Synapses and neurotransmitters Flashcards
What is a synapse?
A junction between 2 neurones allowing signals to pass from one to the other
What is synaptic transmission?
The process of signalling via synapses
What is the evidence for the existence of neurones? (3)
- Golgi stain
- Physiological evidence from reflex studies
- Electron microscopy
What are the 2 kinds of synapses?
- Chemical
- Electrical
What are electrical synapses?
Gap junctions made of connexins which allow current to flow directly between neurones (diffusion)
How can you test for an electrical synapse? (3)
- Inject dye into a cell, will diffuse straight into the adjacent cell via the gap junction
- Stimulate a neurone, record the depolarisation and hyperpolarisation from the adjacent cell
- Connexin gene deletion
What are electrical synapses good for? (2)
- Fast communication
- Synchronising neurones
What was the first evidence for chemical synapses?
- Loewi’s experiment
- Stimulate Vagus nerve, remove fluid, add to recipient heart
- Heart rate slows
- Demonstrates that electrical signalling is converted to a chemical signal
What are the steps of chemical synaptic transmission? (5)
- Package neurotransmitter in vesicles at the pre-synaptic terminal
- Action potential depolarisation causes opening of Ca2+ channels
- Ca2+ influx causes vesicles to fuse with the membrane and release neurotransmitter
- Neurotransmitter diffuses across synaptic cleft and activates receptors on post-synaptic membrane
- Neurotransmitter removed from synaptic cleft
What are the 2 types of synaptic vesicles?
- Synaptic vesicles
- Dense-core secretory granules
What is stored in synaptic vesicles?
Small molecule neurotransmitters
What is stored in dense-core secretory granules?
Peptide neurotransmitters
How are synaptic vesicles filled?
Filled by transporter proteins at the presynaptic terminal
How are dense-core secretory granules filled?
Created and filled by the ER/Golgi secretory apparatus
What happens to synaptic vesicles once they have released their cargo?
Recycled by endocytosis
What happens to dense-core secretory granules once they have released their cargo?
Not recycled, single use
What is synaptotagmin?
Ca2+ binding protein on vesicles
What are the 2 types of SNAREs?
- v-SNAREs (vesicle)
- t-SNAREs (target)
How does Ca2+ cause vesicle fusion?
- Ca2+ binds to synaptotagmin causing a conformational change
- Causes the SNAREs to join together and forces the vesicle to fuse with the membrane
Which toxins target SNAREs? (2)
- Botulinum toxin
- Tetanus toxin
What receptors can neurotransmitters bind to on the postsynaptic neurone?
- Ionotropic (ligand-gated ion channel)
- Metabotropic (G-protein coupled receptor)
How can neurotransmitters be removed from the synaptic cleft? (3)
- Diffuse away
- Taken up into presynaptic neuron/glial cell and recycled
- Destroyed by enzymes in the synaptic cleft
Which direction do signals pass in electrical synapses?
Both directions
Which direction do signals pass in chemical synapses?
One direction
Which kind of synapse has faster signal transmission?
Electrical
Which kind of synapse can have more complicated downstream modulations/transformations?
Chemical
Do motor neuron action potentials always cause muscle cell action potentials?
Yes
Which neurotransmitter is used at neuromuscular junctions?
Acetylcholine (cholinergic)
What allows the neuromuscular junction to be so efficient? (3)
- Large number of active zones on presynaptic membrane
- Junctional folds on postsynaptic membrane
- Junctional folds directly opposite active zones
What are junctional folds?
Folds in the postsynaptic membrane of NMJ filled with neurotransmitter receptors
What proved the existence of vesicles?
- Stimulation of motor neurone caused endplate potentials which were integer multiples of spontaneous motor endplate potentials
- Concluded that neurones release discrete packages of neurotransmitter containing a set amount
- Spontaneous potential occurs when one vesicle accidentally fuses and releases its cargo
What is the criteria for a neurotransmitter? (4)
- Present in presynaptic terminals
- Released in response to stimulation
- Acts on the postsynaptic neuron
- Blocking the neurotransmitter prevents synaptic transmission
How could you determine if a molecule is acting as a neurotransmitter?
- Immunostaining to determine its presence, presence of enzymes to make it/transporter proteins to store it
- Collect the fluid around neurones after stimulation and analyse
- Test if the molecule mimics the effect of stimulating the cell
- Use drugs/delete genes/receptors to block the neurotransmitter
What are the 3 types of neurotransmitters?
- Amino acids (small molecules)
- Amines (small molecules)
- Peptides
How are amino acid neurotransmitters stored?
Synaptic vesicles
How are amine neurotransmitters stored?
Synaptic vesicles
How are peptide neurotransmitters stored?
Dense-core secretory granules
Which neurotransmitters are small molecules?
Amino acids and amines
Which receptors can small molecule neurotransmitters act on? (2)
- Ionotropic
- Metabotropic
Which receptors can peptide neurotransmitters act on?
Metabotropic only
What is co-transmission?
When a peptide-releasing neuron also releases a small molecule transmitter at the same time, called the co-transmitter
What kind of neurotransmitter is glutamate?
Amino acid (small molecule)
What is the most common excitatory neurotransmitter in the CNS?
Glutamate
Which 3 ionotropic receptors does glutamate act on?
- AMPA receptor
- NMDA receptor
- Kainate receptor
How is glutamate action terminated?
Transporter proteins take up glutamate into the presynaptic terminal and glia
What happens when glutamate binds to AMPA receptors?
- Channel opens
- Allows Na+ into neuron and K+ out
- Causes an EPSP
What kind of receptor are AMPA receptors?
Ionotropic
What binds to AMPA receptors?
Glutamate
Which ions can pass through AMPA receptors? (2)
- Na+
- K+
Which ions can pass through NMDA receptors? (3)
- Na+
- K+
- Ca2+
What binds to NMDA receptors?
Glutamate
What kind of receptor are NMDA receptors?
Ionotropic
What makes NMDA receptors different from AMPA receptors?
- NMDA receptors allow Ca2+ in but AMPA don’t
- NMDA receptors are blocked with Mg2+ when the neuron is at resting potential
Why is glutamate binding not enough to open NMDA receptors?
They are blocked with Mg2+ which is attracted to the negative inside of the neuron when at resting potential
How are NMDA receptors opened?
- Depolarisation of the neuron removes the voltage-dependent Mg2+ block (becomes more positive so repels)
- Glutamate binding can open the channel when the neuron is depolarised and the Mg2+ has been removed
How do NMDA receptors act as a coincidence detector?
They are dual-gated which means they are only opened when the neuron is activated right after already being activated
How many subunits do AMPA and NMDA receptors have?
4
Which metabotropic receptors does glutamate act on?
mGluR1, mGluR2 etc.
How can glutamate also be inhibitory?
Can act via an inhibitory metabotropic receptor
Is glutamate excitatory or inhibitory?
Excitatory
Is GABA excitatory or inhibitory?
Inhibitory
What kind of neurotransmitter is GABA?
Amino acid
Not used to synthesis proteins
How is GABA made?
Synthesised from glutamate
Which enzyme converts glutamate to GABA?
Glutamic acid decarboxylase (GAD)
How is GABA action terminated?
Transporter proteins take up GABA into the presynaptic terminal and glia
Which ionotropic receptor does GABA act on?
GABAa receptor
Which ion can pass through GABAa receptors?
Cl-
What happens when GABA binds to GABAa receptors?
- Cl- enters the neuron
- Produces an IPSP
What can too little GABA cause?
Seizures
What can too much GABA cause?
Coma/loss of consciousness
How do drugs modulate the activity of GABAa receptors?
- Bind to an allosteric binding site
- Need GABA to also bind in order to cause an effect
Which drugs can modulate the activity of GABAa receptors? (3)
- Ethanol
- Benzodiazepines
- Barbiturates
What is the effect of ethanol on GABAa receptors?
Enhances the effects of GABA
What are benzodiazepines used to treat?
Anxiety
What is the effect of benzodiazepines on GABAa receptors?
Enhances the effects of GABA
What are barbiturates used for?
- Sedatives (used to be sleeping pills)
- Anti-convulsants
What is the effect of barbiturates on GABAa receptors?
Enhances the effects of GABA
Which metabotropic receptor does GABA act on?
GABAb
Is GABAa receptor ionotropic or metabotropic?
Ionotropic
Is GABAb receptor ionotropic or metabotropic?
Metabotropic
How can GABAb receptors have an autoinhibitory effect?
GABAergic neuron could have GABAb receptors on itself which inhibit further release of GABA from the synaptic terminal
What kind of neurotransmitter is glycine?
Amino acid (small molecule)
Is glycine inhibitory or excitatory? (2)
- Can act like GABA on Cl- channels to be inhibitory (mainly inhibitory)
- Can bind to NMDA glutamate receptors to be excitatory
What happens when Cl- channels on a neurone are opened?
Membrane potential moves closer to the Nernst potential for Cl- (same with any ion)
How could a GABAergic neuron inhibit a neuron presynaptically?
- Release GABA which binds to GABAb receptors
- Causes a signalling cascade which results in Ca2+ channels on the neuron closing so vesicles can’t fuse with the membrane and release neurotransmitter
Which enzyme is involved in the production of acetylcholine?
Choline acetyltransferase (ChAT)
How is acetylcholine made?
- Acetyl CoA plus choline
- Catalysed by choline acetyltransferase (ChAT)
Where is choline acetyltransferase (ChAT) located?
In the cytoplasm of the presynaptic cholinergic neuron
What kind of neurotransmitter is ACh?
Small molecule
How is ACh stored in neurones?
Synaptic vesicles
How is ACh action terminated? (2)
- Destroyed in the synaptic cleft by acetylcholinesterase (AChE)
- Choline taken up again into presynaptic neurone via choline transporter and recycled
What is ACh broken down into by acetylcholinesterase?
Acetic acid and choline
Where does acetyl CoA come from?
Respiration
What are ionotropic ACh receptors called?
Nicotinic receptors
What are metabotropic ACh receptors called?
Muscarinic receptors
Where are nicotinic receptors found in the body? (2)
- Neuromuscular junction (NMJ)
- CNS
What is an agonist for nicotinic receptors apart from ACh?
Nicotine
What is an antagonist for nicotinic receptors?
Curare
What happens when ACh binds to nicotinic receptors?
- Channel opens
- Ions flow through to depolarise the neurone
What is an agonist for muscarinic receptors apart from ACh?
Muscarine
What is an antagonist for muscarinic receptors?
Atropine
Where are muscarinic receptors found in the body? (2)
- CNS
- Autonomic nervous system
Which muscarinic receptors are excitatory? (3)
- M1
- M3
- M5
Which G protein are receptors M1, M3 and M5 coupled with?
Gq (excitatory)
Which muscarinic receptors are inhibitory? (2)
- M2
- M4
Which G proteins are receptors M2 and M4 coupled with?
Gi/o (inhibitory)
Does the brain have more nicotinic or muscarinic receptors?
Muscarinic
Which ACh receptors are in the NMJ?
Nicotinic
Which drugs block ACh release? (2)
- Botulinum toxin
- Black widow spider venom
Which drugs inhibit acetylcholinesterase? (3)
- Nerve gas
- Organophosphate pesticides
- Alzheimer’s treatments
Which drugs activate ACh receptors? (2)
- Nicotine/muscarine
- Neonicotinoid pesticides
Which drugs block ACh receptors?
- Nicotinic: curare, alpha-bungarotoxin
- Muscarinic: atropine
Which neurotransmitters are catecholamines? (3)
- Dopamine
- Noradrenaline/norepinephrine
- Adrenaline/epinephrine
Which molecule is dopamine made from?
L-dopa
Which molecule is noradrenaline made from?
Dopamine
Which molecule is adrenaline made from?
Noradrenaline
Which neurotransmitters are monoamines? (4)
- Dopamine (catecholamine)
- Noradrenaline/norepinephrine (catecholamine)
- Adrenaline/epinephrine (catecholamine)
- Serotonin
What is serotonin abbreviated to?
5-HT (5-hydroxytryptamine)
Which molecule is serotonin made from?
Tryptophan (amino acid)
How are monoamines stored?
Packaged into synaptic vesicles by vesicular monoamine transporters (VMAT)
How is the action of monoamines terminated?
Reuptake transporters take them back up into the presynaptic neurone
Which enzyme destroys monoamines?
Monoamine oxidase (MAO)
Where is monoamine oxidase (MAO) located?
Presynaptic cell
Which enzyme destroys catecholamines?
Catechol-O-methyltransferase (COMT)
Where is catechol-O-methyltransferase (COMT) located?
Postsynaptic cell
Which type of receptors do monoamines mostly activate?
Metabotropic
What are the receptors for dopamine?
- D1 like: D1, D5
- D2 like: D2, D3, D4
What are the receptors for adrenaline/epinephrine and noradrenaline/norepinephrine?
Alpha/beta type adrenergic receptors
What kind of receptors are dopamine receptors?
Metabotropic (G-protein)
What kind of receptors are adrenergic receptors?
Metabotropic (G-protein)
How many types of serotonin receptors are there?
7
What kind of receptors are serotonin receptors?
All metabotropic except 1 which is a ligand-gated Na+/K+ channel
What are the 2 major functions of dopamine?
- Motor control
- Reward
Where in the brain are the motor control dopaminergic neurons?
Substantia nigra
Where in the brain do motor control dopaminergic neurones in the substantia nigra send their axons to?
Striatum
What is the neural pathway which facilitates initiation of voluntary movement?
Nigrostriatal pathway
What does the nigrostriatal pathway do?
Facilitates initiation of voluntary movement
Which neurones die in Parkinson’s disease?
Motor control dopaminergic neurones
Why can’t you give dopamine to Parkinson’s patients?
Doesn’t cross the blood-brain barrier
Which molecule are the catecholamines made from?
Tyrosine (amino acid)
What is given to Parkinson’s patients?
- L-Dopa
- Monoamine oxidase inhibitors
Why is L-Dopa used to treat Parkinson’s?
Precursor to dopamine which can cross the blood-brain barrier and converted to dopamine by dopaminergic neurones to increase dopamine action in the brain
Why are monoamine oxidase inhibitors used to treat Parkinson’s?
Prevents the breakdown of dopamine in the presynaptic neurones to increase dopamine levels in the brain
Where in the brain are the reward dopaminergic neurons?
Ventral tegmental area (VTA)
Where in the brain do reward dopaminergic neurones in the VTA send their axons to? (2)
- Cortex
- Limbic system
What is the neural pathway which mediates reward/motivation?
Mesolimbic pathway
What does the mesolimbic pathway do?
Mediates reward/motivation
Where are noradrenergic neurones located in the brain?
Locus coeruleus
Where in the brain do noradrenergic neurones project to?
Whole brain
What do noradrenergic neurones regulate?
- Arousal
- E.g. sleep/wake/attention/pain/anxiety etc
Where in the brain are serotonergic neurones located?
Raphe nuceli
Where in the brain do serotonergic neurones project to?
Whole brain
What do serotonergic neurones regulate?
- Sleep/wake
- Mood
What does cocaine do?
- Blocks the dopamine reuptake transporter to enhance dopamine signalling
- Rewarding
What do amphetamines do?
- Block storage of dopamine and norepinephrine in vesicles
- Block reuptake of dopamine and norepinephrine
What are examples of amphetamines? (2)
- Crystal meth
- Adderall
What is Adderall used to treat?
ADHD
How do antipsychotics work?
Block dopamine receptors
What is a side effect of antipsychotics?
Parkinson’s-like symptoms
What are 3 classes of antidepressants?
- Tricyclics
- Selective serotonin reuptake inhibitors (SSRIs)
- Monoamine oxidase inhibitors
How do tricyclic antidepressants work?
Inhibit reuptake transporters of noradrenaline and serotonin
What do antidepressants do?
Increase serotonin levels
How do SSRIs work?
Inhibit serotonin reuptake transporters
What are examples of SSRIs? (2)
- Fluoxetine
- Prozac
What is Fluoxetine?
SSRI antidepressant
What is Prozac?
SSRI antidepressant
What are endorphins?
Opioid peptide neurotransmitters
What kind of receptors are opioid receptors?
Metabotropic (G-protein)
What do opioid peptide neurotransmitters regulate? (3)
- Pain (main)
- Coughing
- GI tract function (digestion side effects)
How is ATP used as a neurotransmitter?
Co-transmitter
What are the 2 classes of ATP receptors?
- P2X2
- P2Y2
What kind of receptors are P2X2 ATP receptors?
Ionotropic
What kind of receptors are P2Y2 ATP receptors?
Metabotropic
How are endocannabinoid neurotransmitters stored?
- Not stored
- Lipid soluble so diffuse across the membrane
How are endocannabinoid neurotransmitters released?
- Ca2+ activates the enzymes which make endocannabinoids
- Endocannabinoids made on demand and diffuse across the membrane
What is retrograde signalling?
Endocannabinoids can signal from post to presynaptic neurone
Which kind of receptors do endocannabinoids activate?
Metabotropic
How is nitric oxide neurotransmitter stored?
- Not stored, synthesised on demand
- Gas so can diffuse across membranes
What is the target of nitric oxide?
Soluble guanylate cyclase inside cells
What does guanylate cyclase do?
Converts GTP to cGMP
Which enzyme converts tyrosine to L-Dopa?
Tyrosine hydroxylase
What does tyrosine hydroxylase do?
Converts tyrosine to L-Dopa
Which enzyme converts L-Dopa to dopamine?
Dopa decarboxylase
What does dopa decarboxylase do?
Converts L-Dopa to dopamine
Which enzyme converts dopamine to noradrenaline?
Dopamine beta-hydroxylase
What does dopamine beta-hydroxylase do?
Converts dopamine to noradrenaline
Which enzyme converts noradrenaline to adrenaline?
Phentolamine N-methyltransferase (PNMT)
What does phentolamine N-methyltransferase do?
Converts noradrenaline to adrenaline