Neurotransmitters and Pharmacology Flashcards
What is synaptic transmission? What are its 2 stages? What does it allow?
Information transfer across the synapse requires release of neurotransmitters and their interaction with postsynaptic receptors in event of synaptic transmission. Firstly, transmitter is released from presynaptic neurone. Secondly, synaptic activation of postsynaptic neurone – postsynaptic neurone integrates the signals being received and conducts this message down the axon to the next neurone/effector. ST has a rapid timescale and underlies the diversity of the CNS function properties like plasticity, learning and memory.
What are the three stages of neural propagation? Describe them.
- Information reception – dendrites have spines which increase the surface area from which information is received.
- Soma integrates all the cell signals received and creates coherent signal which propagates
- Axon propagates action potential to synaptic terminals – each neurone may receive and make several hundreds or thousands of synapses.
What are the three stages of neurotransmission in a synapse?
- PRESYNAPTIC: Biosynthesis, packaging and release of neurotransmitter in presynaptic neurone
- SYNAPTIC CLEFT: Receptor action by neurotransmitter in synaptic cleft, binds to receptor and generates action potential in postsynaptic neurone
- POSTSYNAPTIC: Inactivation of neurotransmitter
What are the different possible types of neurotransmitters in the CNS?
Amino acids (glutamate, GABA (gamma aminobutyric acid – inhibitory transmitter), glycine) Amines (noradrenaline, dopamine) Neuropeptides (opioid peptides e.g. endorphins, enkephalins)
How do neurotransmitters differ?
SPEED: May mediate rapid (microsecond to millisecond) or slower (seconds) effects
ABUNDANCE: Vary in abundance from nM to mM in CNS tissue concentrations
Neurons receive multiple transmitter influences which are integrated to produce diverse functional responses
What are essential features of synaptic transmission?
- Calcium is essential – neurotransmitter release requires an increase in intracellular calcium to 200 micromoles, resting cell conc of calcium is about 1 mM
- Transmission is fast – occurs in milliseconds
- Synaptic vesicles provide a source of neurotransmitter and around 4000-10,000 molecules of neurotransmitters in each vesicle – idea of quantum release of NMs
How does neurotransmitter release occur?
- Depolarisation of membrane leads to opening of calcium channels
- Calcium influx occurs and so vesicles are docked onto membrane where they undergo vesicle fusion
- Vesicle opens and allows exocytotic release of transmitter into the synaptic cleft
- Empty vesicle buds off and is pinched off to be recycled
Explain the lifecycle of synaptic vesicles
Synaptic vesicles are filled with neurotransmitter as there are pumps in the membrane which fill the vesicles
With the influx of calcium, they are docked on the membrane and primed to release the neurotransmitter and after each vesicle fuses with membrane, allows rapid efflux of transmitter into the synaptic cleft where it can access receptors on the post-synaptic membrane.
Special proteins on vesicles and presynaptic membrane allow fusion and exocytosis – SNARE proteins are the vesicular proteins (synapsin, synaptobrevin)
How are vesicular proteins targetted by neurotoxins?
Neurotoxins interfere with the neurotransmitter release process.
- Alpha latrotoxin – stimulates neurotransmitter release until depletion, targeting cholinergic synapses where acetylcholine depleted until person suffers from muscular paralysis (main compound in black widow spider toxin)
- Zinc 2+ dependent endopeptidases inhibit transmitter release:
- Tetanus toxin (C. tetani): Inhibits release of GABA and glycine which are inhibitory transmitters, so if their release inhibited, gives rise to spasms and paralysis
- Botilinum toxin (C. botulinum): Causes flaccid paralysis which is paralysis due to complete muscle relaxation – first part of bi-chain molecule binds to cholinergic nerve terminal while other chain cleaves peptide bonds of vesicular proteins so docking and fusion can no longer occur. In worst case scenario, can cause complete respiratory arrest.
How is toxin power assessed?
By minimum dose that can kill a mouse
What are the four requirements for neurotransmitter release?
- Calcium-dependent
- Transmitter containing vesicles to be docked on the presynaptic membrane
- Protein complex formation between vesicle, membrane and cytoplasmic proteins to enable both vesicle docking and a rapid response to calcium ion entry leading to membrane fusion and exocytosis
- ATP and vesicle recycling
What are the 2 types of receptors on postsynaptic neurons?
- Ion-channel linked receptor – fast response in milliseconds and mediate all excitatory and inhibitory transmission
Example: CNS (Glutamate, GABA) Neuromuscular Junction (Acetylcholine at nicotinic receptors) - G-protein coupled receptors – slow response in seconds/minutes where effectors may be enzymes (adenyl cyclase, phospholipase C and CGMP-PDE) or channels (ion). Is composed of 7 alpha-helices segments. When stimulated, binds to a G-protein which then binds to an effector, changing shape of/cause change in action of a particular enzyme.
Example: Acetylcholine at muscarinic receptors (action of signal from vagus nerve on the heart), dopamine, noradrenaline, serotonin, neuropeptides
Describe ion channel linked receptors in more detail
- Rapid activation and rapid information flow
- Multiple subunit combinations possible where different subunit combos give rise to distinct functional properties
- Glutamate receptor leads to depolarisation while GABA and glycine receptors are inhibitory
What are the 2 types of postsynaptic neurons?
- In an excitatory neurotransmitter receptor, would allow influx of sodium resulting in depolarisation and formation of an excitatory postsynaptic potential.
- In an inhibitory neurotransmitter receptor, would allow influx of chloride ions causing hyperpolarisation making it more difficult for depolarisation to occur or an action potential propagating.
- Glutamate is the principal excitatory transmitter in the brain and GABA is the principal inhibitory transmitter – these remain balanced in the brain
What are the 2 types of glutamate receptors?
- AMPA receptors – majority of fast excitatory synapses. Rapid onset offset and desensitisation. Allows sodium ions only.
- NMDA receptors – slow component of excitatory transmission. Serve as coincidence detectors which underlie learning mechanisms. Allows sodium and calcium ions. Hippocampus has many of these because they require another incoming signal before receptor can be activated so, receptor must be pre-activated before glutamate can have effect.
