Neurotransmitters Systems I: Glutamate Flashcards
What is neurotransmission?
Neurotransmission is the fundamental process that drives information transfer between neurons and their targets.
Describe the structure of nerve cells and the functions of its organelles
Soma is the cell body
Axon is important in action potential propagation
Dendrites on the nerve cell body
Myelin sheath (insulating layer) speeds up nerve transmission
Nodes of ranvier are gaps between the myelin sheath - allows the action potential to jump
Synapse is the connection between two neurons
Where are neurotransmitters found in nerve cells?
Neurotransmitters in synaptic vesicles which fuse with the axon terminal membrane by endocytosis
What does the fusion of vesicles with the axon membrane cause?
Causes release of neurotransmitter across the synaptic cleft to bind to receptors on the dendrite on postsynaptic cells
What are neurotransmitters?
Neurotransmitters are chemical messengers that transmit signals from a neuron → target cell across a synapse (neurotransmission)
What are 3 criteria required for a molecule to be classed as a neurotransmitter?
- The molecule must be synthesised and stored in the presynaptic neuron
- The molecule must be released by the presynaptic axon terminal
- The molecule must produce a response in the postsynaptic cell
When are neurotransmitters released from the presynaptic terminal?
The molecule is released by the presynaptic axon terminal upon stimulation by an action potential
Why are neurotransmitters stored within the presynaptic neurons?
Neurotransmission is a rapid process so readily available store of neurotransmitter must be available at all times
How do neurotransmitters produce a response at the postsynaptic membrane?
Neurotransmitters are released from the presynaptic vesicles and diffuse across the synaptic cleft to bind to postsynaptic membrane receptors
How is an action potential is propagated
- Resting potential -70mV
- Depolarisation increased positivity of membrane
potential due to influx of Na+ - Action potential due to accelerated Na+ depolarisation
+30mV - Repolarisation due to Na+ VGCs close and K+ channels
open causing efflux occurs => -ve membrane potential - Hyperpolarisation dips below -70mV to allow the
membrane potential to be reset for another action
potential to occur
Explain how an action potential travels along the axon
Action potential is all or nothing mechanism propagated along the entire length of the axon plasma membrane in one direction
How does an action potential activate VGCCs?
Action potential arrives at presynaptic bouton opening VGCCs causing Ca2+ influx
What is the effect of Ca2+ release in neurotransmission?
Ca2+ causes the vesicles to fuse with the presynaptic membrane causing neurotransmitter release via exocytosis
What are the major central neurotransmitters?
Acetylcholine Glutamate GABA Glycine Monoamines
Describe the effects of Ach
Ach acts on ligand gated ion channels (nicotinic AchR) and metabotropic channels (muscarinic AchR)
What is glutamate?
This is the major excitatory neurotransmitter in the central nervous system (CNS)
Why did it take so long to determine glutamate as a neurotransmitter?
It took a long time to realise glutamate was a neurotransmitter as it is at a crossroad of multiple metabolic pathways
Are glutamate responses inhibitory or excitatory?
Nearly all excitatory neurons in the CNS are glutamatergic and it has been estimated that over half of all brain synapses release glutamate
Where is glutamate synthesised?
Synthesised in the nerve terminals
Outline glutamate synthesis
Glutamate synthesis occurs via the conversion of glutamine → glutamate via the phosphate-activated glutaminase enzyme
NH₂ group converted to OH group via glutaminase
How is glutamate transported to vesicles?
Transported into vesicles by vesicular glutamate transporters (VGLUT)
Counter transport with H+ to drive glutamate entry into vesicles
Describe the varying concentration of glutamate in the cytosol and vesicles
Estimated ~10⁴ increase in [glutamate] in the synaptic vesicles compared to the cytosol - mediated by VGLUT
What type of receptors elicit glutamate responses?
Ionotropic receptors
AMPA, NMDA and Kainate
> AMPA and NMDA make up the majority of excitatory neurotransmission in the brain
What are the ionotropic glutamate receptors named after?
They are named after the agonists that activate them
Summarise the ionotropic effects of glutamate receptors
Influx Efflux
AMPA Na+ K+
NMDA Na+ Ca2+ K+
Kainate Na+ K+
Describe the composition of AMPA receptors
Four subunits (plus alternative splice variants) GluA1, GluA2, GluA3, GluA4
Describe the structure of the AMPA receptor?
Hetero-tetrameric - ‘dimer of dimers’
2GluA2 subunits
Plus 2 GluA1, 3 or 4 subunits
What causes the AMPA receptors to open?
Four orthosteric binding sites
Two sites must be occupied for channel opening
What is the effect of increased binding to AMPA receptors?
Current increases as more binding sites are occupied
As more binding sites are occupied current and influx of Na+ will increase
How does the GluA2 subunit prevent excitotoxicity?
Presence of GluA2 subunits prevents Ca2+ flow into the cell
Protective against excitotoxicity
How many subunits is the NMDA receptor composed of?
3 subunits (plus alternative splice variants) GluN1 (or NR1), GluN2 (or NR2), GluN3 (or NR3)
Describe the structure formed by the 3 NMDA receptor sunbinit
Hetero-tetrameric - ‘dimer of dimers’
2 GluN1 subunits
Plus 2 GluN2 (or GluN3)
→ GluN3 subunits are inhibitory to NMDA receptor function (reason unknown)
What mechanisms are in place to mediate NMDA receptor activation?
NMDA receptors are ligand and voltage gated
What ligands are required to bind to NMDA for channel opening?
Glutamate (GluN2) and Glycine or D-serine (GluN1)
All sites must be occupied for channel opening
Why is NMDA voltage gated?
Mg2+ block present at resting membrane potential
What is synaptic plasiticity?
The ability of synapses to modify their strength
Outline how glutamate release activates its receptors
- Release of glutamate
- Glutamate binds to AMPA + NMDA receptors
- Influx of Na+ into the postsynaptic cell
- Removes Mg2+ block allowing Na+ and Ca2+ to enter
the cell - Leads to receptor trafficking→ increased AMPA
increases Na+ influx - Activates CamKII enzyme increasing ionic conductance
of the receptors - => increased Na+/Ca2+ entry
What is receptor trafficking?
New AMPA receptors are made and inserted at the postsynaptic membrane
What is the significance of receptor trafficking?
Receptor trafficking underlies a process called Long Term Potentiation (LTP)
Causes synaptic strengthening (inc. AMPA & ionic conductance)
Important in learning + memory
What are LTPs?
Underlying Long term potentiation (LTP) are increased excitatory postsynaptic potentials (EPPs)
These events can trigger action potentials
What are the 5 subunits of kainate receptors?
Five subunits (plus alternate splice variants) GluR5 (GluK1) GluR6 (GluK2) GluR7 (GluK3) KA1 (GluK4) KA2 (GluK5)
Describe the structure formed by kainate subunits
Tetrameric
GluK1-3 can form homomers or heteromers
GluK4 & 5 are only form heteromers with GluK1-3 subunits
How is kainate binding mediated?
Ligand gated ion channel
Glutamate binding required for channel opening not well understood
How many kainate receptors are in the brain?
Limited distribution in the brain - function less well understood
Describe the structure of metabotropic receptors
GPCRs with extracellular venus fly trap domain for ligand binding
Have 7 transmembrane domains
Intracellular C terminal domain
All coupled to G proteins linked to several signalling pathways
How many metabotropic glutamate receptors are there?
8 subtypes of metabotropic receptors mGlu1-8
What are the 3 groups metabotropic glutamate receptors are categorised into?
Group 1
- (mGlu1 & 5)
- coupled to Gq
- predominantly postsynaptic
Group 2
- (mGlu2 & 3)
- Gi and Go - inhibit AC decreasing cAMP
- presynaptic
Group 3
- (mGlu4,6,7 & 8)
- Gi and Go - inhibit AC decreasing cAMP
- presynaptic
What are the glutamate reuptake receptors?
Excitatory amino acid transporters (EAAT)
Once glutamate is bound to its receptor; some transporters reuptake glutamate - EAAT
What is excitotoxicity?
This is the pathological process by which excessive excitatory stimulation can lead to neuronal damage and death
What is one of the most common cause of excitotoxicity?
Non functional vesicular glutamate receptors (VGLUT) causes spontaneous activation
Explain how nonfunctional VGLUTs cause excitotoxicity
Glutamate can’t enter synaptic vesicles so accumulates in the cytosol
=> inc. [glutamate] in cytosol = EAAT reverse their functions
Normally glutamate moves from a [high] → [low] from the synaptic cleft back into the cell
If there’s high [glutamate] in the cell it will move back into the cleft
=> glutamate binds to its receptors when re entering cleft
=> binds to NMDA and AMPA receptors removing Mg2+
block
=> Ca2+ influx via NMDA receptors
What are the effects of increased Ca2+?
Excessive Ca2+:
Mitochondrial damage
Oxidative stress
Apoptosis
What other disorders has excitotoxicity been associated with?
Excitotoxicity has been linked to:
Stroke
Autism
Alzheimer’s Disease
Explain the role of excitotoxicity in Alzheimer’s disease
In alzheimrs we have glutamate mediated excitotoxicity - excessive glutamate can lead to cell death which causes shrinkage in the Alzheimer’s disease brain
What drug can be given to alleviate some of the excitotoxic effects in alzheimers?
Memantine is a NMDA receptor antagonist - blocking NMDA receptor preventing excessive glutamate release
What makes a neurotransmitter a neurotransmitter?
Synthesised and stored in the pre-synaptic terminal
Released upon stimulation
Mediates a synaptic response
