Synaptic Transmission, Neurotransmitters and receptors Flashcards
What are the main differences between electrical and chemical synapses
- Fewer, bidirectional, faster, narrower, less tightly regulated, enable synchronous firing of networks, electron dense on both membranes of the pre and post synaptic sides
- Gap junctions made up of connexons are key features of electrical synapses
- Current tends to dissipate across the membrane – broader peak and also lower magnitude (not good for long distance)
- Involved in the invertebrate escape response circuits e.g. crayfish
- Respiratory centre neurones - Brainstem
- Hypothalamic endocrine neurons
- Chemical synapses – use chemicals (neurotransmitters) to stimulate post-synaptic electrical flow (regulated)
- Pre-synaptic bouton has the neurotransmitter vesicles
- Post-synaptic bouton has the electron dense areas
- Influx of Ca2+ in response to the AP to cause the fusion and release of neurotransmitter vesicles into the synaptic cleft – if Ca2+ channels blocked no transmission occurs
- Membrane needs to be recycled – clathrin coating allows membrane recycling into endosomes
- Neurotransmitter also need to be recycled – normally transporters for the neurotransmitter on glial, post-synaptic and pre-synaptic membrane to reabsorb the NT out of the synaptic cleft
- Defined quantities of NT being released – experiment involving electrophysiology of muscle contraction found spontaneous activity (small peaks) of the synapses. Showed quantal release of NT as different size responses
What is the criteria for a NT?
- Must be present within the presynaptic neuron
- Must be released in response to depolarisation of the presynaptic neuron & release must be Ca2+-dependent
- Specific receptors must be present on postsynaptic cell
What are the different classes of NTs?
• Small molecules:
o Amino acids, ATP, Ach, purines, biogenic amines (dopamines, serotonin) – general facilitate short term effects
• Peptide NTs:
o Substance P, vasopressin, CRH, opioids – tend to facilitate longer term effects
o Can co-exist in the same neuron, but tend to be in different vesicles
How are small molecule NTs synthesised normally?
• Small molecules tend to be synthesised in the terminal. The enzymes to synthesise them tend to be synthesised in the body and transported to the terminal via slow axonal transport – 0.5-5 mm/day
How are peptide NTs synthesised normally?
• Peptide neurotransmitter tend to be synthesised in the cell body and then transported to terminal via fast axonal transport – 400mm/day (often a precursor that is then cleaved)
What do small clear vesicles tend to contain? WHat about dense-core vesicles?
What is significant about a neurons which has both?
- Small clear vesicles – (small molecule NT) Glu, GABA, Gly, Ach, ATP etc.
- Dense-core vesicles – (peptide, biogenic amines) serotonin, histamine, neuropeptides, catecholamines
• When both are present in the same neurons they tend to have different Ca2+-sensitivity - stimulus specificity, to allow NT release specificity
what are there proteins specifically for regarding a synaptic vesicle’s lifetime?
o Transmitter loading, mobilization, docking, priming, fusion, coating, budding, uncoating
What proteins does exocytosis involve?
• Exocytosis involves v- and t- SNARE complexes and Ca2+ binding proteins. They are localised to near Ca2+ channels (v gated) as have calcium dependent protein-protein interactions. Chaperones involved in the making and breaking of complexes
Which proteins do botulinium toxins target?
• Botulinum toxins target the SNARE proteins – mainly peripheral and visceral neuromuscular synapses – weakness
Which proteins do the tetanus toxins target?
• Tetanus toxins target the Snare proteins too – mainly inhibitory spinal interneurons – tetanic contractions
What is clathrin and what is it involved in?
- Clathrin - Triskelion shape
- Enables pinching off of the vesicles during endocytosis
- Slow 10-20s
- They are slow so found that there are other mechanisms for synaptic vesicle recycling – ultrafast endocytosis (very fast <0.1s)
Why do NT need to be removed?
• Need to be removed otherwise can cause excitotoxicity
What are some specific inactivating proteins?
• Specific inactivating enzymes
- acetylcholinesterase (AChE)
- monoamine oxidase (MAO) & catechol-O-methyltransferase (COMT)
What is the involvement of astrocytes in removal of NT?
e.g. glutamate recycling, EAT1 and EAT2 (excitatory amino acid transporter) on astrocytes which uptake glutamate, the cell then converts to glutamine, glutamine transported ot the original neuron, to be turned into glutamate and reused
What strategies can be used pharmacologically to up regulate a neurotransmission?
- Supplement transmitter or a precursor – L-DOPA for parkinsosn
- Inhibit clearance by trnaportes e.g. SSRIs for depression
- Inhibit enzymatic breakdown of neurotransmitter e.g. ACHE inhibitors for the dementia
What strategies can be used pharmacologically to down regulate neurotransmission?
- Presynaptic – problem here is conserved nature of machinery so difficult to target to a specific site e.g. local application of botox
- Postynaptic – block specific receptors e.g. antipsychotics target D2 dopamine receptors (cause many side affects though)
What are receptors for glutamate and aspartate?
NMDA
What charge do glutamate and aspartate (excitatory) have?
-2 at physiological ph
What charge does GABA and Glycine (inhibitory) have?
-1 at physiological ph
What is the difference between GABAaR and GABAbR
a - ionotropic, Cl- influx through ion pore
b- metabotropic, K+ channel efflux via 2nd messengers
What are agonists of GABAaR often used for? Give some examples.
sedatives anxiolytics, anti-consvulsants, anaestetics
E.g.• Barbiturates (e.g. pentobarbital) strongly activate – euthanasia
• Benzodiazepines (e.g. diazepam) enhance activity
What are some examples of GABAaR inhibitors and what are they used for?
• Inhibitors (e.g. picrotoxin, PTZ) used experimentally as convulsants – animal models of epilepsy, not really clinically used
Flumazenil - for benzodiazepam OD
