Chemicals in the Brain Flashcards

(55 cards)

1
Q

what types of chemical synapses are there?

A

axodendritic - axon connects to dendrite
axosomatic - axon connects to soma
axoaxonic - axon connects to another axon

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2
Q

what is the structure of the presynaptic terminal?

A
synaptic button 
synaptic cleft 
cytoskeleton
mitochondria
synaptic vesicles 
active zone
secretory granules
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3
Q

what occurs during synaptic transmission?

A

action potential reaches synaptic terminal
neurotrnsmitted molecules are released from presynaptic neuron
neurotransmitter diffuses across the synaptic cleft
neurotransmitter reaches postsynaptic membrane
receptors initiate a response

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4
Q

what responses can receptors initiate?

A

direct excitatory/inhibitory neurotransmission - membrane of cell is slightly depolarised or hyperpolarised
neuromodulation - alters presynaptic cell’s ability to release more transmitter of postsynaptic cell’s ability to respond

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5
Q

criteria to define a neurotransmitter

A

synthesised in the neuron
present in presynaptic terminal, released in sufficient amount to exert a defined effect in postsynaptic neuron/effector organ
when administered exogenously, mimics action of endogenous transmitter
specific mechanism exists for its removal from the synaptic cleft

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6
Q

how how synaptic vesicles released?

A

pool of vesicles above the active zone is anchored to cytoskeleton by synapsin
action potential arriving at terminal causes voltage gated Ca2+ channels to open
Ca2+ flows into cytoplasm
Ca2+ activates CaMKII , phosphorylating synapsin
P-synapsin can no longer bind to skeleton, so vesicles dock to active zone (SNARE complex)

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7
Q

what are vesicles anchored to cytoskeleton by?

A

synapsin

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8
Q

how does Ca2+ affect synaptic vesicle release?

A

activates calcium calmodulin activated kinase II (CAMKII) which phosphorylates synapsin

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9
Q

what is the mechanism of exocytosis?

A

vesicle docks in active zone
SNARE complexes form to pull membranes together
Ca2+ binds to synaptotagmin (found on vescicle)
Ca2+ bound synaptotagmin binds to SNAREs and plasma membrane
catalyses membrane fusion

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10
Q

how are synaptic vesicles recycled?

A

membrane is rapidly recovered by endocytosis

new vesicles bud off and are refilled with transmitter

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11
Q

what is priming?

A

docked vessels are not ready for fusion
must be primed before they are able to respond to Ca2+
thought to involve partial assembly of SNARE complexes

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12
Q

what do clostridial toxins do?

A

cleave snare proteins by proteolysis, blocking neurotransmitter release
e.g. botulinium toxin, tetanus toxin

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13
Q

what is botulinium toxin (BoTX)?

A

clostridial toxin - blocks ACh neuromuscular transmission
acts directly at neuromuscular junction
muscles lose all input, become permanently relaxed
used for treatment of muscle spasms

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14
Q

what is tetanus toxin (TeTX)?

A

clostridial toxin - blocks GABA/Gly interneurons in the spinal cord
inhibits release of GABA and glycine at inhibitory neurons
causes disinhibition of cholinergic neurons
permanent muscle contraction

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15
Q

how can disease affect the presynaptic terminal

A

LEMS (Lambert-Eaton myasthenic syndrome): attacks presynaptic Ca2+ channels
cognitive disorders: impair transsynaptic signalling
congenital myathenic syndromes (muscle weakness): impaired vesicle recycling
latrotoxin: triggers vesicle fusion
BoTX and TeTX: affect SNARE proteins involved in vesicle fusion

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16
Q

membrane transporters

A

vesicular transporters

plasma membrane transportrs

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17
Q

how do vesicular transporters work?

A

powered by proton gradient
ATPase proton pump loads vesicles with H+
vesicles become acidic (pH 5.5) compared to cytoplasm (pH 7.2)
one glutamate traded for one H+

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18
Q

how do plasma membrane transporters work?

A

powered by electrochemical gradient
[Na+] is higher outside, [K+] is higher inside
glutamate is co-transported with 2 Na+

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19
Q

What role do glial cells play?

A

astrocytes wrap around synapses
transmitters released by presynaptic cell are taken up by astrocyte
when activated, astrocytes experience increase in intracellular calcium, releasing transmitters of their own into synapse which can enhance or inhibit synaptic activity
as astrocytes have thousands of connections with neural synapses, signals initiated at a single synapse my propagate elsewhere

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20
Q

what are fast neurotransmitters?

A

synthesised locally in presynaptic terminal
stored in synaptic vesicles - docked close to voltage-gated calcium channels
released in response to local Ca2+ increased
released in short bursts when membrane is depolarised (brief, localised impulses)
eg. amino acids, monoamines, acetylcholine

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21
Q

what are slow neurotransmitters?

A

synthesised in cell soma transported to terminal
stored in secretory granules, further from membrane
released in response to global increase in Ca2+ (high frequency impulses)
eg. neuropeptides

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22
Q

what action do excitatory neurotransmitters have in the CNS ?

A

slightly depolarise postsynaptic cells membrane

e.g. glutamate (Glu)

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23
Q

what action to inhibitory neurotransmitters have in the CNS?

A

slightly hyperpolarise postsynaptic cells membrane

e.g. GABA - brain, glycine (Gly) - brain stem and spinal cord

24
Q

what is the serotonergic system?

A

diffuse modulatory system - modulation affects large neural networks
changes likelihood excitation/inhibition
functions in: mood, sleep, pain, emotion, appetite

25
where is serotonin synthesised?
mostly in the raphe nuclei in the brain stem | small number of neurons, with many connections from core
26
what is the differences between neuromodulation and neurotransmission?
most neurotransmitters have modulating rather than information-transmitting effects: activate/inhibit entire circuits of neurons exceptions = Glu and GABA e.g. ACh secretion activates the cerebral cortex, facilitating learning information is remembered by neurons secreting Glu and GABA
27
How is glutamate synthesised, transported and reuptaken?
synthesised in presynaptic terminal from 2 sources: glucose from Krebs cycle of glutamine converted by glutaminase to glutamate loaded and stored in vesicles by vesicular glutamate transporters (VGLUTs) reuptake occurs via excitatory amino acid transporters (EATTs) in membrane of presynaptic cell and surrounding glia in glia, glutamate is converted to glutamine glutamine is transported back to nerve terminal to be converted to Glu
28
How is GABA synthesised, transported and reuptaken?
synthesised from glutamate by glutamic acid decarboxylase (GAD) loaded and stored in vesicles by vesicular GABA transporter (GAT) - Gly uses same transporter cleared from synapse by reuptake using transporters on glia and neurons higher proportion GABA made de novo to refill vesicles, rather than recycling
29
what can occur in dysregulation of amino acid release?
too much Glu/too little GABA: hyper-excitability, epilepsy, excitotoxicity too much GABA: sedation, coma
30
what occurs in cerebral ischaemia?
metabolic events retaining electrochemical gradient are abolished reversal of Na+/K+ gradient transporters release glutamate from cells excitoxic cell death Ca2+ activates enzymes causing autodigestion
31
What does GHB do?
GABA metabolite which can be converted back to GABA increases amount of available GABA too much can cause unconsciousness and coma
32
types of monoamine
catelcholamines - synthesised from tyrosine = dopamine, adrenaline, noradrenaline indolamines - synthesised from tryptophan = serotonin (5-HT)
33
how are catelcholamines synthesised?
tyrosine is converted to dopa by tyrosine hydroxylase dopa is converted to dopamine by dopa decarboxylase dopamine is converted to noradrenaline by dopamine beta-hydroxylase (DBH) noradrenaline is converted to adrenaline by phentolamine n-methyltransferase (PNMT)
34
what is special about noradrenaline?
it is the only transmitter synthesised within vesicles, as DBH is only located in synaptic vesicles
35
how are catelcholamines stored?
loaded into vesicles by vesicular monoamine transporters (VMAs) controlled by proton gradient
36
how are catelcholamines released and reuptaken?
released by Ca2+ dependent exocytosis - binds and activates receptor signal is terminated by reuptake into axon terminal by transporters powered by by electochemicla gradient = dopamine transporters (DATs) and norepinephrine transporters (NETs) in cytoplasm: - reloaded back into vesicles - enzymatically degraded by monoamine oxidases (MAOs) - inactivated by catelchol-O-methyl-transferase (COMT)
37
which drugs can modulate catelcholamines?
amphetamine, cocaine, selegiline, entacapone
38
how does amphetamine modulate catelcholamines?
reverses transporter and blocks reuptake of DA and NE | more still in synapse
39
how do cocaine and methylphenidate (ritalin) modulate catelcholamines?
block DA reuptake into terminals | more DA in synaptic cleft = extended action on postsynaptic neuron
40
how does selegiline modulate catelcholamines?
MAO inhibitor found in dopaminergic terminals prevents degradation of DA, more is released on subsequent activations treatment of early stage PD, depression, dementia
41
how does entacapone modulate catelcholamines?
COMT inhibitor | treatment of early stage PD
42
how is serotonin synthesised?
tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase 5-HTP is converted to serotonin by 5-HTP decarboxylase
43
how is serotonin stored, released and reuptaken?
stored in vesicles signal terminated by serotonin transporters (SERTs) on presynaptic membrane destroyed by MAOs in cytoplasm
44
which drugs can modulate serotonin?
fluoxetine (Prozac) fenfluramine MDMA
45
how does fluoxetine (Prozac) modulate serotonin?
blocks reuptake of serotinin SSRI - selective serotonin reuptake inhibitor treatment of depression, OCD, anxiety
46
how does fenfluramine modulate serotonin?
stimulates release of serotonin and inhibits its reuptake | has been used as an appetite suppressant
47
how does MDMA modulate serotonin?
causes NE and serotonin transporters to run backwards neurotransmitter is release into synapse assessed for therapeutic use in PTSD
48
How is acetylcholine synthesised?
choline acetyltransferase converts choline and acetyl CoA into acetylcholine
49
how is acetylcholine stored, degraded and reuptaken?
packaged into vesicles by vesicular acetylcholine transporter rapidly degraded in synaptic cleft by acetylcholinesterase (made in cholinergic neuron, associated with axonal membrane) choline is transported back into presynaptic terminal and converted to ACh
50
how to acetylcholinesterase inhibitors work?
block breakdown of ACh, prolonging it action in synaptic cleft eg. neostigamine - treats myasthenia gravis (MG)
51
what are neuropeptides?
slow neurotransmitters vary in methods of synthesis an release from amino acids short polypeptide chain: 3-36 amino acids over 100 identified e.g. endorphine, vasopressin, endogenous opioids
52
how are neuropeptides released and degraded?
follow secretory pathway - dense core vesicle fusion and exocytosis occur due to global elevations in Ca2+ vesicle membrane is recycled, but not refilled neuropeptide binds to and activates receptor signalling is terminated by diffusion and degradation by proteases release is slower than smaller molecule, signals can be maintained for longer
53
how can soluble gases (NO/CO) act as neurotransmitters?
No is made in postsynaptic neuron by nitric oxide synthase gas rapidly diffuses across synaptic cleft to presynaptic cell activates guanylyl cyclase to make cGMP within seconds, NO is converted to inactive compound (signal switched off) =retrograde signalling
54
how is nitric oxide synthase activated?
binding of Ca2+ and calmodulin
55
how can endocannabinoids act as neurotransmitters?
small lipids mostly cause reduced GABA at certain inhibitory terminals active component in marijuana