Neurotransmitters and pharmacology Flashcards
What are the 4 characteristics of neurotransmission?
- Rapid timescale
- Diversity - neurons receive multiple transmitter influences that integrate to produce diverse functional responses.
- Plasticity
- Learning and memory - through formation of several synapses
Structure and function of a neurone
- Spines increase the surface area for receipt of information from other parts of the nervous system
- Positive and negative information is integrated before passage onto axon.
List the 3 stages of synaptic transmission.
- Biosynthesis, packaging and release of neurotransmitter stored in vesicles in the presynaptic terminal
- Binding of a neurotransmitter to a postsynaptic receptor, activating it and inducing a response.
- Inactivation of the neurotransmitter by reuptake (may or may not involve break down).
What are the variety of different neurotransmitters in the CNS?
Variety of neurotransmitters within the CNS can be:
- Amino acids (large proportion)
- Glutamate - single most important excitatory neurotransmitter in the brain),
- y-aminobutyric acid (GABA) - single most important inhibitory neurotransmitter in the brain
- glycine (Gly) - inhibitory transmitter, active mainly in the spinal cord and the brain stem.
- Amines
- Noradrenaline (NA) - neurotransmitter from the sympathetic nervous system and CNS
- Dopamine (DA)
- Neuropeptides
- Opioid peptides like endorphins and enkephalin.
How does the concentration of neurotransmitters and timescale of effect vary amongst neurotransmitters?
- The concentration of neurotransmitters varies from nM to mM in CNS tissues.
- The timescale for effect can also vary from rapid (us-ms) to slower effects (secs - mins)
What happens when a CNS synapse is activated?
- Action potential arrives down the axon and depolarises the whole nerve terminal
- Voltage-gated calcium ion channels open, calcium enters the presynaptic terminal and binds to the vesicles.
- This promotes vesicle exocytosis and release of neurotransmitters into the synaptic cleft.
- The neurotransmitters then diffuse across the cleft and bind to the post-synaptic receptors.
- The synapse in the picture is an excitatory synapse as the receptors allow the influx of Na+ ions, leading to the depolarisation of the postsynaptic cell and generates an action potential.
- Finally, the rapid inactivation step, in this case, involves reuptake of the neurotransmitter back into the presynaptic cell to be repackaged into vesicles and reused.
- Alternatively, neurotransmitter inactivation can involve enzymatic degradation within the synaptic cleft (eg breakdown of acetylcholine by acetylcholinesterase of the synaptic cleft).
Mechanisms involved in neurotransmitter release
- Protein complex formation between vesicle, membrane and cytoplasmic proteins allow for vesicle docking leading and a to a rapid response to Ca”+ entry and eventually membrane fusion and exocytosis.
- Calcium influx causes the vesicles to dock on the presynaptic membrane in the synaptic zone.
- The vesicles are then primed to release the neurotransmitter.
- They fuse to the presynaptic membrane and release neurotransmitters by exocytosis.
- The process requires a good supply of ATP and vesicle recycling.
How do the synaptic vesicles get filled with neurotransmitters?
The surfaces of vesicles have various protein pumps that pump neurotransmitters into the vesicles.
What about the synaptic vesicles helps them fuse to the membrane?
- Special proteins on the vesicle (vesicular proteins) and presynaptic membrane enable fusion and exocytosis.
- SNARE proteins like synapsin, synaptobrevin, SNAP25 are vesicular proteins.
Apart from aiding in vesicular fusion to the presynaptic membrane, what else do vesicular proteins do?
- They can be targets for neurotoxins
What toxins bind to vesicular proteins?
- Alpha latrotoxins
- Zn2+ dependent endopeptidases
- Tetanus toxin (C tetani)
- Botulinum toxin (C botulinum)
What are the effects of the neurotoxin Alpha latrotoxin?
- Alpha latrotoxin from black widow spiders:
- It stimulates transmitter release until depletion. It focuses on cholinergic neurones
- The toxin binds to the cholinergic terminal of the nerve and causes a mass release of acetylcholine until it is depleted and this leads to muscular paralysis.
What are the effects of neurotoxins that are Zn2+ dependent endopeptidases?
- Zn2+ dependent endopeptidases:
- inhibit transmitter release.
What are the effects of the neurotoxin tetanus toxin?
- Tetanus toxin (C tetani):
- Causes spasms and paralysis by inhibiting the release of two main neurotransmitters GABA and glycine.
- The inhibition of the release of these inhibitory neurotransmitters leads to over-stimulation.
What are the effects of the neurotoxin Botulinum toxin?
- BOTULINUM Toxin (C botulinum):
- It is a 2 chain molecule that causes flaccid paralysis due to complete muscle relaxation
- The first part of it binds to the nerve terminal (cholinergic nerve terminal)
- The second chain penetrates the nerve terminal and binds to the vesicular protein, cleaving their peptide bonds and inactivating them.
- Very potent toxin that gives rise to botulism, a very nasty food poisoning.
- Also injected in botox surgeries to relax muscles in the forehead.
What are the 2 main types of receptors to know at this stage? Briefly describe how quickly the respond.
- Ion channel-linked receptors
- Fast response (msecs)
- Mediate all fast excitatory and inhibitory transmission.
- G-protein-coupled receptors
- Slow response (secs/mins)
- Effectors may be enzymes (adenyl cyclase, phospholipase C, cGMP-PDE) or channels (e.g Ca2+ or K+)
Describe how postsynaptic excitatory neurotransmitter receptors are activated and what are the ramifications of this?
- E.g glutamate receptors
- Release of glutamate causes it to diffuse across the synaptic cleft and bind to the glutamate receptors on the post-synaptic membrane.
- This causes a rapid influx of Na+ ions down the electrochemical gradient.
- This generates an excitatory post-synaptic potential
Describe how postsynaptic inhibitory neurotransmitter receptors are activated and what are the ramifications of this?
- E.g GABA A receptors
- Release of GABA causes it to diffuse across the synaptic cleft and bind to the GABA A receptors on the post-synaptic membrane.
- This causes a rapid influx of Cl- ions down the electrochemical gradient.
- This generates an inhibitory post-synaptic potential (IPSP).
What are the 2 different types of glutamate receptors important to know at this stage?
- AMPA receptors (named after selective agonists):
- Mediate majority of the fast excitatory responses to glutamate.
- Have a rapid onset, offset and desensitisation
- NMDA receptors (named after selective agonists):
- Permeable to Na+ and Ca2+ ions.
- Provide the slow component of excitatory transmission.
- Serve as coincidence detectors which underlies learning and memory mechanisms.
- Hippocampus has a high density of these receptors.
- Needs another signal before glutamate can activate the receptor.
Recall significant events that take place in the pre and postsynaptic membranes, and the synaptic cleft of an excitatory Glu synapse.
What happens when glutamate is in excess in synapses (when glutamate and GABA don’t balance)?
- Increased concentration of glutamate in synapses can lead to seizures (convulsion) due to cells firing continuously.
Recall significant events that take place in the pre and postsynaptic membranes, and the synaptic cleft of an inhibitory GABA A synapse.
Structure of GABA receptor and its pharmacologically important binding domains.
- Pentameric organisation
- Barbiturates and benzodiazepines important anticonvulsants.
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