Neurotransmitters Flashcards
Recall the structure of neurons
- Dendrites detect the input (covered in dendritic spines).
- Information propagates down the dendrite and is integrated in the soma.
- The AP is generated at the axon hillock.
▪ The synapse is an area of high resistance.
▪ The synaptic cleft is about 20-100nm wide.
▪ There are lots of mitochondria in the axon terminal because energy is needed for NT release.
▪ It takes ~2ms for the AP to get from one cell to the next.
Describe neurotransmission
Information transfer across the synapse requires release of neurotransmitters and their interaction with postsynaptic receptors
Describe the two types of synaptic transmission
Chemical (neurotransmitter required)
Electrical (cytoplasmic connection between the cells- seen in astrocytes and cardio myocytes).
Explain the diversity of synapses
Different genes encoding different receptors.
Describe synaptic plasticity
Synapses can modify their response over time (structural changes, changes in the number of synapses).
How do we detect synapses
Fluorescent antibodies that bind to synaptic proteins.
What are spines
Protrusions that stick out from synapses
What happens when the post-synaptic neurone receives the impulse
it integrates the action potential and generates a new action potential rapidly
Why is it important that synapses involve chemical transfer rather than electrical transfer
Chemicals can transfer lots of information in a small amount of space, whereas electrical conduction would need a large surface area
How long does it take to transmit an action potential from one cell to the next
2ms
Describe the structure of a synapse
Presynaptic nerve ending /terminal
GAP ~ 20 - 100 nm
Postsynaptic region (dendrite or cell soma)
Why do synapses require lots of mitochondria
Due to their high energy demand
What is meant by an asymmetric synapse
Asymmetric refers to the direction of travel of the information.
What are the three stages of synaptic transmission
Biosynthesis, packaging and
release of neurotransmitter (T).
II. Receptor
action
III. InactivationDescribe the diversity of neurotransmitters
Provide enormous diversity in variety of transmitters and their receptors.
Amino acids (e.g. glutamate, gamma amino butyric acid [GABA], glycine [gly]), amines (e.g. noradrenaline [NA] and dopamine [DA] ) and neuropeptides (e.g. opioid peptides).
May mediate rapid (µs - ms) or slower effects (ms)
Vary in abundance from mM to nM CNS tissue concentrations.
Neurones receive multiple transmitter influences which are integrated to produce diverse functional responses
Describe the amino acid neurotransmitters
Glutamate, GABA, glycine. Large prevalence and a large number of effects in the CNS. GABA is the major inhibitory neurotransmitter in the CNS. Glutamate is the major stimulatory neurotransmitter in the CNS, it is also highly abundant in the brain and is the most potent neurotransmitter (only small quantities are needed to transmit the signal). Other neurotransmitters tend to modulate or augment glutamate transmission.
Glycine is found in the brain and spinal cord.
What are the essential components for synaptic transmission
Restricted to specialised structures - the SYNAPSE Fast ~ within ms (200 s) Calcium is essential - transmitter release requires an increase in intracellular Ca2+ (200 M) Synaptic vesicles (SVs) provide the source of neurotransmitter (4,000-10,000 molecules per SV)
What does the effect of the neurotransmitter depend on
The type of receptor present at its synapse. One neurotransmitter can have different effects throughout the nervous system, depending on the receptors it acts upon.
How do the effects of amines and neuropeptides compare to that of amino acids
They have slower effects.
Describe the mechanism of neurotransmission
- Action potential arrives at the terminal bouton and the depolarisation opens VGCCs in the presynaptic terminal.
- Calcium ions enter the terminal bouton. Ca2+ influx results in the phosphorylation and alteration of several pre-synaptic calcium-binding proteins. This process liberates vesicles from their presynaptic actin network.
- The vesicle membrane then fuses with the pre-synaptic membrane and the contents are released into the synaptic cleft. The vesicle membrane is then invaginated back into the presynaptic terminal and recycled to form more vesicles which are filled with transmitter for reuse. This process is used by viruses to get into the interior of the cell (poliovirus or herpes virus).
- The transmitter diffuses across the cleft to postsynaptic receptors and, in some systems, to presynaptic receptors to regulate transmitter release. Once the transmitter is bound to the receptor it causes a change in postsynaptic membrane potential (excitatory or inhibitory).
- The effect of the chemical transmitter is terminated by one or more of the following mechanisms:
Enzymatic destruction of the NT
Re-uptake of the neurotransmitter in the terminal bouton
Uptake of neurotransmitter into glial cells
Diffusion out of cleft.
Sodium-Potassium pumps then restore membrane potential
Where are the vesicles found in the pre-synaptic membrane
- Vesicles are either: i. Docked in the active zone at the site of synapse. ii. Floating in the terminal region.
Describe how vesicles release their contents
- 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 super helix.
- This forms a stable complex of the vesicle at the synapse, full of NT. The vesicle then awaits the Ca2+ signal.
- At these sites of docking, a large concentration of VGCCs exist and Ca2+ can enter which causes a calcium dependant change in a calcium sensor protein on the vesicle.
- The complex undergoes a conformational change and this drives the release of transmitter into the synaptic cleft (pore opened)
Describe how the vesicular proteins are targets for neurotoxins
Tetanus – Spastic Paralysis – Zinc-dependant endopeptidases that inhibit transmitter release. C. Tetani
Botulinum – Flaccid Paralysis. C.Botulinum
Binds to protein at site of release and prevents the vesicle closing down and recycling, the NT is released to complete depletion.
What does neurotransmitter release require
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 Ca2+ entry leading to membrane fusion and exocytosis.
ATP and vesicle recycling
Describe the structure and functional units of ionotropic receptors
Structure- transmembrane ion channel composed of five subunits, binding sites for ligand and modulators outside cell
Functional Units- Each subunit has 4 transmembrane domains and subunits create a charge field to attract other cations or anions.
Describe metabotropic receptors
Structure- Single transmembrane protein with sites for interaction with ligand outside cell and interaction with G=Protein inside cell
Functional Units- Seven transmembrane domains with specific amino acid residues with domains important for ligand binding.
Describe the roles of ion channel receptors
FAST msecs
Mediate all fast excitatory and inhibitory transmission
Describe the roles of G-protein coupled receptors
SLOW secs/mins
Effectors may be enzymes (adenyl cyclase, phospholipase C, cGMP-PDE) or channels (e.g. Ca2+ or K+)
Give some examples of ion channel receptors
CNS: Glutamate,
Gamma amino butyric acid (GABA)
NMJ: Acetylcholine (ACh) at nicotinic receptors
Nicotinic cholinergic receptors (nAChR), glutamate (GLUR),
GABA (GABAR), Glycine (GlyR) receptors.
Describe some examples of G-Protein couples receptors
CNS and PNS: ACh at muscarinic receptors, dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5HT) and neuropeptides e.g. enkephalin.
Where are GLUR receptors found
On dendritic spines
Where are GABA receptors found
on the soma- can have downstream effects to reverse effects of glutamate receptors.
Describe glycine receptors
They are inhibitory
What are the different types of glutamate receptors
AMPA
NMDA
mGLUR- G-protein
Describe AMPA
This is a glutamate-gated Na+ and K+ channel. Activation of AMPA receptors at normal negative membrane potentials permits passage of Na+ into the cell, permitting a rapid and large depolarisation. AMPA are the principal receptor through which neuronal transmission occurs.
Majority of FAST excitatory synapses. Rapid onset, offset and desensitisation.
Describe NMDA
NMDA receptors require certain conditions for activation:
Presence of glutamate
Removal of Mg2+ ion block in channel
This occurs when the membrane potential of the neuron is raised (depolarisation) following AMPA activation.
NMDA activation permits movement of large amounts of Na+ and Ca2+
Slow component of excitatory transmission
Serve as coincidence detectors which underlie learning mechanisms.
Describe the roles of Ca2+ that enters through the NMDA receptors
Involved with learning and memory
Ca2+ modifies the AMPA receptor potentiating the AMPA receptor response and activates protein synthesis which modifies synapse formation
How is glutamate formed
Glutamate is formed from intermediary metabolism (e.g. glycolysis and kreb’s cycle – formed from the transamination of alpha-ketoglutarate).
Describe the reuptake of glutamate
▪ Transporters on the pre-synaptic membrane and on glial cells causes uptake of glutamate once it’s fulfilled its role. o The main transporter is EAAT2 (Excitatory AminoAcid 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 epilepsy
Characterised by recurrent seizures due to abnormal neuronal excitability
Despite advances in modulating seizure generation and propagation, the disease is disabling.
30% are refractory to treatment.
How is GABA synthesised
▪ 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
What are the two types of GABA receptors
GABAa and GABAb
How does GABA act as an inhibitory neurotransmitter
GABA inhibits synaptic function by permitting the movement of Cl- into the postsynaptic cell therefore hyperpolarising the cell and preventing depolarisation.
Describe the reuptake of GABA
- There are transporters on glial cells and on the presynaptic neurone which take up GABA (known as the GABA transporters – GAT). 3. Once GABA has been taken up, it is inactivated by GABA transaminase, giving Succinate semialdehyde (which feeds into the TCA cycle).
Describe how we can exploit the GABA receptor
There is a binding site for: o Benzodiazepines (e.g. diazepam). o Barbiturates (e.g. for treatment of epilepsy – alters the frequency of channel opening
Steroid, ethanol, Zn and convulsants can also bind.
Drugs facilitating GABA transmission are:
antiepileptic
sedative
muscle relaxant
anxiolytic
Upon binding to the allosteric sites, increases the frequency of GABA opening, enhancing its activation.
