T1 L6 Chemicals in the brain Flashcards
How is the pool of vesicles above the active zone anchored to the cytoskeleton?
By synapsin
What activates calcium calmodulin activated kinase II?
Calcium ions
What does calcium calmodulin activated kinase II do?
Phosphorylates synapsin
P-synapsin can no longer bind to the cytoskeleton so vesicles dock to the active zone
What does the SNARE complex do?
It docks vesicles to the plasma membrane at the active zone
Describe the 4 steps of exocytosis during neurotransmitter release
1) Vesicle docks
2) SNARE complexe form to pull membranes together
3) Entering calcium binds to synaptotagmin
4) Calcium-bound synaptotagmin catalyses membrane fusion by binding to SNAREs and the plasma membrane
What does the botulinum toxin do?
Decreases neuromuscular transmission of acetylcholine
Where does botox come from?
Clostridium botulinum
Where do tetanus toxins come from?
Clostridium Tetani
What does botox do?
Acts directly at neuromuscular junction
Muscles lose all input so become permanently relaxed
What does the tetanus toxin do?
Inhibits the release of Glycine and GABA at inhibitory neurons
Results in dis-inhibition of cholinergic neutrons
Causes permanent muscle contraction
What diseases affect the presynaptic terminal?
Congenital myasthenic syndromes LEMS Cognitive disorders Botulinum & tetanus toxins Latrotoxin
How does LEMS affect the presynaptic terminal?
Attacks presynaptic calcium channels
How does congenital myasthenic syndrome affect the presynaptic terminal?
Results in impaired vesicle recycling
How does latrotoxin affect the presynaptic terminal?
Triggers vesicle fusion
How do cognitive disorders affect the presynaptic terminal?
They impair transsynaptic signalling
How are vesicular transporters powered by proton gradients?
ATPase proton pump loads up vesicles with H+
Makes vesicles acidic
How are plasma membrane transporters powered by electrochemical gradients?
Na concentration is higher outside & K is higher inside
Glutamate is cotransported with 2 Na+
What are astrocytes?
A type of glial cell with extensions that wrap around the gaps or synapses between neurons
What are the categories of neurotransmitters?
Amino acids
Monoamines
Acetylcholine
Neuropeptides
Where are neuropeptides synthesised?
In the cell soma & transported to the terminal
Where are neuropeptides stored?
In secretory granules
What stimulates a release of neuropeptides?
A global increase in calcium ions
Where are amino acids, monoamines & acetylcholine synthesised & stored?
Synthesised locally in presynaptic terminal
Stored in synaptic vesicles
What stimulates a release of amino acids, monoamines or acetylcholine?
A local increase in calcium ions
Give an example of a fast neurotransmitter
Amino acids
Give an example of a slow neurotransmitter
Neuropeptides
What is a fast neurotransmitter?
Stored in synaptic vesicles docked close to a voltage-gated calcium channels in membrane of nerve terminal
Released in short burst when membrane is depolarised
What is a slow neurotransmitter?
Stored in separate vesicles further from the membrane
Release is slower as they have to migrate first to the membrane & only occurs when calcium builds up sufficiently
Give an example of an excitatory amino acid transmitter?
Glutamate in the CNS
Slightly depolarises postsynaptic cell’s membrane
Give an example of an inhibitory amino acid transmitter?
GABA in the brain
Glycine in the spinal cord & brainstem
Slightly hyperpolarises postsynaptic cell’s membrane
Give an example of a modulatory system
Serotonergic system
What is modulation?
Affects large neural networks, cortex, spinal cord, cerebellum
Changes how likely these areas are to be excited
What are some functions of the serotonergic system?
Mood Sleep Pain Emotion Appetite
What are the 2 ways glutamate is synthesised?
From glucose via the Krebs cycle
From glutamine converted by glutamine into glutamate
What do vesicular glutamate transporters do?
Load & store glutamate into vesicles
How is glutamate taken back up?
By excitatory amino acid transporters in the plasma membrane of presynaptic cell & surrounding glia
How is glutamate converted to glutamine?
By glial cells
Glutamine then transported from the glia back to nerve terminals where it is converted back into glutamate
How is GABA synthesised?
From glutamate in a reaction catalysed by glutamic acid decarboxylase
What do vesicular GABA transporters do?
Load & store GABA into vesicles
Gly also uses this transporter
How is GABA cleared from the synapse?
By reuptake using transporters on glia & neutrons including non-GABAergic neurons
What happens if there is too much Glu or too little GABA?
Hyper excitability
Epilepsy
Excitotoxicity
What happens if there is too much GABA?
Sedation / coma
What happens in cerebral ischaemia?
Metabolic events that retain electrical gradient are abolished
Reversal of Na/K gradient
Transporters release glutamate from cells by reverse operation
Excitotoxic cell death
What happens with GHB (date-rape drug)?
GABA metabolite that is converted back to GABA
Increases amount of available GABA
Too much leads to unconsciousness & coma
What are the 2 types of monoamines?
Catecholamines
Indolamines
Give some examples of catecholamines
Dopamine
Epinephrine
Norepinephrine
Give an example of an indolamine
Serotonin
Describe the path of dopamine synthesis
Tyrosine –> dopa –> dopamine –> NE –> epinephrine
What do vesicular monoamine transporters do?
Load catecholamines into vesicles for storages
What does L-DOPA (Levodopa) do?
Precursor of dopamine
Used to treat Parkinson’s disease
Dopa decarboxylase converts it into dopamine increasing the pool of releasable transmitter
How is catecholamine released?
By calcium dependent exocytosis
What happens once catecholamine is released?
It binds and activates the receptor
How is the signal for catecholamine release terminated?
By reuptake into the axon terminal by transporters powered by the electrochemical gradient.
Dopamine transporters, norepinephrine transporters
What happens to catecholamines in the cytoplasm?
They are reloaded back into vesicles
Enzymatically degraded by monoamine oxidases (MAOs)
Inactivated by catechol-O-methyl-transferase (COMT)
What effect does amphetamine have on catecholamine?
Reverse transporter so pumps out transmitter & blocks uptake (DA & NE)
What effect does cocaine & methylphenidate have on catecholamine?
(Ritalin) block DA reuptake into terminals
More DA in synaptic cleft - extended action on postsynaptic neuron
What effect does selegiline have on catecholamine?
MAO inhibitor found in dopaminergic nerve terminals
Prevents degradation of DA allowing more to be released on subsequent activations
Used to treat early-stage PD, depression & dementia
What effect does entacopone have on catecholamine?
COMT inhibitor
Treatment of PD
How is serotonin synthesised?
Tryptophan –> 5-hydroxytryptophan –> serotonin
Describe serotonin storage, release & reuptake
Stored in vesicles
Signal terminated by reuptake by serotonin transporters on presynaptic membrane
Destroyed by MAOs in the cytoplasm
What drugs module the release and reuptake of serotonin?
Fluoxetine
Fenfluramine
MDMA
How does fluoxetine (prozac) affect serotonin?
Blocks reuptake of serotonin
SSRI - selective serotonin reuptake inhibitor
Treatment of depression & OCD
How does fenfluramine affect serotonin?
Stimulates the release of serotonin & inhibits its reuptake
Has been used as an appetite suppressant in the treatment of obesity
How does MDMA affect serotonin?
(Ecstasy) causes NE & serotonin transporters to run backwards released neurotransmitter into synapse / extracellular space
Describe the synthesis of acetylcholine
Choline acetyltransferase converts choline & acetyl CoA into acetylcholine
What is the function of vesicular acetylcholine transporter?
Packages acetylcholine into vesicles
What does acetylcholinesterase do?
Rapidly degrades acetylcholine in the synaptic cleft.
Choline is then transported back into the presynaptic terminal & converted to acetylcholine
Describe the synthesis & secretion of acetylcholinesterase
Made by cholinergic neuron
Secreted into synaptic cleft & associated with axonal membrane
What do acetylcholinesterase inhibitors do?
Block the breakdown of acetylcholine which prolongs its actions in the synaptic cleft
Give an example of an acetylcholinesterase inhibitor
Neostigmine
Describe the properties of neuropeptides
Slow transmission
Vary in their methods of synthesis & release from small molecule transmitters
Short polypeptide chains 3-36 amino acids
Over 100 neuropeptides described
Describe the process of neuropeptide release & degradation
Follow secretory pathway
Not released in same way as small molecule transmitters
1) Dense core vesicle fusion & exocytosis occurs due to global elevations of Ca2+
2) Neuropeptide vesicle membrane is recycled but not refilled
3) Bind to & activate receptor
4) Neuropeptide signalling is terminated by diffusion from site of release & degradation. by proteases in extracellular environment
5) Release is slower than small molecule release & signals may be maintained for longer
Describe what happens to nitric oxide
1) Nitric oxide is made in postsynaptic neuron by nitric oxide synthase
2) Gas rapidly diffuses from its site of synthesis
3) Activates guanylyl cyclase which makes cGMP
4) Within a few sec of being produced, NO is converted to biologically inactive compound
5) Potentially useful for coordinating activities of multiple cells in a small region
How is nitric oxide synthase activated?
By the binding of Ca2+ & calmodulin
What are endocannabinoids?
Small lipids which mostly cause reduced GABA release at certain inhibitory terminals
