more difficult to obtain as barried in brain.
2. Muscarinic acetylcholine receptor
- Important in the heart
- Slows down the heart rate
- Not ion channels, work in a different way
- Will not mention this type of acetylcholine receptor in this module
Patch-clamp recording of acetylcholine receptor-channel currents
• Patch clamping
- Is a micro version of voltage clamping that enables you to record the current
• If apply patch-clamping technique to muscle fibers, will observe inward currents when acetylcholine applied.
• Patch of membrane revealing individual opening and closing of ion channels
• Patch clamp recording of acetylcholine receptors Inward current (downward deflection), downward deflection, and
transients opening of nicotinic receptors. Summating to give rise to excitation of muscle
• At the molecular level, it is noisy but at the cellular level all, the receptors average out.
