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Molecular Neuroscience I > 5 - Transporters > Flashcards

5 - Transporters Flashcards

ATP-Binding cassette transporter KO = knockout

1
Q

What is an ABC transporter?

A

ATP-binding cassette transporter

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2
Q

What is one direction transport through a channel called?

A

Uniport transport

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3
Q

What does DAT-KO mean?

A

DAT (dopamine transporter) knockout

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4
Q

Amphetamines are known to block the function of what receptor? Causing what?

A

The function of the DAT transporter, causing the release of dopamine from vesicles and overstimulation of dopamine receptors

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5
Q

What are SSRIs?

A

SERT-selective inhibitors, blocks the action of SERT uptake transporters for the treatment of depression

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6
Q

What are some problems with norepinephrine and 5-HT transport inhibitors used as antidepressents?

A

Unpleasant side effects, such as sweating. Thought to have caused murder case. Bad withdrawal. Sometimes prescribed to kids.

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7
Q

What is EAAT-4 important for?

A

Depolarization of resting neurons into the active state.

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8
Q

How can ACh transporters be used to mark Alzheimers?

A

Lower density of the transporter can indicate the onset of Alzheimer’s disease (something wrong with cholinergic transmission)

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9
Q

Where are ATP transporters present?

A
  • Adrenal gland
  • Glial cell processes
  • Dendritic processes
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10
Q

What are ABC transporters famous for?

A
  • Cancer, Group of ABC transporters on surface of cell responsible for removal of unwanted receptors
  • In vertebrates, they only pump substrate out of the cell
  • Drugs stop working because ABC transporters are over expressed to pump drug out of cell (anti-cancer drugs)
  • Some of these transporters involved in blood brain barrier (activated disrupted with cancer, occasionally)
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11
Q

In the brain, the major degeneration of cells with ABC receptors is in the ____?

A

Retina

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12
Q

Most ABC related diseases are connected to the ____ system

A

Immune system

And reducing the effects of chemotherapy

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13
Q

What are three types of transport across cell membranes?

A
  • Simple diffusion
  • Facilitates diffusion
  • Active transport (requires ATP)
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14
Q

Slow neurotransmitters (metabotropic, eg. catecholamines) are mostly taken up by ____ and fast neurotransmitters (ionotropic, eg. GABA, glycine and glutamate) are primarily taken up by ____

A

Slow neurotransmitters (metabotropic, eg. catecholamines) are mostly taken up by presynaptic terminal and fast neurotransmitters (ionotropic, eg. GABA, glycine and glutamate) are primarily taken up by glia

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15
Q

What are the two types of solute carriers (SLC) membrane transporters for neurotransmitters?

A
  • Plasma membrane transporters

- Vesicular transporters

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16
Q

What are plasma membrane transporters?

A

Terminate neurotransmission by removing neurotransmitters from the synaptic cleft

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17
Q

What are vesicular transporters?

A

Load neurotransmitters into synaptic vesicles

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18
Q

What is the VMAT1-2 vesicular transporter?

A

Vesicular transporter for

  • Dopamine
  • 5-HT
  • Norepinephrine
  • Histamine
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19
Q

What is the VAChT vesicular transporter?

A

Acetylcholine vesicle loader

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20
Q

What is the VGAT vesicular transporter?

A

Vesicular transporter for

  • GABA
  • Glycine
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21
Q

What is the VGLUT1-3 vesicular transporter?

A

Vesicular transporter for glutamate

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22
Q

What is the VNUT vesicular transporter?

A

Vesicular transporter for ATP

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23
Q

What are plasma membrane monoamine transporters?

A

Belongs to the sodium symporter (NSS) family of plasma membrane transporters.

Undergoes a conformational change when a ligand binds, outer gate closes and inner gates opens, allowing substrate to reach the cytoplasm.

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24
Q

Describe the properties of SERT (serotonin transporter), DAT (dopamine transporter) and NET (norepinephrine transporter)

A

SLC6 (solute carriers) family of transporter

Sodium symport and co-transport of Cl- with influx of norepinephrine, serotonin and/or dopamine

SERT additionally transports K, but out of the cell

25
Q

Describe the properties of GAT1, BGT1, GAT2 and GAT3

A

SLC6 (solute carriers) family of transporter

Sodium symport and co-transport of Cl- with influx of GABA

26
Q

Describe the properties of GLYT1 and GLYT2

A

SLC6 (solute carriers) family of transporter

Sodium symport (Na influx) and co-transport of Cl- (Cl- influx) with transport of glycine into the cell

27
Q

What do monoaminergic neurons do with released neurotransmitters?

A

Recycle them

28
Q

What do DAT (dopamine transporter) knockout mice show?

A

Locomotor hyperactivity, and decrease in habituation when exposed to a novel environment.

29
Q

What happens when DAT knockout mice are treated with amphetamines?

A

Hyperactivity is reduced, which is in contrast to wild-type animals, where amphetamines cause hyperactivity (resembles ADHD)

30
Q

What do NET (norepinephrine transporter) knockout mice show?

A

Reduced locomotor activity upon exposure to a novel environment and elevated locomotor responses to psychstimulants

31
Q

What do SERT (serotonin transporter) knockout mice show?

A

Increases anxiety and stress-related behaviours. Reduced exploratory behaviour in the elevated plus-maze test

32
Q

What effect does amphetamines have on DAT? What is the consequence of this?

A

Amphetamines block DATs and prevent reuptake of dopamine at the synapse, this casues overstimulation of dopamine receptors

33
Q

What does transport direction of DAT, SERT and NET transporters depend on?

A

N-terminus conformation

Amphetamines can reverse the direction of transport, truncating the N-terminus can block the reversal of transport induced by amphetamine.

34
Q

How do DAT transporters interact with regulatory proteins?

A

At C and N termini,

C terminus can change DAT clustering and increased transporter functino

N terminus can interact with syntaxin (part of SNARE) to facilitate NT release

35
Q

What does ubiquitinatio nof the DAT N terminus by the E3 ubiquitin ligase cause?

A

PKC-mediated DAT internalization

36
Q

What do dopamine D2Rs interacting with DATs do?

A

Increase surface expression of DATs acting wither directly or via stimulating ERK/MAPK pathway

37
Q

What does synaptogyrin-3 (SyG3) do?

A

It’s located close to synaptic vesicles and may be involved in N-terminus to N-terminus interaction with DAT to recycle released dopamine back to synaptic vesicles.

38
Q

Depression is associated with what 3 impaired neurotransmitter transmissions?

A
  • 5-HT
  • NE
  • DA
39
Q

True or false? GABA transporters (GATs) can have reverse transporter action as a form of non-vesicular GABA secretion.

A

True, especially during development

40
Q

What do GAT1 GABA transporter knockout mice show?

A

Reduction in anxiety and depression like behaviours

41
Q

Where are GLYT1 glycine transporters found?

A

Glia

Also, inhibited by N-methylglycine

42
Q

Where are GLYT2 glycine transporters found?

A

Neurons in the spinal cord, the brainstem and the cerebellum

Not inhibited by N-methylglycine

43
Q

What do GLYT1 knockout mice show?

A

Severe motor defects and early death

44
Q

What do GLYT2 knockout mice show?

A

development of hyperekplexia (exaggerated surprise)

45
Q

What are the two steps of transport via excitatory amino acid transporters?

A
  1. Co-transport of 1 glutamate with 3 sodium ions and 1 proton into the cell cytosol
  2. Counter-transport of 1 potassium ion to return transporters to their externally facing, unoccupied state
46
Q

What do mice knockouts for the GLT1/EAAT2 (excitatory amino acid transporter) genes do?

A

Develop hippocampal pathology and seizures, and die early

47
Q

What does loss of GLAST/EAAT1 and GLT1/EAAT2 transporters do?

A

Leads to glutamate triggers excitotoxicity and progressive paralysis in rats

48
Q

What do mice with an equilibrative nucleoside transporter 1 (ENT1) knockout show?

A
  • Increased alcohol preference

- Reduced EAAT2 protein levels in the striatum

49
Q

What do VMAT1 and VMAT2 transport into vesicles?

A
  • Dopamine
  • 5-HT
  • Norepinephrine

VMAT2 transports histamine as well

50
Q

What does VNUT transport into vesicles?

A

ATP

51
Q

What is the structure of a typical secretory vesicle (SV)?

A

Phospholipid bilayer membrane contains about 180 proteins, the membrane also typically contains transporters, which loads neurotransmitters into the capsule

52
Q

What type of cells are mammalian vesicular monoamine transporter 1 (VMAT1) found?

A

Neuroendocrine cells

53
Q

What type of cells are mammalian vesicular monoamine transporter 2 (VMAT2) found?

A

All aminergic neurons

54
Q

How are neurotransmitters driven into secretory vesicles?

A
  • A V-ATPase on the transporter generates a gradient across the vesicle membranes
  • The vesicular transporters use this gradient to drive the transport of transmitters into secretory vesicles
55
Q

True or false? VNUT transporters can store ATP into secretory vesicles

A

True

56
Q

What is the structure of ABC transporters?

A

Dimers containing two transmembrane domains and two nucleotide binding domains. Transmembrane domains form the ligand binding sites and provide specificity, wherease two nucleotide binding domains bind ATP. The nucleotide binding domains are homologous throughout the family of transporters

57
Q

What type of transporter acts as the gatekeeper of the brain? How?

A

ABCB1, ABCC4-5 and ABCG2 ABC transporters are the main ABC transporters at the human blood-brain barrier

58
Q

What is the mechanism for ABC transport?

A
  • Ligand binds to a pocket formed by transmembrane domains
  • Triggers conformational change in the nucleotide binding domain, resulting in higher affinity for ATP
  • Two molecules of ATP bind to nucleotdie domains and induce closing of dimer and extrusion of ligand
  • ATP hydrolysis opens the channel and when products of this reaction (orthophosphate (Pi) and ADP) are released, the transporter is restored to the open state
59
Q

The release of what products from an ABC transporter signals that it is restored to the open state?

A
  • Orthophosphate (Pi)

- ADP

Molecular Neuroscience I (8 decks)

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