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202 retake: theme 1 > T1 L6: chemicals in the brain > Flashcards

T1 L6: chemicals in the brain Flashcards

1
Q

what are the sequence of events in a typical chemical synapse transmission

A
  • look at slide 5
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2
Q

describe synaptic vesicle release and recycling

A

1- Pool of vesicles above the active zone is
anchored to the cytoskeleton by synapsin
- Action potential to presynaptic terminal, voltage
gated Ca2+ channels open, Ca2+ flows into the cytoplasm

2- - 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

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3
Q

describe synaptic vesicle release and recycling (2)

A

SNARE* complex at active zone

docks vesicles to the plasma membrane

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4
Q

describe the mechanism of exocytosis during neurotransmitter release

A
  • vesicle docks
  • SNARE complexes form to pull membranes together
    3) entering Ca2+ binds to synaptotagmin
    4) Ca2+ bound synaptotagmin catalyses membrane fusion by binding to SNAREs and the plasma membrane
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5
Q

how is the vesicle membrane recovered and recycled

A
  • vesicle membrane is rapidly recovered via ENDOCYTOSIS, new vesicles bud off and are refilled with transmitter
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6
Q

describe the cleavage of snare proteins by clostridial toxins

A

Sites of proteolysis that blocks neurotransmitter release.

Botulinum acts directly at the neuromuscular junction. The muscles lose all input and so become permanently relaxed (treatment of muscle spasms).

Tetanus toxin inhibits the release of Glycine and GABA at inhibitory neurons, resulting in dis-inhibition of cholinergic neurons, which causes permanent muscle contraction. @spinalcord

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7
Q

what is the function of Botox and tetanus

A

-prevent transmitter release

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8
Q

which bacteria produce Botulinum and tetanus toxins

A

from bacteria Clostridium botulinum and tetani respectively

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9
Q

which diseases affect the presynaptic terminal

A
  • Congenital myasthenic syndromes result in impaired vesicle recycling
  • cognitive disorders impair Transynaptic signalling
  • LEMS attacks presynaptic calcium channels
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10
Q

describe how the Vesicular transporters powered by proton gradient

A

ATPase proton pump loads up vesicles with H+
making vesicles acidic (pH5.5) compared to neutral pH of cytoplasm (pH7.2)
e.g. 1 glutamate traded for 1 H+ (counter-transport mechanism)

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11
Q

describe how the Plasma membrane transporters powered by electrochemical gradient

A

-[Na+] higher outside / [K+] higher inside

Glutamate co-transported with 2 Na+

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12
Q

what are the different categories of neurotransmitters and describe them

A

Amino acids-Synthesized locally in presynaptic terminal

Monoamines- Stored in synaptic vesicles

Acetylcholine-Released in response to local increase in Ca2+

Neuropeptides-Synthesized in the cell soma and transported to the terminal
Stored in secretory granules
Released in response to global increase in Ca2+

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13
Q

give some examples of fast and slow neurotransmitters in the CNS

A

1) fast - AA

2) Slow - Neuropeptides

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14
Q

describe the differential release of neuropeptide and small molecule co-transmitters

A

1) with low- frequency stimulation: there’s preferential release of small-molecule neurotransmitter
2) with high-frequency stimulation there’s release of both transmitters

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15
Q

what are the excitatory neurotransmitters in the CNS

A
  • Glutamate -CNS
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16
Q

what are the inhibitory neurotransmitters in the CNS

A

2) (γ-aminobutyric acid) GABA (brain)

Glycine (Gly) (spinal cord and brain stem)

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17
Q

what does the serotonergic system function in

A
  • mood
  • sleep
  • pain
  • emotion
  • appetite
18
Q

why are there neurotransmitters and neuromodulators

A

-other neurotransmitters In general, they have modulating effects rather than information-transmitting effects. That is, the release of neurotransmitters (other than GABA or Glu) tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions. For example, secretion of Ach activates the cerebral cortex and facilitates learning, but the information that is learned and remembered is transmitted by neurons that secrete Glu and GABA.

19
Q

describe the life cycle of glutamate

A

synthesized in presynaptic terminal from 2 sources:
1) from glucose via the Krebs cycle
2) from glutamine converted by
glutaminase into Glutamate

  • loaded and stored in vesicles by vesicular glutamate transporters (VGLUTs)
  • 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 is transported from the glia (“ball boys”) back to nerve terminals where it is converted back into Glutamate.
20
Q

describe the life cycle of GABA (γ-aminobutyric acid)

A

synthesized from glutamate (Glu)
in a reaction catalyzed by
glutamic acid decarboxylase (GAD)

loaded and stored into vesicles by a
vesicular GABA transporter, GAT
(Gly uses the same transporter)

cleared from synapse by reuptake using transporters on glia and neurons including non-GABAergic neurons

higher proportion of GABA is made de novo to refill vesicles rather than recycling

21
Q

what occurs if there is too much GABA

A

-Sedation/coma

22
Q

what occurs if there is too much GLU

A

Hyper-excitability

-epilepsy

23
Q

what occurs during cerebral ischaemia

A
  • 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)
24
Q

what occurs during GHB GHB γ-hydroxybutyrate (date rape drug)
induction

A
  • a GABA metabolite that can be converted back to GABA
  • Increases amount of available GABA
  • too much leads to unconsciousness and coma
25
Q

name some monoamines

A
  • Catecholamines:
  • Dopamine
  • Epinephrine (adrenaline)
  • Norepinephrine

Indolamines:
-Serotonin
(5-Hydroxytryptamine, 5-HT)

26
Q

go through dopamine synthesis in slide 28-29

A

Tyrosine

(TH)

L-Dihydroxy-phenylalanine (dopa)

(dopa decarboxylase)

Dopamine (DA)

(DBH)

Norepinephrine
(PNMT)

Epinephrine

27
Q

how are catecholamines stored

A

Loaded into vesicles by
Vesicular monoamine transporters (VMATs)
(proton gradient like Glu and GABA transporters)

28
Q

describe the common drug that modulates catecholamine synthesis

A
  • L-DOPA, Levodopa, the precursor of dopamine, is used as a treatment for Parkinson’s disease . Dopa decarboxylase converts it into dopamine increasing the pool of releasable transmitter.
29
Q

describe catecholamine release and reuptake

A

released by Ca2+ dependant exocytosis

binds and activates receptor

signal terminated by reuptake into the axon terminal by transporters powered by electrochemical gradient (Dopamine transporters (DATs), Norepinephine transporters (NETs) etc.)

in the cytoplasm the catecholamines are:
- reloaded back into vesicles
- enzymatically degraded by Monoamine oxidases (MAOs)
or
- inactivated by Catechol-O-methyl-transferase (COMT)

30
Q

describe the modulation of catecholamine release reuptake by drugs

A

Amphetamine reverses transporter so pumps out transmitter and blocks
reuptake (DA & NE)

Cocaine and Methylphenidate (Ritalin) block DA reuptake into terminals. More DA in synaptic cleft – extended action on postsynaptic neuron.

Selegiline - MAO inhibitor found in dopaminergic nerve terminals thus preventing the degradation of DA allowing more to be released on subsequent activations (treatment of early-stagePD,depression anddementia).

Entacapone - COMT inhibitor (treatment of PD)

31
Q

describe the synthesis of serotonin (5-HT)

A
  • Tryptophan

(tryptophan hydroxylase)

5-HTP

(5-HTP decarboxylase )

5-HT-5-hydroxytryptamine

32
Q

describe the storage and release of 5-HT

A

stored in vesicles

signal terminated by reuptake by Serotonin transporters (SERTs) on presynaptic membrane

- destroyed by MAOs in the cytoplasm
33
Q

what drugs modulate serotonin release and reuptake

A

Fluoxetine (Prozac) blocks reuptake of serotonin (SSRI – selective serotonin reuptake inhibitor) (treatment of depression, OCD)

Fenfluramine stimulates the release of serotonin and inhibits its reuptake (has been used as an appetite suppressant in the treatment of obesity)

MDMA, methylenedioxymethamphetamine (ecstasy) causes NE and serotonin transporters to run backwards releasing neurotransmitter into synapse/extracellular space (assessed for therapeutic potential in PTSD)

34
Q

describe the origin, release and reuptake of ACh

A 
Choline acetyltransferase (ChAT, CAT) 
converts choline+ Acetyl CoA  (coenzyme A)
into acetylcholine.

is packaged into vesicles by
vesicular acetylcholine transporter (VAChT).

rapidly degraded in synaptic cleft 
by acetylcholinesterase (AChE)

Choline is transported back into the
presynaptic terminal and converted to
acetylcholine

  • amount of choline is rate limiting step
  • AChE is made by the cholinergic neuron, secreted into synaptic cleft and associated with the axonal membrane
35
Q

what drug modulates ACh degradation

A

Neostigmine (treatment of myasthenia gravis, MG)

AChE (Acetylcholinesterase) inhibitors

block the breakdown of ACh, prolonging its actions in the synaptic cleft
36
Q

how long are neuropeptide transmitters

A

-Short polypeptide chains (3 to 36 amino acids)

37
Q

give some common examples of neuropeptides in the body

A

-endorphins, neuropeptide Y, substance P, endogenous opioids, vasopressin

38
Q

describe the release and degradation of neuropeptides

A
  • Follow the secretory pathway and NOT released in the same manner as small molecule transmitters

dense core vesicle fusion and exocytosis occurs as a result of global elevations of Ca2+ (sustained or repeated depolarization or release of Ca2+ from intracellular stores)

neuropeptide vesicle membrane recycled but not refilled

bind to and activate receptor

neuropeptides signalling is terminated by diffusion from site of release and degradation by proteases in the extracellular environment

release is slower than small molecule release and signals may be maintained for longer

39
Q

name another type of retrograde transmitter and describe it

A 
Soluble gases
Nitric oxide (NO) and Carbon monoxide

1) Nitric oxide made in postsynaptic neuron by Nitric oxide synthase
(activated by the binding of Ca2+ and calmodulin)
2) The gas is not stored but rapidly diffuses from its site of synthesis. Diffuses between cells (into presynaptic cell - retrograde transmitter)
Activates guanylyl cyclase which makes the second messenger cGMP
4) Within a few seconds of being produced NO is converted to biologically inactive compound (switching off the signal)
5) Potentially useful for coordinating activities of multiple cells in a small region (tens of micrometers) (how big is a neuron?)

40
Q

name another type of retrograde transmitter

A

Endocannabinoids
Small lipids which mostly cause reduced GABA release at certain inhibitory terminals.

A cannabinoid is also the active component of marijuana (Cannabis sativa).

202 retake: theme 1 (21 decks)

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