Neurotransmitters Flashcards
What is neurotransmission?
Information transfer across the synapse requires release of neurotransmitters and their interaction with postsynaptic receptors
What are structures of neurones?
- Dendrites detect the input and are covered in dendritic spines
- The information then propagates down the dendrite and integration occurs the soma
- The action potential is generated at the axon hillock
- The axon is an area of high resistant
- The synaptic cleft 20-100nm wide
- There are lots of mitochondria in the axn terminal because energy is needed to release neurotransmitter
- It takes about 2ms for the AP to get from one cell to the next
What are the steps of synaptic transmission?
What are the properties of synaptic transmission?
Rapid timescale
Diversity
Adaptability- changing all the time in response to environment
Plasticity
Learning and memory
Neurotransmission is restricted to specialised structures- synapses. What are they made of?
- Pre-synaptic nerve ending/ terminal
- GAP ~ 20-100nm
- Postsynaptic region (dendrite or cell soma)
Describe the mechanism of neurotransmission
- Action potential comes along and the VGCC gets activated
- Ca enters the nerve terminal and you get exocytosis of the neurotransmitter
- It diffuses across the gap and interacts with the receptors
- You have to get rid of the transmitter- this is done by transporters
- These take the amino acids back into the terminal and other transporters (in presynaptic) take it back to the synaptic vesicles
- Sodium and potassium pumps bring it back to RMP (presynaptic)
What are the 3 steps to synaptic transmission?
- Biosynthesis, packaging and release of neurotransmitter
- Receptor action
- Inactivation
There are 3 classes of neurotransmitter- what are they?
There is a huge diversity in variety of transmitters and their receptors
- Amino acids- e.g. glutamate, gamma amino butyric acid (GABA) and glycine
- Amines- e.g. noradrenaline (NA) and dopamine (DA)
- Neuropeptides (e.g. opioid peptides)
They can mediate rapid (microsecond- milliseconds) or slower effects.
They vary in abundance from mM to nM CNS tissue concentrations
GABA- inhibitor
What is essential component to synaptic transmission?
- Calcium is essential- transmitter release requires an increase in intracellular Ca
- Synaptic vesicles provide a source of neurotransmitter
What are the stages of rapid vesicle release?
- Vesicles are either docked in the active zone at site of synapse and floating in the terminal region.
- There is an interaction between the presynaptic membrane and the vesicle proteins allowing the vesicle to be docked stably.
- There are alpha helical structures which interact together to form a superhelix
- This forms a stable complex of the vesicle at the synapse full of neurotransmitter. The vesicle awaits the Ca signal
- At these sites of docking, a large conc of VGCCs exist and Ca enter which cause the Ca dependent change in Ca sensor protein on the vesicle
- The complex undergoes a conformational change and this drives the release of neurotransmitter into the cleft
What are the naturally occuring toxins that have effect on synapses?
- Tetanus toxins- spastic paralysis- zinc dependent endopeptidases that inhibit transmitter release
- Botulinum- flaccid paralysis
- Alpha latrotoxin- binds to protein at site of release and prevents the vesicle closing down and recycling, the NT released to complete depletion. Toxin comes from black widow spider
What does NT transmitter require?
- DOCKING- transmitter filled vesicles dock onto the pre-synaptic membrane
- PROTEIN COMPLEX FORMATION- between vesicle, membrane and cytoplasmic proteins to enable both vesicle docking and a rapid response to Ca entry leading to membrane fusion and exocytosis
- ATP and VESICLE RECYCLING
Which types of receptors are used for fast/ slow transmission?
ION CHANNEL RECEPTOR= FAST they mediate all fast excitatory and inhibitory transmission
In the CNS: glutamate and GABA. NMJ= ACh at nicotinic receptors
G-PROTEIN COUPLED RECEPTORS= SLOW effectors may be enzymes like adenyl cyclase or channels like Ca2+ etc..
CNS and PNS: ACh, Dopamine, Noradrenaline, 5-hydroxytryptamine, Neuropeptides
What are ion channel linked receptors?
Rapid activation micro to millisec
Diversity and rapid information flow- multiple subunit combinations distinct functional properties.
Nicotinic cholinergic receptors (nAChR), glutamate (GLUR), GABA (GABAR), glycine (GlyR) receptors
Give an example and describe one excitatory and inhibitory ion channel receptors
Glutamate= excitatory- allows influx of Na+- there are two main types of glutamate receptor:
- AMPA receptor: responsible for the majority of fast excitatory synapses
- NMDA receptor: slow component of the excitatory mechanism. Needs 2 inputs for the receptor to become activated- depolarised membrane and glutamate binding. NMDA activation dependent on state of depolarisation of the cell. This lets in Ca
GABA= inhibitory- allows influx of Cl-
Describe the glutamate excitatory synapse mechanism
Glutamate is formed in the krebs cycle
It interacts with the receptor and causes entry of sodium and calcium through the NMDA receptor.
Transporters on the pre-synaptic membrane and on glial cells causes uptake of glutamate once it’s fulfilled its role.
The main transporter is EAAT2 (Excitatory Amino-Acid Transporter 2) which is found on glial cells and on the pre-synaptic membrane.
Once in glial cells or in the neurones, glutamate is then inactivated by glutamine synthetase to make glutamine (addition of an amino-acid).
Abnormal cells firing leads to seizures associated with excess glutamate in the synapse.
Describe GABA inhibitory synapse mechanism
GABA is the main inhibitory NT.
* Both glutamate and GABA have very similar structures, removal of a carboxyl group in glutamate = GABA.
* GABA is synthesised by Glutamic Acid Decarboxylase (GAD) – Known as the Vitamin B6 enzyme.
- GABA binds to the receptor and allows entry Cl- ions which hyper-polarises the cell.
- There are transporters on glial cells and on the pre-synaptic neurone which take up GABA (known as the GABA transporters – GAT).
- Once GABA has been taken up, it is inactivated by GABA transaminase, giving Succinate semialdehyde which will feed into the TCA cycle
Describe the structure of the GABA receptor
Pentameric organisation of the GABA receptor and pharmacology important binding domains
Epilepsy treatment for epilepsy focusing on dampning down excitatory activity by facilitating inhibitory transmission
