HNS07 Chemical Neurotransmission II Flashcards
***Criteria that define a Neurotransmitter
- Must be ***present in presynaptic terminal, but presence alone is not sufficient —> biosynthetic enzyme and precursors are additional evidence
- Must be ***released into synapse upon arrival of action potential at terminal
- Presence in synapse is ***prolonged if NT-degrading enzyme / NT-reuptake transporters are inactivated
- NT must ***activate receptors on postsynaptic membrane upon binding
- ***Exogenous NT can mimic the effect; postsynaptic responses to receptor agonists + antagonists; nowadays high resolution detection of postsynaptic receptors available
Properties of some major NT
Small molecules
Class I:
- ACh
- excitatory
- Choline + Acetyl CoA
Class II: Amines 1. Catecholamines (ALL from ***Tyrosine) —> Epinephrine: excitatory —> Norepinephrine: excitatory —> Dopamine: excitatory + inhibitory
- Serotonin (5-hydroxytryptamine / 5HT)
- most inhibitory
- from ***Typtophan - Histamine
- excitatory
- from Histidine
Class III: Amino acid
- Glutamate:
- excitatory
- from Glutamine - GABA:
- inhibitory
- from ***Glutamate - Glycine:
- inhibitory
- from Serine
Others:
- ATP
- excitatory
- from ADP
Large molecules
- Neuropeptides (Substance P, Endorphins)
- excitatory / inhibitory
- from amino acids
Synthesis, packaging, secretion, and removal of NT
Small molecules NT vs Peptide molecules NT
Small molecules NT:
1. Enzymes required for NT synthesis formed in cell body (through transcription, translation)
—> nucleus —> rER —> Golgi —> microtubules —> terminal
2. ***Slow axonal transport of enzymes (0.5-5mm/day —> slow)
3. Synthesis and packaging of NT occur in terminal (enzymes convert precursor into NT)
4. NT re-used by transporting precursor back into terminal
Peptide molecules NT:
- Synthesis of NT precursor and enzymes in cell body
- Transport of enzymes and pre-peptide precursors down microtubule tracks (up to 400mm/day —> fast)
- Enzymes modify pre-peptide precursor —> peptide NT
- NT diffuses away and degraded by proteolytic enzymes (no recovery / reuse since have to taken up by cell body again)
Postsynaptic NT receptors
Protein subunits:
- 4 transmembrane helices (N + C terminal outside of cell)
- 3 transmembrane helices + pore loop (N terminal outside, C terminal inside)
—> Assembled subunits (with NT binding site/receptors + ion channel enclosed)
Types of NT receptors:
- AMPA
- NMDA
- Kainate
- GABA
- Glycine
- nACh
- Serotonin
- Purines (for ATP)
ACh and nACh receptor
nACh receptor: multimeric structure
Synthesis of ACh: Choline acetyltransferase (transported to axonal terminal from cell body): Choline + Acetyl CoA
Opening of channel:
ACh receptor-mediated channel normally closed
—> ACh binds at specific site on receptor
—> non-selective cation channel opens
—> Na enter postsynaptic cell (extracellular Na higher)
—> AChE breaks down ACh (choline + acetyl CoA)
—> causing channel to close again
Events:
- Action potential drives at axon terminal
- Na channel opens —> depolarisation —> voltage-gated Ca channels to open
- Ca enter cell —> fusion of ACh vesicles with presynaptic membrane
- ACh molecules diffuse across synaptic cleft —> bind to receptors on postsynaptic membrane
- Activated receptor open chemically gated cation channels —> depolarises postsynaptic membrane
- Spreading depolarisation —> over threshold —> trigger an action potential in postsynaptic membrane
- ACh broken down by AChE —> ***choline taken up by presynaptic cell + vesicles recycled
Other ligands at nACh receptor
Agonists:
- Nicotine
- Arecoline (seeds from betel nut, alkaloid agonist —> produce euphoria)
Antagonists (block neuromuscular transmission —> paralysis):
- ***α-bungarotoxin (snake)
- ***α-neurotoxin (cobra)
- Erabutoxin (sea snake)
- Curare (plant toxin)
Glutamate and ionotropic (allow ion influx) glutamate receptor
2 types of ionotropic glutamate receptor:
- AMPA receptor
- allow rapid influx of Na —> depolarisation of postsynaptic cell —> removal of Mg from NMDA receptor - NMDA receptor (higher affinity for glutamate)
- Mg blocks NMDA receptor channel at ambient concentration
- depolarisation causes Mg to be removed —> allow Na + Ca to enter
- Ca act as a second messenger —> trigger long-term cellular effects e.g. further insertion of AMPA receptor into postsynaptic membrane —> enhancing synaptic strength
Excitatory postsynaptic current (EPSC)
- AMPA component first —> then NMDA component
- can use respective blocker to find out the respective component (e.g. NBQX block AMPA —> EPSC only contributed by NMDA component)
- NMDA blocked by D-AP5
Repeated stimulation can change properties of synapse
High frequency stimulation of neuron
—> sensitivity to stimulation ↑
—> ↑ sensitivity persists even when low-level stimulation resumes
Conclusion:
High frequency stimulation of axons can cause long-lasting ↑ in sensitivity of postsynaptic neuron to that stimulation
—> ***due to ↑ presynpatic release of NT + ↑ postsynaptic insertion of receptors
Glutamate-glutamine cycle between neurons and astrocytes
Glutamate —>
- Reuptaked by **EAAT (sodium-dependent excitatory a.a. transporter) in presynpatic membrane
—> repackaged into vesicles by **VGLUT (vesicular glutamate transporter)
OR
—> feed into TCA cycle (via α-ketoglutarate) - Taken up by **peri-synaptic Astrocytes via **EAAT
—> **Glutamine synthetase: Glutamate —> Glutamine
—> glutamine transported out of astrocyte via **SNAT (sodium-coupled neutral amino acid transporter)
—> taken up by presynaptic neuron via **SNAT
—> **Glutaminase (cleaves off amine group): Glutamine —> Glutamate —> repackaged into vesicles by ***VGLUT (vesicular glutamate transporter)
Glutamate and metabotropic glutamate receptor (mGluRs)
G-protein coupled receptor:
- NT bind to receptor
- Receptor activates G protein —> GTP replace GDP on α-subunit
- α-subunit activates ion channel directly / indirectly through second messenger
- Ion (Na/Ca) flow through
***mGluRs contribute to plasticity of NMDARs at mature synapses
Low frequency stimulation:
mGluR triggered
—> cytoplasmic components mediate enhancement of Ca entry via NMDA receptor
—> also trigger release of Ca from internal store via RyR
—> low level of Ca (since low frequency simulation)
—> ***Removal / Internalisation of NMDA receptors into neuron
—> decrease in sensitivity to glutamate
—> Long Term Depression of NMDA (LTD)
High frequency stimulation:
more Ca entry
—> cytoplasmic components mediate enhancement of Ca entry via NMDA receptor
—> also trigger release of Ca from internal store via RyR
—> high level of Ca (since high frequency simulation)
—> increase in ***insertion of NMDA to surface
—> mediate high sensitivity response to stimulation
—> Long Term Potentiation (LTP)
Ionotropic receptor vs Metabotropic receptor
Type:
Ligand-gated ion channels vs G-protein coupled receptor (NOT a channel itself)
Response:
Channel allows **ion flux to change cell voltage (depolarisation to promote / hyperpolarisation to inhibit) vs Receptor act through **2nd messenger to cause cellular effect (contribute to plasticity of NMDARs: LTD / LTP)
Speed of response:
Rapid vs Slow
Length of response:
Short-acting vs Prolonged response
GABA (Gamma aminobutyric acid) and GABA receptor
GABA receptor: Pentameric structure, Anion channel
GABAa receptor: 2α, 2β, 1γ subunits
GABAc receptor: 5p subunits
GABA bind to a site in-between α and β subunit
—> allow **Cl to enter (higher extracellular conc)
—> **hyperpolarisation of postsynaptic terminal
—> more difficult to elicit action potential in postsynaptic cell
Clinical relevance to GABA channel
Picrotoxin: block GABA channel
**Barbiturate, **Benzodiazepine: GABA agonists
Spatial summation vs Temporal summation
Spatial summation:
Several excitatory postsynaptic potentials (EPSPs) arrive at axonal hillock simultaneously
Temporal summation:
Postsynaptic potentials created at the SAME synapse in rapid succession can be summed
Both summation can cause potential to exceed threshold —> action potential
