Chemicals in the brain

Question 1

NMJ

i) what causes VG calcium channels to open in the presyn terminal?
ii) which way does calcium move? why? what does this cause?
iii) which two ways can a neurotransmitter be removed from the synapse?

Answer 1

i) arrival of an AP at the pre syn terminal causes calcium channels to open
ii) calcium moves in through VG calcium channels as there is a high concentration of calcium outside and a low concentration inside the cell - causes NT vesicle fusion
iii) removal by glial uptake or enzymatic degradation

Question 2

SYNAPTIC VESICLE RELEASE AND RECYCLING

i) what anchors vesicles to the cytoskeleton of the active zone?
ii) what does the influx of calcium to the presynaptic cell activate and what does this then cause?
iii) what does this then allow? why?
iv) what complex is then formed to allow docking of vesicles to the plasma membrane of the active zone?

Answer 2

i) synapsin
ii) influx of calcium activates calcium calmodulin activated kinase II - this causes phosphorylation of synapsin to P-synapsin
iii) when synapse > P-synapsin it can no longer bind the cytoskeleton therefore vesicles dock to the active zone
iv) SNARE complex

Question 3

SNARES

i) what role do they play?
ii) what happens if there is SNARE dysfunction?
iii) what type of SNAREs are specific for a) vesicles b) terminal

Answer 3

i) dock vesicles to the plasma membrane in the active zone
ii) dysfunc = vesicles cant dock to the plasma membrane and you dont get neurotransmission
iii) a) vesicle = V snares b) terminal = T snares

Question 4

EXOCYTOSIS & NT RELEASE

i) what effect does calcium influx have on SNARE complexes?
ii) what does calcium bind on the vesicle membrane? what does this catalyse?
iii) what pulls the vesicle and plasma membrane together when an AP arrives?
iv) how long after exocytosis of NT is there endocytosis and recycling?

Answer 4

i) calcium influx to the pre syn cell causes SNARE complexes to form
ii) calcium binds synaptogamin on vesicle membrane which catalyses mem fusion by binding SNAREs
iii) SNARE complexes
iv) 10-20 seconds

Question 5

ENDOCYTOSIS AND TOXINS

i) what type of toxins cleave SNARE proteins? Give two examples
ii) what is the site of action of botilinium toxin? what does it do here? what is it used to treat?
iii) what is the overall effect of botulinum toxin on muscles?
iv) what is the site of action of tetanus toxin? what does it do here? (2)
v) what is the end result of tetanus toxin on muscles? why?

Answer 5

i) Clostridial toxins eg. Botilnium toxin and tetanus toxin
ii) site of action is NMJ where it blocks synaptic transmission (excitation is blocked) - used as a treatment for muscle spams
iii) muscles lose all input and become permanently relaxed as excitation is blocked
iv) site of action is interneurons in the spinal cord where it blocks GABA and Glycine (therefore is excitatory)
v) permanent muscle contraction due to disinhibition of cholinergic neurons which cause

Question 6

DISEASES AND THE PRESYNAPTIC TERMINAL

i) give three conditions that affect the pre synaptic terminal and what each does
ii) what specific proteins to botox and tetox affect? what are these proteins involved in?
iii) what does latrotoxin do? which animal can release it?

Answer 6

i) 1) congenital myasethic syndromes - impaired vesicle recycling,
2) cognitive disorders - impair trans-synaptic signalling,
3) LEMS - attacks pre syn calcium channels (can increase calcium therefore cant increase SNAREs)

ii) snare proteins that are involved in vesicle fusion
iii) triggers vesicle fusion and released by black widow spiders

Question 7

MEMBRANE TRANSPORTERS

i) which gradient powers vesicular transporters?
ii) which pump allows vesicles be loaded with H+? what does this do to the pH of the vesicle compared to the cytoplasm?
iii) what exchanged in and out of vesicles to allow loading of neurotransmitter?
iv) what gradient are plasma membrane transporters powered by? what movement does this allow?
v) what is the NT co-transported with? what is this driven by?

Answer 7

i) proton gradient
ii) ATPase proton pump - makes vesicles acidic in relation to neutral pH of cytoplasm
iii) H+ out (along proton gradient) and GABA/glutamate in
iv) electrochemical gradient - allows movement of NT from outside the presyn cell back in
v) co-transp of NT with 2xNa+ as there is high Na outside the cell and high K+ inside the cell

Question 8

GLIAL CELLS

i) give three roles of glial cells
ii) what proportion of cells in the brain do they make up?

Answer 8

1) mop up excess NT
2) release NT
3) respond to NT

ii) make up majority of cells in the brain

Question 9

CATEGORIES OF NEUROTRANSMITTER

i) what are the three types of small molecule neurotransmitter? give an example of each?
ii) where are neuropeptides synthesised? where are they stored?
iii) what are neuropeptides released in response to?
iv) where are small molecule NTs synthesised and stored? what are they released in response to?

Answer 9

i) 1) amino acids - GABA, glycine, glutamate
2) monoamines - catecholamines eg dopamine, adrenaline and noradrenaline or indolamines such as serotonin
3) acetylcholine

ii) in the cell soma, stored in secretory granules which appear larger and darker
iii) released in response to a global increase in calcium
iv) small molecs are synth locally in the presyn terminal and stored in vesicles - released in response to local calcium increase

Question 10

NT RELEASE

i) what type of transmitter are released in response to a global increase in calcium?
ii) give an example of a fast and slow neurotransmitter
iii) what type of NTs will be released after a low frequency brief pulse?
iv) what type of NTs will be released after a high frequency pulse? (2)
v) what type of calcium increase does a) low freq stimulations and b) high freq stimulations cause?

Answer 10

i) neuropeptides
ii) fast - amino acids such as GABA and glu slow - neuropeptides
iii) only fast NTs
iv) both slow and fast NTs
v) low freq stimulations = localised calcium increase therefore preferential release of small molecules Its - high freq stimulations = diffuse calcium release therefore release of neuropeptides also

Question 11

NTs IN THE CNS

i) which type of NT slightly depolarises the post synaptic membrane and makes it more likely to fire an action potential? give an eg
ii) what is the main inhibitory transmitter in a) the brain b) the spinal cord and brainstem
iii) how do inhibitory NTs make it less likely for an AP to be fired?

Answer 11

i) excitatory eg glutamate
ii) a) GABA b) Glycine
iii) slightly hyperpolarises the post synaptic cell membrane

Question 12

SEROTONERGIC SYSTEM

i) are they exclusively excitatory or inhibitory?
ii) name four things they function in
iii) what area do serotonergic neurons mostly arise from? iv) where is serotonin synthesised?
v) where do serotonergic neurons project?

Answer 12

i) not strictly either
ii) mood, sleep, pain, emotion, appetite
iii) mostly arise from the brainstem
iv) synthesised in the raphe nucleus in the brainstem
v) have diffuse projections eg spinal cord, cerebellum, MB, neocortex

Question 13

GLUTAMATE

i) what are the two routes by which glutamate is synthesised?
ii) which transporters load and store glu in vesicles?
iii) what transporters reuptake glutamate from the synaptic cleft into the pre synaptic cell?
iv) what is the role of glial cells in recycling of glutamate?

Answer 13

i) 1) from glucose via the Krebs cycle 2) glutamine > glutaminase > glutamate
ii) VGLUTs
iii) excitatory amino acid transporters (EAAT)
iv) convert it to glutamine then transport it back to the nerve terminal where it converted to glutamate

Question 14

GABA

i) is it excite or inhib?
ii) what enzyme catalyses the conversion of glutamate to GABA?
iii) what transporter is GABA loaded and stored into vesicles by? what other NT uses this same transporter?
iv) how is it cleared from the synapse? which two cells aid this?
v) is there more recycling of GABA or de novo synthesis to refill the vesicles?

Answer 14

i) main inhibitory NT
ii) glutamic acid decarboxylase (GAD)
iii) loaded into vesicles by GABA transporter (GAT) which is also used by Glycine
iv) cleared by reuptake using transporters on glial and neurons (inc non GABAergic neurons)
v) more de novo synthesis than recycling

Question 15

REG OF AMINO ACID TRANSMITTER RELEASE

i) what does too much glutamate or too little GABA cause?
ii) what does too much GABA cause?

Answer 15

i) hyperexcitability/epilepsy/excitotoxicity
ii) sedation and coma

Question 16

CEREBRAL ISCHAEMIA

i) what happens to the metabolic events that retain the electrochemical gradient?
ii) what happens to the Na/K gradient?
iii) which NT do transporters release from cells? which mechanism does this happen by?
iv) what happens to cells overall? how does excess calcium cause this?

Answer 16

i) Metabolic events that maint the EC gradient are abolished
ii) Na/K gradient is abolished
iii) glutamate is released by reverse operation (transporters release Glu rather than bringing it in)
iv) overall = excitotoxic cell death - excess calcium signals to enzymes which causes digestion of the over excited cell (death)

Question 17

GHB

i) what is it aka?
ii) what NT is it derived from?
iii) what effect does it have on GABA?
iv) what can too much lead to?

Answer 17

I) date rape drug

ii) derived from GABA
iii) increases amount available and synthesis of GABA
iv) too much can lead to unconsciousness and coma

Question 18

MONOAMINES

i) give three examples that fall under the catecholamine group ii) give one example that falls under the indolamine group
iii) what do all catecholamines have in common?

Answer 18

i) dopamine, adrenaline and noradrenaline
ii) serotonin
iii) have a catechol group in their structure

Question 19

CATECHOLAMINE SYNTHESIS

i) what is the precursor for this synthesis?
ii) what is the product of the first step of catecholamine synth?
iii) what important property does LDOPA have? what enzyme converts it to dopamine? which disease group may benefit from this?
iv) what does the second step of catecholamine synth start and end with?
v) which enzyme catalyses DA to noradrenaline?
vi) which NT can only be synthesised in vesicles? why?

Answer 19

i) tyrosine
ii) LDOPA
iii) LDOPA can cross the BBB - DOPA decarboxylase converts LDOPA to DA - can be given to patients with Parkinson’s disease
iv) second step starts with DA and ends with adrenaline
v) DBH
vi) noradrenaline as requires DBH enzyme that it is only found in the vesicles

Question 20

CATECHOLAMINE STORAGE/RELEASE/REUPTAKE

i) which transporters load catecholamines into vesicles? what gradient is used to achieve this?
ii) which ion increases in the pre syn cell to allow release of the NT?
iii) which two transporters allow the signal to be terminated? what gradient are these powered by?
iv) what three things can happen to catecholamines once they are back in the cytoplasm? which molecule allows each

Answer 20

i) VMATs - uses H+ gradient
ii) calcium
iii) dopamine transporters (DAT) and norepinephrine transporters (NET) allow sig termination and are powered by the elec chem gradient
iv) 1) repacked into vesicles, 2) enzymatic degradation by MAOs, 3) inactivation by COMT

Question 21

DRUG MODULATION OF CATECHOLAMINES

i) what effect do amphetamines have on catecholamine transporters? which two NTs does this affect?
ii) what is the mechanism of action of cocaine and methylphenidate? what does this result in?
iii) what type of drug is selegine? and what is its mechanism of action?
iv) what conditions can selegine be used for? (3)
v) what type of drug is entacapone and what condition can it be used in?

Answer 21

i) reverse transporters so that they pump transmitter out and prevent reuptake of dopamine and noradrenaline
ii) block DA reuptake so there is more in the synaptic cleft and it has extended action on post syn neutron
iii) an MAO inhibitor that prevents DA degradation which allows more DA to be released in subsequent activations
iv) early stage PD, depression and dementia
v) COMT inhibitor used in treatment of Parkinson’s

Question 22

SEROTONIN STORAGE/SYNTH/REUPTAKE

i) what is the precursor to serotonin?
ii) where is it stored after synthesis?
iii) which reuptake transporters terminate the signal? where are these found?
iv) what is serotonin destroyed by? where does this happen?

Answer 22

i) tryptophan
ii) in vesicles
iii) serotonin reuptake transporters (SERTs) found on the presynaptic membrane
iv) destroyed by MAOs in the cytoplasm

Question 23

DRUGS THAT MODULATE SEROTONIN

i) what does fluoxetine block? what drug class does it therefore belong to?
ii) name two conditions fluoxetine can be used to treat
iii) what two actions does fenfluramine have? give an example of what it may be used for?
iv) which two transporters does MDMA cause to run backwards? what does this cause?
v) in what condition may MDMA have therapeutic potential?

Answer 23

i) blocks serotonin reuptake there is an SSRI
ii) used to treat depression and OCD
iii) stimulates serotonin release and prevents its reuptake can be used as an appetite suppressant in obesity
iv) MDMA cause NA and 5HT transporters to run backwards which causes increased NT release into the synapse
v) may have therapeutic benefit in PTSD

Question 24

ACETYL CHOLINE

i) where is it the main NT?
ii) what enzyme catalyses choline + co-A to acetyl choline?
iii) which transporter allows Ach to be packaged into vesicles?
iv) which enzyme rapidly degrades it in the synaptic cleft?
v) what happens after its been degraded in the cleft?
vi) name a drug that blocks breakdown of Ach? how does this work? what can this be used to treat?

Answer 24

i) at the NMJ
ii) choline acetyltransferase
iii) vesicular acetylcholine transporter (VAchT)
iv) acetylcholinesterase
v) choline is transported back to pre syn terminal and re converted to Act
vi) neostigmine can block Ach breakdown by inhibiting acetylcholinesterase - can be used to treat myasthenia gravis

Question 25

NEUROPEPTIDES

i) what is the speed of transmission? why?
ii) what is the structure of neuropeptides?
iii) give three examples of a neuropeptides
iv) where are neuropeptide precursors synthesised and how do they get to the terminal of the cell?
v) are neuropeptides recycled?

Answer 25

i) slow transmission as they are large and packaged into vesicles in the back of the syn terminal
ii) short polypeptide chains 3-36 amino acids
iii) endorphins, substance P, endog opioids, vasopressin, neuropeptide Y
iv) synthesised in the soma and transported down microtubules to the terminal
v) no - they are degraded by proteolytic enzymes

Question 26

NEUROPEPTIDE RELEASE AND DEGRADATION

i) are they released in the name way as small molecules transmitters?
ii) what allows dense core vesicle fusion and exocytosis? name two ways this can be achieved?
iii) how is neuropep signalling terminated?
iv) are signals maintained for shorter or longer than small molecules?

Answer 26

i) no - they follow the secretory pathway
ii) global increase in calcium allows vesicle fusion and exocytosis - achieved by sustained/repeated depolarisation or release of calcium from intracellular stores (not local ca influx)
iii) signalling is terminated by diffusion from site of release and degradation by proteases in the extra cell enviro (not recycled)
iv) signals maint for longer than small molecules

Question 27

NITIRIC OXIDE

i) where is nitric oxide made?
ii) what does NOS do and what is it activated by?
iii) where does NO diffuse once its been made? what kind of transmitter therefore is it?
iv) what does NO activate when it reaches the target cell? which second messenger is then made?
v) what is NO converted to after a few seconds? what does this do?
vi) what may NO be useful for?

Answer 27

i) made in post synaptic neuron
ii) NOS makes NO and is activated with calcium binds calmodulin
iii) NO diffuses to the pre syn cell and is therefore a retrograde transmitter
iv) NO activates guanyl cyclase which makes cGMP
v) NO is converted to a biol inactive compound after a few seconds which switches off the signal
vi) NO may be useful for co-ordinating activity of multiple cells in a small region

Question 28

RETROGRADE SIGNALLING

i) what is it?
ii) name three molecules that use it?
iii) which small lipids can reduce GABA activity?

Answer 28

i) movement of a transmitter from post syn to pre syn cell
ii) NO, CO and endocannabinoids
iii) endocannabinoids are small lipids that reduce GABA activity