Neurotransmitters Flashcards
How is electrical information transmitted across a synapse?
Release of neurotransmitters, and their interaction with post-synaptic receptors
What are the three stages of synaptic transmission?
Biosynthesis, packaging and release of neurotransmitter
Receptor action
Inactivation: Cleavage of neurotransmitter from synaptic cleft
What are the different types of neurotransmitters?
Amino acids (GABA)
Amines (NA and Dopamine)
Neuropeptides (Opioids)
What is the effect of calcium ion influx within the presynaptic knob?
Stimulates vesicular fusion with presynaptic membrane via the vesicular adherent proteins, causes exocytosis of neurotransmitter
How are neurotransmitters released?
Released in quanta
How fast is electromechanical transduction?
200 microseconds
How are neurotransmitter removed from the synaptic cleft?
Neurotransmitter channel
Transporter reuptake proteins
Hydrolysed by enzyme
Where are synaptic vesicles docked?
Synaptic zone
How are neurotransmitters pumped into synaptic vesicles?
Associated protein pumps
How does exocytosis occur?
Special proteins on the vesicle and presynaptic membrane form a protein complex with cytoplasmic protein enables fusion.
What is the purpose of vesicular proteins?
Assist docking of vesicles to the presynaptic membrane, scudded by priming and fusion.
What happens to the vesicular membrane upon exocytosis?
Migrates to synaptic zone, and buds into the presynaptic terminal, absorbed into a cistern.
What effect does alpha-latrotoxin exert on neurotransmitters?
Stimulates transmitter release to depletion. Binds to cholinergic receptors, interrupting with cholinergic transmission
Triggers exocytosis ACh in neurosecretory cells attributed to pore formation within the presynaptic membrane contributing towards Ca2+ ion influx, via alpha latrotoxin induced channels
What channels are formed within the presynaptic membrane in response to alpha-latrotoxin?
Alpha-latrotoxin induced channels
Which type of endopeptidases inhibit transmitter release?
Zinc-dependent endopeptidases
How does botulism toxin C cause flaccid paralysis?
Cholinergic nerve terminal, endopeptidase hydrolyses vesicular protein, hence this prevents the synaptic vesicles from docking and fusion to the presynaptic membrane- inhibition of acetylcholine release
What effect does Tetanus toxin C exert?
Binds to presynaptic membrane of neuromuscular junction, internalised and transported retoaxonally to the spinal cord
Blockage of neurotransmitter release from spinal inhibitory interneurones
What type of receptors induces a fast response?
Ion-channel receptors
How is a response elicited?
Influx of ions contribute towards altering the electrochemical gradients, and polarity of the cell, hyperpolarsaition and depolarisation of membrane elicits a response
Which receptors are examples of ion channel receptors?
Nicotinic cholinergic receptors
Glutamate
GABA
Glycine receptors
Which type of receptors elicit a slow response?
G-coupled receptor
What effects are elicited by G-coupled receptors?
Membrane intrinsic enzymes (Adenyl cyclase phospholipase C)
Or ion channels (Ca2+)
G coupled proteins involve sequential actions of phosphorylation and dissociation that resulting the formation of a secondary messenger (transcription factor), elucidate a response to electrical signals
What are the examples of G-coupled receptors?
ACh at muscarininic receptors Dopamine Noradrenaline Serotonin Neuropeptides
What is an excitatory neurotransmitter receptor?
Influx of positively charged ions (Na+)
Results in depolarisation of post-synaptic membrane, increasing positive charge in the post synaptic cell, exceeds the threshold level, an action potential is triggered - travels along the postsynaptic neurone
What are inhibitory post-synaptic potentials?
Occurs during an influx of negative ions (Cl-) reducing the tendency of the stimulation of an action potential in the postsynaptic fibre
What are the two types of glutamate receptors?
AMPA and NMDA receptors
What are AMPA- receptors?
Alpha-amino-3 hydroxy-5-metyl- 4 isoazole propionic acid
Majority of fast excitatory synapses. Rapid onset, offstent and densification. Overstimulation can cause inactivation of receptor
ENABLES NA ion influx
What are NMDA receptor?
N-methyl-D-aspartate. Slow component of excitatory transmission. Serves as coincidence detectors, underlie learning mechanisms
Selectively stimulates NMDA receptors, allow both CA and sodium intracellular influx
Which type of receptor is concerned with both sodium and calcium intracellular influx?
NMDA receptor
Which type of receptor is exclusively involved with only sodium influx?
AMPA receptor
Which type of glutamate receptor is associated with fast excitatory synapses?
AMPA receptor
What are coincidence receptors?
Memory of hippocampus for activation, input is required for depolarisation
Which type of synapses of excitatory?
Glutamate
How is glutamate synthesised?
Synthesised from glucose via TCA cycle and transamination
Glutamate packaged into secretary synaptic vesicles, vesicles fuse with the presynaptic membrane, releasing neurotransmitter into the synaptic cleft through exocytosis
How is glutamate released?
Glutamate diffuse across synaptic cleft, reversible binding onto ion channel-linked receptors on the post synaptic membrane
How is glutamate taken up from the synaptic cleft?
Rapid uptake of glutamate by excitatory amino acid transporters (EAATs) from the synaptic cleft
How do glial cells (ASTROCYTES) remove glutamate from the synaptic cleft?
Enzymatically modified by glutamine synthetase to glutamine in astrocytes.
Glial cells modulate extracellular glutamate levels
Recyled between neurones and glia by glutamate-glutamine cycle
Excess glutamate in synapse taken up by EAATs.
Glutamine transported back into neurones for glutamate conversion
What enzyme modifies glutamate into glutamine within the glial cell?
Glutamine synthetase
How is glutamate recycled between neurones and glial cells?
Glutamate-glutamine cycle
How are seizures monitored?
EEG
What is the pathophysiology of epilepsy?
Excess glutamate present in the synaptic cleft (Extracellular)
Causes abnormal firing
Dysfunctional GABA system, therefore excitation cannot be reduced within the glutamate CNS synapse
What is the function performed by GABA receptors?
Inhibitory receipts to reduce tendency of stimulating action potentials in post synaptic membrane
What is epilepsy?
A neurological disorder characterised by sudden recurrent episodes of sensory disturbance, loss of consciousness and convolutions, associated with abnormal electrical activity in the brain
What are the side effects with epileptic medications?
Influences behaviour and affects concentration
What is the burden of epilepsy?
Time out of education
Impacts employment opportunities
Prelude affects driving and family life
Accidental injury
What are the inequalities in epilepsy?
Low income countries, risk of premature death of people x 3
Economically deprived areas
What is the role of primary care in the treatment of epilepsy?
Weekly/frequently (Gp and community pharmacy)
What is the morbidity associated with epilepsy?
Substantial, with `accidental injury an indirect social impacts, predominantly.
Early diagnosis,
How is GABA formed?
Decarboxylation of glutamate by glutamic acid decarboxylase,
Which enzyme decarboxylates glutamic acid into GABA?
Glutamic acid decarboxylase (GAD)
What is the cofactor for GABA synthesis?
Pyridoxal phosphate
Can GABA penetrate the blood brain barrier?
No
How is GABA packaged into vesicles?
Vesicle GABA transporters (VGAT)
Where is GABA formed?
GABAergic neurones
Upon depolarisation what happens to GABA vesicles?
GABA synaptic vesicles fuse with presynaptic membrane, GABA released into the synaptic cleft by exocytosis diffuses to target GABA receptors distributed on the post synaptic membrane.
Reversibly binds to ion channel linked receptors
How is GABA removed from the synaptic cleft?
Rapid uptake into both presynaptic terminals, and surrounding glial cells.
Membrane GABA transporters (GAT), uptake GABA into presynaptic terminals available for re-use
What is the fate of GABA in glial cells?
GABA transaminase to succinate semi-aldehyde
Why cannot glial cells synthesis GABA?
Lack glutamic acid decarboxylase (GAD)
How is GABA recovered?
GABA is converted to glutamine by the GABA shunt, transferred into the presynaptic neurones
Which enzyme converts glutamine into glutamate?
Glutaminase
What is the structure of the GABA receptor?
Pentameric organisation of the GABA receptor , and pharmacologically important binding domain.
Arranged in circle to form channel born, closed until GABA ligand is bound to recognition site.
What effect does Diazepam have within epileptic treatment?
Targets GABA receptors in the post synaptic membrane, results in increased inhibition of the post synaptic neurone
Behaves as agonist, enabling increased receptor binding to GABA
contributes to increased Cl- ion influx, therefore hyperpolarise, making it difficult to depolarise the membrane
What are agonists?
Activate receptors
What is a positive allosteric modulator (PAM)?
GABA receptors cannot be activated itself, acts at a different site to agonist. GABA is required in conjugation with PAM for stimulation
What is the target for lamotrigine?
Voltage gated sodium ion channels
What is the mechanism of lamotrigine?
Voltage gated sodium ion channels blocked
Prevents Na+ influx into the presynaptic knob, hence depolarisation is reduced
This reduces glutamate release and derived excitation of post-synaptic membrane is reduced
What is the target for pregabalin?
Voltage-hated calcium channels blocked, reduces influx of calcium into presynaptic knob, results inhibition of glutamate vesicles fusing with the membrane, reduces glutamate exocytosis into the synaptic cleft, reduction of excitatory neurotransmission
What protein does Levetiracetam bind to?
SV2a protein
What is the purpose of SV2a protein?
Reduces exocytosis for
glutamergic synapse, reduces excitatory stimulation
What protein does Tiagabine bind onto?
GABA reuptake protein
What is the mechanism of action of Tiagabine?
Inhibition of GABA re-uptake protein in inhibitory neurone, hence enhances GABAergic transmission results in reduction of GABA uptake and removal from synaptic cleft, therefore stimulates greater inhibitory response.
Increases number of GABA molecules acting on the receptors, increasing hyper polarisation, thus decreases stimulation of action potential
What effect does Viagbatrin have?
Behaves as an antagonist, inhibiting the enzyme (GABA transaminase), therefore more GABA is present in the synaptic knob , and packaged into vesicles & released.
