Chemicals in the brain Flashcards
How are vesicles above the active zone anchored to the cytoskeleton in a synapse?
By the protein synapsin
What role does calcium play in synaptic vesicle release?
Activates calcium calmodulin activated kinase II which phosphorylates synapsin
What is the role of phosphorylated synapsin?
No longer binds to cytoskeleton so vesicles are free to dock to active zone
What does the SNARE complex do in synaptic vesicle transmission?
At active zone the SNARE complex docks vesicles to the plasma membrane.
What are the four stages of priming in exocytosis of neurotransmitter release?
a. vesicle docks
b. SNARE complexes form to pull membranes together
c. entering calcium binds synaptotagmin
d. Ca-synaptotagmin catalyses membrane fusion by binding SNAREs and plasma membrane
What occurs in congenital myasthenic syndrome?
Pre-synaptic terminal disease resulting in impaired vesicle recycling meaning less vesicles partake in NT release
What occurs in Latrotoxin?
Pre-synaptic terminal disease triggers vesicle fusion causing increase in available NT
What occurs in Botulin and Tetanus poisoning?
Pre-synaptic terminal affected. Affects SNARE proteins in vesicle fusion
What occurs to do with the presynaptic terminal in cognitive disorders?
Impaired transynaptic signalling
What occurs in presynaptic terminal disease LEMS?
Attacks presynaptic calcium channels. No increase in calcium so no SNARE complex forms
How does Botox act at the presynaptic terminal?
Acts directly at neuromuscular junction, affecting SNARE proteins so muscle loses all input and is permanently relaxed
How does Tetanus act at the presynaptic terminal?
Inhibits release of GABA and glycine at inhibitory neurons. Leads to disinhibition of cholinergic neurons causing permanent muscle contraction
What is the role of membrane transporters at the presynaptic terminal?
Enable neurotransmitters to enter vesicles as loaded against their concentration gradient
What is the role of vesicular transporters at presynaptic terminal?
Enable NT into vesicle. Powered by a proton gradient. ATPase proton pump loads vesicles with H+. Acidic vesicle compared to neutral cytoplasm facilitates 1 glutamate to be traded for 1 H+.
What is the role of plasma membrane transporters at presynaptic terminal?
Enable NT into presynaptic terminal. Powered by electrochemical gradient. High Na concentration outside and high K+ inside. Glutamate co-transported with 2 Na into plasma membrane of presynaptic terminal
What are the 4 categories of neurotransmitters?
Amino acids
Monoamines
Acetylcholine
Neuropeptides
What are the properties of small sized neurotransmitters? (amino acids, monoamines, acetylcholine)
synthesised locally in presynaptic terminal
stored in synaptic vesicles
released in response to local increase in calcium
what are the properties of neuropeptides? (small proteins)
synthesised in cell soma
transported to terminal
stored in larger secretory granules
released in response to global increase in calcium
what is the excitatory amino acid transmitter and where is it located?
Glutamate: in CNS
what are the inhibitory amino acid transmitters and where are they located?
GABA: brain
Glycine: spinal cord and brainstem
how is Glutamate synthesised?
- glucose via krebs
2. glutamine converted by glutaminase
how is glutamate loaded and stored?
by vesicular glutamate transporters (VGLUTS)
How is glutamate reuptaken
by excitatory amino acid transports located in pre-synaptic membrane and surrounding glia
How is GABA synthesised?
from glutamate in reaction catalysed by glutamic acid decarboxylase
How is GABA loaded and stored?
by vesicular GABA transporter (GAT)
How is GABA reuptaken?
using transporters on glia and neurons including non-gabaergic neurons
What occurs in cerebral ischaemia?
the electrochemical gradient is abolished, resulting in reversal of Na/K gradients. transporters release glutamate by reverse operation leading to excitotoxic cell death
What is the result of GHB- the date rape drug?
It is a GABA metabolite that can be converted back to GABA resulting in increased GABA availability. causes unconsciousness and coma
What are catecholamines and indolamines examples of?
Monoamines
what are the two types of catecholamines?
Dopamine and norepinephrine
How is dopamine formed?
Tyrosine (tyrosine hydroxylase) –> L-dopa (dopa decarboxylase) –> Dopamine
How is epinephrine formed?
Dopamine (dopamine beta-hydroxylase) –> norepinephrine (phentolamine N-methyltransferase) –> epinephrine
How are catecholamines stored and loaded into vesicles?
Loaded against concentration gradient via vesicular monoamine transporters (VMTs)
How are catecholamines reuptaken?
reuptake into own axon terminal by transporters powered by electrochemical gradient: dopamine transporters (DATS) or norepinephrine transporters (NATS)
In the cytoplasm degraded by monoamine oxidases and inactivated by COMTs
What is the mechanism of action of amphetamine?
reverses the transporter that reuptakes dopamine and norepinephrine. blocks its reuptake causing increased availability of neurotransmitter
What is the mechanism of action of cocaine and methylphenidate?
blocks dopamine reuptake into terminals. increases amount in synaptic cleft so signal remains
what is the mechanism of action of selegeline?
MAO inhibitor in dopaminergic nerve terminals. prevents degradation causing increased amount released on subsequent activations. treats early stages of PD
What is the mechanism of action of entacapone
COMT inhibitor. dopamine not broken down. treatment for PD
What type of monoamine is serotonin?
Indolamine
How is serotonin synthesised?
Tryptophan (tryptophan hydroxylase) –> 5-HTP (5-HTP decarboxylase) –> 5-HT
How is serotonin reuptaken?
By serotonin transporters (SERTs) on presynaptic membrane or destroyed by MAOs
What is the mechanism of action of fluoxetine (prozac)?
Blocks serotonin reuptake. Is an SSRI
What is the mechanism of action of fenfluramine?
stimulates serotonin release. inhibits reuptake
What is the mechanism of MDMA?
NE + serotonin transporters run backwards, releasing NT into synapse
How is acetylcholine synthesised?
Choline + acetyl CoA (choline acetyltransferase) –> acetylcholine
What is the mechanism of action of neostigmine?
Acetylcholinesterase inhibitor: blocks breakdown of Ach to prolong its action. used to treat myasthenia gravis
How is acetylcholine packaged into vesicles?
by vesicular Ach transporters (VAChT)
How is ACh degraded in the synaptic cleft?
by acetylcholinesterase
How are neuropeptides released?
by dense core vesicle fusion and exocytosis. in response to global increase in calcium. binds to and activates a receptor
how are neuropeptides degraded?
signal terminated by diffusion from site of release and degradation by proteases
How does NO work via retrograde signalling?
NO is made in postsynaptic neuron by NO synthase. Not stored so diffuses retrograde to presynaptic. activates guanyl cyclase–? cGMP. Switched off naturally by conversion to inactive form
