Excitable cells 10: Neurotransmitters n malarky Flashcards
5 general stages of chemical synaptic transmission?
1) Neurotransmitter synthesis
2) Neurotransmitter storage into synaptic vesicles
3) Synaptic vesicle cycling, exocytosis, and transmitter release
4) Transmitter binds to receptor whose identity determines post-synaptic response
5) Removal of neurotransmitter from synaptic cleft
Describe the process of synaptic vesicle cycling and exocytosis
- Budding of early endosome to create vesicle
- Neurotransmitter uptake in vesicle and direct recycling
- > Translocation
- > Vesicles enter reserve pool
- Vesicles in reserve pool undergo docking and priming to enter the readily releasable pool
- Primed vesicles induced to fuse with plasma membrane by sustained depolarisation -> causing elevated cytoplasmic Ca2+
- > exocytosis
What is vesicular fusion mediated by? What is the mechanism?
Mediated by SNARE complex
- between vesicle and plasma membrane
Synaptotagmin within SNARE complex is a calcium sensor -> regulates SNARE zipping
- Calcium influx from VOCCs -> bound by synaptotagmin
- > conformational change bringing vesicle and plasma membrane in close proximity
- > fusion is induced
What toxins inhibit vesicle fusion and transmitter release?
Botulinum toxins -> disrupt proteins in SNARE complex
What is meant by ‘quantum’ in the context of transmitter release?
Synaptic vesicles: elementary units of synaptic transmission (quantum)
-> post-synaptic electrical signal amplitude is proportional to the amount of neurotransmitter released (quanta)
Each vesicle contains approx. 10,000 ACh molecules
2 major types of synaptic receptors?
- examples of receptors which produce excitatory and inhibitory responses
Ionotropic -> Ion channels
- e.g. Nicotinic Acetylcholine, NMDA (glutamate) ,
- > result in EPSPs (Excitatory post-synaptic potentials)
- e.g. GABAa
- > result in IPSPs (Inhibitory post-synaptic potentials)
Metabotropic -> GPCRs
- e.g. Muscarinic Acetylcholine, adrenoceptors, GABAb, metabotropic glutamate, opioid
What makes a response excitatory or inhibitory in a post-synaptic cell
EPSPs and IPSPs
Excitatory -> Depolarisation, Inward current (Ca2+, Na+)
-> Increasing fire rate
Inhibitory -> Hyperpolarisation, Inward Cl-
-> decreasing fire rate
Hierarchy of neurotransmitters? examples of each tier?
Mediators and Modulators
1) Amino-acid transmitters
- mediate transmission via ionotropic receptors
- Glutamate (excite), GABA (inhib)
2) Catecholamine (NA, DA) and peptide (enkephalin)
- modulate transmission via metabotrophic receptors
- alter probability of release of Glutamate, ACh, GABA etc. from pre-synaptic axon terminals
3) Acetylcholine
- mediates via Ionotropic (Nicotinic)
- modulates via Metabotropic (muscarinic)
How do metabotropic receptors (GPCRs) modulate release of mediating transmitters?
Different to usual GPCR pathway
To fascillate release: (Gs-coupled e.g. NA at Beta-adrenoceptors)
- Gs -> AC -> cAMP -> binds directly to and opens HCN-channel -> cation-influx -> depolarisation
- > more NT release
To diminish release: (Gi-coupled e.g. NA at Alpha2-adrenoceptors)
- Gi(beta-gamma) -> opens K+ channels -> K+ efflux - Hyperpolarisation
- inhibits VOCC -> diminished Ca2+ influx
- > less NT release
3 Major methods of terminating NT signal in synaptic cleft
- examples of NT regulated by each method
Re-uptake
- GABA, Glutamate, Glycine, Catecholamines
Enzyme
- ACh via ACh-esterase
Diffusion
- GABA, Glutamate
5 Locations in synapse transmission for drug targets and examples of drugs
1) Precursors of NT synthesis (DOPA) + inhibitors of precursor degredation (MAO-I)
2) Inhibitors of synaptic vesicle uptake (reserpine)
3) Inhibitors of vesicular release (botox)
4) Receptor ligands, pre and post synaptic (agonists, antagonists, allosteric modulators)
5) Inhibitors of NT removal from synaptic cleft
- uptake (SSRIs)
- ACh-esterase (pyridostigmine)
Why is pressure painful when focused, but not when broadly spread?
C fibres synapse with 2nd-order projection neuron
-> spinothalamic tract -> pain
Abeta fibres enter dorsal horn
-> dorsal column, but also make dorsal horn synapses with both projection AND inhibitory neurone
If C and Abeta fibres of one dermatome are activated simultaneously, then Abeta activation of inter-neurone can inhibit projection neurone of spinithalamic tract
Presence of inhibitory interneurone prevents light touch from causing pain
WHat is mechanical allodynia and why/how does it occur?
Pain stimulated by light touch (usually on injured tissue)
Caused by unsilencing of dorsal horn circuits
- tissue injury increases Cl- conc. in projection neuron (PN) (decreased expression of K+/Cl- co-transporter
- Now previously inhibitory synapses from Abeta-fibre via interneuron causes Cl- efflux from PN
- > results in DEpolarisation
- > activation of pain pathway
Overview of mechanism of pain control? Regulated how? Opioids?
GABAergic neurons from the brain are excited, which then go onto to induce an inhibitory response in the projection neuron
(Inhibit responses from Adelta / C fibres)
- regulated by inhibitory interneuron -> inhibits pain inhibition (you feel pain more)
- opioid receptors on the interneuron coupled with Gi inhibit regulatory inhibitory interneuron -> feel pain less
