Chemicals in the brain Flashcards
What are the first five steps of a typical chemical synapse transmission
1) Transmitter is synthesized and then stored in vesicles
2) An action potential invades the presynaptic terminal
3) Depolarization of presynaptic terminal causes opening of voltage-gated Ca2+ channels
4) Influx of Ca2+ through channels
5) Ca2+ causes vesicles to fuse with presynaptic membrane
What are the next six steps of a typical chemical synapse transmission
6) Transmitter is released into synaptic cleft via exocytosis
7) Transmitter binds to receptor molecules in postsynaptic membrane
8) Opening or closing of postsynaptic channels
9) Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postynaptic cell
10) Removal of neurotransmitter by glial uptake or enzymatic degradation
11) Retrieval of vesicular membrane plasma membrane
What anchors pools of vesicles to the cytoskeleton above the active zone
- Synapsin(a protein)
What does the influx of Ca2+ into the presynaptic terminal cause
- Ca2+ activates calcium calmodulin activated kinase II(CaMKII) which phosphorylates synapsin
- P-synapsin can no longer bind to the cytoskeleton, vesicles dock to the active zone
Purpose of the SNARE complex
- SNARE complex at active zone docks vesicles to the plasma membrane
What is NSF
- N-ethylmaledimide-sensitive factor, an ATPase(enyme) involved in membrane fusion
- Involved in priming
What are v-SNAREs and t-SNAREs and what are their purposes
v-SNARE - vesicle SNARE
t-SNARE - target SNARE
- combo of v and t snares to allow for priming and docking
What is SNAP
- Soluble NSF attachment protein receptor
What are the vesicle-associate membrane proteins involved in exocytosis
- Synaptobrevin
- Synaptotagmin
What are the plasma membrane proteins associated proteins involved in exocytosis
- Syntaxin
- SNAP-25(synaptosome-associated protein of 25kDa)
What is the process of synaptic vesicle release involving plasma membrane proteins
1) Vesicle docks
2) SNARE complexes form to pull membranes together
3) Entering Ca2+ binds to synaptogamin
4) Ca2+ bound synaptogamin catalyses membrane fusion by binding to SNAREs and the plasma membrane
How does synaptic vesicle recycling occur?
- Vesicle membrane is rapidly recovered via endocytosis, new vesicles bud off and are refilled with neurotransmitter
What is priming
- Docked vesicles are not ready for fusion, and need to be primed before they are able to respond rapidly to Ca2+ concentration increases
- Priming is thought to involve partial assembly of SNARE complexes
Examples of cleavage of SNARE proteins by clostridial toxins
- Botulinum toxin(BoTX) decreases neuromuscular transmission Ach
- Tetanus toxin(TeTX) decreases interneurons at spinal cord, GABA, Gly
Where does botox act
- Botox acts directly at the neuromuscular junction, the muscles lose all input and so become permanently relaxed(treatment of muscle spasms)
How does the tetanus toxin cause dis-inhibition of cholinergic neurons
- Inhibits the release of glycine and GABA at inhibitory neurons, resulting in dis-inhibition(lack of restraint) of cholinergic neurons, which causes permanent contracting
What is LEMS
- Lambert-Eaton myasthenic syndrome is a rare autoimmune disorder characterized by muscle weakness of the limbs
How does LEMS occur
- It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels, and likely other nerve terminal proteins
What do congenital myasthenic syndromes cause
- Result in impaired vesicle recycling
- Muscle weakness
What are vesicular transporters powered by
- Powered by proton gradient
- ATPase proton pump loads up vesicles with h+ making vesicles acidic(pH 5.5) compared to neutral pH of cytoplasm of 7.2
- The H+ ions in the vesicles are exchanged for with neurotransmitters(eg 1 glutamate/gaba traded for 1H+ counter-transport mechanism)
What is the reaction carried out by ATPase
- ATP + H2O + H+ in –> ADP + Phosphate + H+ out(reversible reaction)
What are plasma membrane transporters powered by
- Electrochemical gradient
- [Na+] higher outside/[K+] higher inside
- Glutamate co-transported with 2 Na+
- Many psychoactive drugs, such as amphetamines and cocaine, block certain transporters
What are the categories of neurotransmitters
- Amino acids, monoamines and acetylcholine
- Neuropeptides(larger)
Synthesis, storage and release of amino acids, monoamines and acetylcholine
- Synthesized locally in presynaptic terminal
- Stored in synaptic vesicles
- Released in response to local increase in Ca2+
What are neuropeptides
- Synthesized in the cell soma and transported to the terminal
- Stored in secretory granules
- Released in response to global increase in Ca2+
Time course and frequency of fast transmitters
- Fast transmitters(eg Glu) are stored in synaptic vesicles that are docked close to voltage-gated calcium channels in the membrane of the nerve terminal
- are released in a short burst when the membrane is depolarised
Time course and frequency of slow transmitters
- Are stored in separate vesicles further from the membrane
- Release is slower, because they must migrate to the membrane, and occurs only when [Ca2+] builds up sufficiently
- Slow transmitters respond to an accumulation of impulses over time
How do fast amino acid transmitters work
Excitatory - Slightly depolarises the postsynaptic cell’s membrane - glutamate(CNS)
Inhibitory - Slightly hyperpolarises the postynspatic cell’s membrane(GABA - brain)
- GABA is only specific to the brain
What is the function of diffuse modulatory systems
- Mood
- Sleep
- Pain
- Emotion
- Appetite
What is a core in a diffuse modulatory system
Core - small set of neurons, most arise from brain stem
1 can affect more than 100,000
- Modulation changes how likely areas of the brain are able to respond to neurotransmitters
What are the two potential sources of glutamate
Synthesized in presynaptic terminal from
1) From glucose via the krebs cycle
2) From glutamine converted by glutaminase into glutamate
What is glutamate loaded and stored into vesicles by
- Loaded and stored into vesicles by vesicular glutamate transporters(VGLUTs)
What is reuptake of glutamate carried out by?
- Reuptake by excitatory amino acid transporters(EAATs) in the plasma membrane of presynaptic cell and surrounding glia
- Glial cells convert glu to glutamine and this transported from the glia back to nerve terminals where it is converted back into glutamate
How is GABA synthesised and stored
- Synthesized from glutamate in a reaction catalysed by glutamic acid decarboxylase(GAD)
- Loaded and stored into vesicles by a vesicular GABA transporter, GAT(gly uses same transporter)
How is GABA transmission terminated
- Cleared from synapse by reuptake using transporters on glia and neurons including non-GABAergic neurons
What neurotransmitter is made de novo rather than recycled
- Higher proportion of GABA is made de novo to refill vesicles rather than recycling
What does too much glu/too little GABA cause
- hyper-excitability, epilepsy and excitotoxicity
What does too much GABA cause
- Sedation/coma
Metabolic effects of cerebral ischaemia
- The metabolic events that retain the electrochemical gradient are abolished
- Reversal of the Na+/K+ gradient
- Transporters release glutamate from cells by reverse operation
- Excitotoxic cell death(Ca2+ –> enzymes –> digestion)
What is GHB(gamma-hydroxybutyrate) - date rape drug
- A GABA metabolite that can be converted back to GABA
- Increases amount of available GABA
- Too much leads to unconsciousness and coma
