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5BBM0218 Physiology and Pharmacology of CNS > L8: Amino Acid Transmitters > Flashcards

L8: Amino Acid Transmitters Flashcards

1
Q

How many isoforms of plasma membrane reuptake transporters for glutamate are there, and what are their different cellular locations?

A

5 different isoforms of plasma membrane reuptake transporters for glutamate:

EAAT1: Primarily found in glial cells.
EAAT2: Present in glial cells and some neurons.
EAAT3 and EAAT4: Primarily located in neurons.
EAAT5: Found in the retina.

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2
Q

What drives the uptake of glutamate through plasma membrane reuptake transporters?

A

Glutamate transporters drive uptake through two mechanisms:
a) Co-transport of 2-3 Na+ and H+ into the cell.
b) Counter-transport of K+

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3
Q

What is the role of plasma membrane reuptake transporters for glutamate?

A
  • to terminate synaptic transmission or recycle transmitter molecules by clearing glutamate from the synaptic cleft
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4
Q

What are the vesicular membrane transporters responsible for?

A
  • vesicular membrane transporters (VGluT1-3) are responsible for transporting glutamate into synaptic vesicles
  • this transport is driven by the electrical gradient and H+ outflow
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5
Q

What is the role of vesicular membrane transporters?

A
  • neurotransmitter storage
  • they package glutamate into synaptic vesicles for later release during synaptic transmission
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6
Q

What is the major fast excitatory neurotransmitter in the brain?

A

Glutamate

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7
Q

Name the two types of receptors glutamate acts on and their subtypes

A

Ionotropic receptors: NMDA, AMPA, and Kainate receptors.
Metabotropic receptors: G-protein coupled receptors

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8
Q

What are the roles of astrocytes in glutamate-mediated neurotransmission?

A
  • Reuptake of glutamate via EAATs (excitatory amino acid transporters) in astrocytes.
  • Conversion of glutamate to glutamine (Gln) through enzyme glutamine synthase.
  • Transport of Gln back into the pre-synaptic terminal for conversion back to glutamate via glutaminase
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9
Q

What is the usual structure of an ionotropic glutamate receptor?

A
  • 4 subunits, each having 3 domains and a large extracellular N-terminal region where the ligand binding site is located
  • the pore is situated in the middle of the subunits
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10
Q

How does the activity of AMPA receptors differ from NMDA receptors in terms of current influx?

A
  • activation of AMPA receptors leads to fast synaptic current influx of Na+ ions, causing depolarization
  • whereas NMDA receptors have a slower onset and decay
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11
Q

What causes the fast decay of AMPA receptor currents?

A
  • due to their low Kd (dissociation constant) for neurotransmitter binding
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12
Q

What are the specific ions that NMDA receptors are highly permeable to?

A
  • Ca2+ ions in addition to Na+ and K+ ions
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13
Q

How do NMDA receptors differ from AMPA receptors in terms of their requirement for activation?

A
  • NMDA receptors require both glycine and glutamate to be present to activate them
  • AMPA receptors can be activated by glutamate alone
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14
Q

How are NMDA receptors blocked at resting membrane potentials?

A
  • blocked by Mg2+ at resting membrane potentials, preventing ion influx
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15
Q

What causes the removal of the Mg2+ block in NMDA receptors?

A
  • Mg2+ block in NMDA receptors is removed when the neuron is depolarized
  • and the membrane potential rises above a certain threshold
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16
Q

How does the onset and decay of NMDA receptor currents differ from AMPA receptor currents?

A
  • NMDA receptors have a slower onset and decay compared to AMPA receptors due to their complex activation & deactivation mechanisms
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17
Q

What specific neurotransmitter binding sites are present on NMDA receptors?

A

NMDA receptors have binding sites for both glutamate & glycine

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18
Q

Why do NMDA receptors require both glutamate and glycine to activate?

A
  • binding of glutamate and glycine necessary for conformational changes that allow NMDA receptors to open their ion channels
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19
Q

What type of current influx is caused by NMDA receptor activation?

A
  • influx of Na+, K+, and Ca2+ ions, contributing to various cellular responses.
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20
Q

What are the steps involved in the activation of NMDA receptors?

A
  1. Binding of Glutamate to the AMPA receptor.
  2. Localized EPSP (Excitatory Postsynaptic Potential) caused by AMPA receptor stimulation.
  3. Membrane potential rises above -40mV.
  4. Removal of the Mg2+ block in the NMDA receptor due to the rise in membrane potential.
  5. Binding of Glutamate to the NMDA receptor.
  6. Conformational change in the NMDA receptor.
  7. Flow of Na+, K+, and Ca2+ through the NMDA receptor ion channel.
  8. Postsynaptic EPSP generation.
  9. Dissociation of Glutamate from the glutamate receptors and its removal from the synaptic cleft.
  10. NMDA receptor deactivation and change to a closed state.
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21
Q

What are the subunit compositions of AMPA receptors?

A
  • Glu1-4 subunits, with 2 subunits of one type and 2 subunits of another type (2+2)
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22
Q

What ions are AMPA receptors permeable to?

A

K+ and Na+, and some AMPA receptors are also permeable to Ca2+.

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23
Q

What are the subunit compositions of NMDA receptors?

A

composed of 2 Glu1 subunits and 2 Glu2 subunits (2+2)

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24
Q

What ions are NMDA receptors permeable to?

A

K+, Na+, and Ca2+

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25
Q

Where can kinate receptors be found in the brain?

A

pre- and post-synaptically

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26
Q

How are GluK1-3 subunits assembled in functional channels?

A
  • GluK1-3 subunits can form functional homomeric or heteromeric channels, with 2 subunits of one type and 2 subunits of another type (2+2)
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27
Q

What is the requirement for GluK4 or GluK5 subunits to form functional channels?

A
  • need to combine with one of GluK1-3 subunits to form functional channels.
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28
Q

What is the role of kinate receptors postsynaptically?

A
  • Postsynaptically, kinate receptors ↑ the excitability of cells, causing long-lasting EPSPs via poorly defined G-proteins
29
Q

What is the presynaptic function of kinate receptors?

A

modulate neurotransmitter release

30
Q

How many transmembrane domains do metabotropic glutamate receptors (mGluR1-8) have?

A

7 transmembrane domains

31
Q

How do metabotropic glutamate receptors usually act?

A
  • act as dimers, where one molecule combines with another to form a functional receptor
32
Q

Where can metabotropic glutamate receptors be found?

A

both postsynaptically and presynaptically

33
Q

What are the three groups of metabotropic glutamate receptors (mGluRs) and their associated G-proteins?

A
  • Group I: mGluR1, mGluR5 (Gq) - ↑ in IP3 and DAG, leading to increased Ca2+ concentration and activation of Protein kinase C.
  • Group II: mGluR2, mGluR3 (Gi/o) - inhibit adenyl cyclase and modify ion channel activity via the βγ subunit.
  • Group III: mGluR4, mGluR6-8 (Gi/o) - inhibit adenyl cyclase and modify ion channel activity via the βγ subunit.
34
Q

How can glutamate act as an inhibitory transmitter at the presynaptic terminal?

A
  • Glutamate can inhibit NT release at presynaptic terminal by inhibiting voltage-gated calcium channels (VGCCs), ↓ calcium influx & subsequently ↓ NT release
35
Q

How can glutamate act as an inhibitory transmitter at the post-synaptic neuron?

A
  • Glutamate can modulate the excitability of the post-synaptic neuron and modify the activity of K+ channels - leading to inhibitory effects on neuron’s activity
36
Q

What is the role of GABA in the CNS ?

A
  • inhibitory neurotransmitter in the CNS
  • meaning it ↓ activity of neurons and helps maintain balance and control over brain excitability
37
Q

How is GABA formed from glutamate?

A
  • GABA is formed from glutamate through the action of the enzyme Glutamic Acid Decarboxylase (GAD)
38
Q

How is GABA destroyed or metabolized?

A
  • by the enzyme GABA Transaminase
  • an inhibitor of this enzyme is Vigabatrin, which can be used as an antiepileptic drug.
39
Q

How is GABA stored and taken back up after release?

A
  • stored in synaptic vesicles through vesicular uptake mediated by the VGAT (vesicular GABA transporter) & VIAAT (vesicular inhibitory amino acid transporter) transporters
  • during reuptake, GABA can be taken back up by either pre or post-synaptic neurons or astrocytes, helping to terminate its action at the synapse
  • energy for reuptake from H+ electrochemical gradient - which moves GABA in the opposite direction back into the cells
40
Q

What type of receptor is GABAa?

A

ionotropic receptors found only post-synaptically

41
Q

How many subunits make up a GABAa receptor, and what are they?

A
  • Each GABAa receptor is composed of 5 subunits: 2 alpha (a), 2 beta (b), and 1 gamma (y)
  • Each subunit has 4 transmembrane domains
42
Q

What is the most common configuration of GABAa receptors in the brain?

A
  • most common configuration in the brain is a1b2y2
  • making up approximately 60% of GABAa receptors
43
Q

What happens when GABAa receptors are activated?

A
  • activation of GABAa receptors opens Cl- channels
  • leading to inhibitory postsynaptic potentials (IPSPs) & fast hyperpolarization
  • this inhibits depolarization caused by excitatory inputs
44
Q

Where are the binding sites for GABA on the GABAa receptor?

A

two binding sites: one on the alpha subunit and another on the beta subunit.

45
Q

What is the role of the allosteric binding site on GABAa receptors?

A
  • The allosteric binding site on GABAa receptors allows drugs to act and enhance their activity.
46
Q

The allosteric binding site on GABAa receptors allows drugs to act and enhance their activity.

A
  • allosteric binding site on GABAa receptors allows drugs to act & enhance their activity
47
Q

What type of receptor is GABAb?

A
  • metabotropic receptors found both pre and post-synaptically
48
Q

What are the effects of convulsants on the body?

A

Convulsants induce sudden muscle contractions and seizures

49
Q

How do volatile general anesthetics like enflurane affect GABAa receptors?

A
  • Volatile general anesthetics promote GABAa channel activation
50
Q

What is the role of benzodiazepines in GABAa receptors?

A
  • Benzodiazepines = anxiolytic drugs that bind to a site of interaction between the alpha and gamma subunits of GABAa receptors
  • they facilitate the binding of GABA, enhancing its effects.
51
Q

Where are GABAb receptors located, and how many transmembrane domains do they have?

A
  • found both pre and post-synaptically and have 7 transmembrane domains
52
Q

How are GABAb receptors coupled to G proteins, and what are their effects?

A
  • GABAb receptors are Gi-coupled, which inhibits adenyl cyclase
  • they have longer-lasting effects compared to GABAa receptors
53
Q

What are the subunits involved in GABAb receptor dimers?

A
  • GABAb receptors form dimers between GABA1 (binding site associated) and GABA2 (G-protein associated)
54
Q

What are the effects of GABAb receptors on neurotransmitter release?

A
  • Presynaptic GABAb receptors cause a decrease in the activation of voltage-gated calcium channels (VGCC)
  • leading to less NT release
55
Q

What are the effects of GABAb receptors on the postsynaptic neuron?

A
  • Postsynaptic GABAb receptors cause increased opening of K+ channels
  • leading to hyperpolarization and ↓ firing of APs
56
Q

Provide an example of a drug affecting GABAb receptors

A
  • Baclofen is an agonist used to treat muscle spasticity by acting on GABAb receptors
57
Q

What type of neurotransmitter is glycine?

A

an inhibitory neurotransmitter

58
Q

How is glycine synthesized?

A
  • from L-Serine by the enzyme Serine hydroxymethyl transferase
59
Q

What are the processes of uptake and reuptake of glycine?

A
  • vesicular uptake occurs via VIAAT using an H+ gradient
  • reuptake driven by Na+ & Cl- transporters in astrocytes & nerves
60
Q

How many subunits make up the glycine receptor, and where is the glycine binding site located?

A
  • consists of 5 subunits, with 4 transmembrane domains each
  • the glycine binding site is on the alpha (a) subunit
61
Q

What is the most common configuration of the glycine receptor?

A

a3 b2 or a2 b3

62
Q

What happens when the glycine receptor is activated?

A
  • activation of the glycine receptor causes an influx of Cl- ions and leads to an inhibitory postsynaptic potential (IPSP)
63
Q

Provide examples of glycine receptor antagonists and their effects

A
  • Strychnine is a glycine receptor antagonist that competes with glycine, leading to convulsant effects
  • Picrotoxin is a non-competitive inhibitor that inhibits the glycine receptor ion channel
64
Q

How do antagonists like strychnine affect glycine receptors?

A
  • Antagonists like strychnine bind to the alpha subunit of glycine receptors & block the binding of glycine - leading to convulsant effects
65
Q

What is the role of glycine as a neurotransmitter?

A
  • inhibitory NT, contributing to the regulation of neuronal excitability
66
Q

How many transmembrane domains do glycine receptor subunits have?

A
  • each glycine receptor subunit has 4 transmembrane domains
67
Q

What type of receptor is the glycine receptor?

A
  • nicotinic type receptor
68
Q

How many subunits make up the glycine receptor, and how many transmembrane domains do they have?

A
  • consists of 5 subunits with 4 transmembrane domains each
  • the subunits include a1, a2, a3, a4, and only 1 b subunit
69
Q

Where is the glycine binding site located on the glycine receptor?

A

located on the alpha (a) subunit of the glycine receptor

5BBM0218 Physiology and Pharmacology of CNS (17 decks)

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