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BM324: Fundamental Pharmacology > Block E Lecture 3: Excitatory Amino Acids Neurotransmitters > Flashcards

Block E Lecture 3: Excitatory Amino Acids Neurotransmitters Flashcards

1
Q
A
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2
Q

What kind of neurotransmitter is glutamate?

A

An excitatory neurotransmitter

(Slide 4)

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3
Q

What are 3 example of glutamate receptor agonists?

A

Quisqualate, Kainate and NMDA

(Slide 4)

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4
Q

What are the 5 subtypes of glutamate receptors?

A

NMDA

Kainate

AMPA

Delta

GPCR (metabotropic)

(Slide 5)

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5
Q

What agonists act on each of the 5 glutamate
receptor subtypes?

A

NMDA -> NMDA

Kainate > Kainate

Quisqualate acts on AMPA receptors and the GPCRs

Delta receptors are not traditionally ligand-gated

(Slide 5)

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6
Q

What is the structure of the GPCR glutamate receptor?

A

They usually function as homodimers, each of its subunits have 7 membrane-spanning (Transmembrane) domains, similar to muscarinic and adrenoceptor receptors

8 different subunits which only pair with other subunits which are the same to form a receptor

(Slide 6)

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7
Q

How were the 8 variants of the glutamate GPCR identified and what are they called?

A

They were identified by molecular biology and are labelled mGlu1-mGlu8

(Slide 6)

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8
Q

What 3 groups are the 8 glutamate GPCR variants divided into what is the division based on?

A

Groups are based on molecular biology, coupling, effector mechanisms and pharmacology

Group 1: mGlu1 and mGlu5

Group 2: mGlu2 and mGlu3

Group 3: mGlu4,6,7 and 8

(Slide 9)

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9
Q

What is the coupling effector mechanisms and 2nd messengers used by groups 1,2 and 3 of the glutamate GPCR variants?

A

Group 1 uses Gq/11 coupling whereas groups 2 and 3 use Gi/o coupling

Group 1 uses an increase in PLC as an effector mechanism whereas groups 2 and 3 use a decrease in adenylate cyclase (AC)

Group 1 uses an increase of IP3 and DAG as second messengers whereas groups 2 and 3 use a decrease in cAMP levels

(Slide 10)

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10
Q

Where are group I of GPCR glutamate receptors usually located?

A

On postsynaptic neuron membranes

(Slide 12)

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11
Q

What 3 cellular responses does the activation of group I of GPCR glutamate receptors lead to?

A

An increase in Na+ and K+ ion conductance (aka excitation)

An increase in inhibitory postsynaptic potential (inhibition)

A modulation of voltage-dependent Ca2+ channels

(Slide 12)

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12
Q

Where are group II and III of GPCR glutamate receptors usually located?

A

On presynaptic neuron membranes

(Slide 12)

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13
Q

What cellular responses do group II and III of GPCR glutamate receptors lead to?

A

An increased presynaptic inhibition

Reduced activity of postsynaptic potentials (both excitatory and inhibitory)

(Slide 12)

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14
Q

How do the different GPCR glutamate receptor groups modulate NMDA receptor activity?

A

Group I increases activity whereas groups II and III decrease it

(Slide 13)

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15
Q

Other than modulating NDMA receptor activity, what are 2 other functional roles that GPCR glutamate receptors have?

A

Synaptic plasticity: They participate in long-term potentiation and depression

They control the hypothalamic-pituitary-adrenal axis via regulation of cortisol levels and stress responses

(Slide 13)

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16
Q

What are the structure of the ionotropic glutamate receptors?

A

They are integral cation channels, and are each composed of 4 subunits, which each receptor class having multiple subunits

(Slide 15)

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17
Q

How does the isotropic glutamate receptor subunit structure differ to that of e.g nicotinic?

A

The TM2 domain is inserted into the cell membrane, but it doesn’t cross it which leads to the N- and C- terminals being on opposites sides of the cell membrane

(Slide 16)

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18
Q

How were the 4 major classes of isotopic glutamate defied?

A

By their responses to selective agonists

(Slide 17)

19
Q

What are 3 examples of AMPA receptor agonists?

A

Glutamate

AMPA

Quisqualate

(S)-5-fluorowillardine

(Slide 18)

20
Q

State a AMPA receptor antagonist.

A

NBQX

Tezampanel

(Slide 18)

21
Q

What are 2 examples of AMPA receptor ligand ion channel blockers?

A

Polyamines, argiotoxin, jorotoxin and Mg2+ ions (only some subtypes)

(Slide 18)

22
Q

What is the function of AMPA receptors and how does it do this?

A

Fast, excitatory synaptic transmission which is enable due to their ability to move cations across the cell membrane and cause depolarisation

(Slide 19)

23
Q

What are 3 examples of kainate receptor agonists?

A

Glutamate

Kainate

ATPA

(S)-5-iodowillardine

Dysiherbaine

(Slide 20)

24
Q

What is an example of a kainate receptor antagonist?

A

2,4-epi-neodysiherbaine

(Slide 20)

25
Q

What is an example of a kainate receptor ion channel blocker?

A

Polyamines and Mg2+ ions (only some subtypes)

(Slide 20)

26
Q

What are the function of kainate receptors postsynaptically and presynaptically?

A

Postsynaptic; fast excitatory synaptic transmission (but slower EPSPs then AMPA receptors)

Presynaptic: Inhibitory (modulate the release of GABA)

(Slide 21)

27
Q

What are 4 diseases / disorders are kainate receptors thought to be involved in?

A

Schizophrenia

Depression

Autism

Huntington’s Disease

Bipolar disorder

Epilepsy

(Slide 21)

28
Q

Why are delta receptors considered an “orphan” iGluR?

A

As their endogenous ligand is unknown

(Slide 22)

29
Q

What 3 things do delta receptors play a key role in?

A

Synaptogenesis

Synaptic plasticity

Motor co-ordination

(Slide 22)

30
Q

State an example of an NMDA ion channel blocker.

A

Ketamine

PCP

MK801

Mg2+ ions

(Slide 24)

31
Q

What are 2 examples of NMDA allosteric modulators?

A

Glycine and Zn2+ ions

(Slide 24)

32
Q

What kind of ion channel are NMDA receptors?

A

Non-selective cation channel (but all subtypes pass calcium ions)

(Slide 24)

33
Q

How does magnesium block NMDA receptors?

A

In a voltage-dependent manner. Blocking is greatest at resting membrane potential but reduces as the membrane depolarises.

Results in receptor functionality being dependent on cells resting membrane potential

(Slide 27)

34
Q

How can AMPA receptors activate NMDA receptors?

A

As the AMPA current depolarises the cell, meaning magnesium is removed from the NMDA channel, resulting in NMDA receptors becoming activated and depolarising the cell even more

(Slide 28)

35
Q

What are 3 conditions that NMDA receptors could be targeted to treat?

A

Epilepsy

Excitotoxicity (damage due to stroke)

Memory loss

Dissociative anaesthesia

Psychiatric disorders

(Slide 29)

36
Q

Why are NMDA antagonists not clinically effective?

A

As they produce too many unwanted effects (such as loss of motor co-ordination)

(Slide 30)

37
Q

What is ischaemia?

A

A less-than-normal amount of blood flow to part of your body lead to a stroke.

(Slide 31)

38
Q

How can ischaemia lead to excitotoxicity (damage from a stroke)?

A
  1. Ischaemia causes cell death and damage.
  2. Cell damage results in glutamate leakage
  3. Glutamate leakage results in sustained NMDA receptor activation
  4. Sustained receptor activation results in a sustained rise in intracellular Ca2+ ions
  5. Cell undergoes programmed cell death (apoptosis)

Steps 3-5 are considered excitotoxicity

(Slide 31)

39
Q

NMDA receptors can cause LTP. What is this?

A

LTP stands for long-term potentiation and is the long-lasting enhancement of synaptic transmission after high frequency stimulation of afferent inputs

(Slide 32)

40
Q

What is long-term potentiation blocked by?

A

MK801 (NMDA receptor channel blocker), preventing NMDA receptor-mediated Ca2+ ion flux, preventing up-regulation of AMPA receptors

(Slides 32 and 33)

41
Q

What is ketamine used for clinically, how does it work and what does it produce in adults?

A

It’s used clinically as an anaesthetic, and it blocks NMDA receptor ion channel at the MK801 site. It produces vivid dreams in adults

(Slide 34)

42
Q

How does phencyclidine (PCP) work and what does it produce in patients?

A

It works by blocking NMDA receptor ion channels at the MK801 site, and it produces hallucinations in patients (schizophrenic like symptoms as well)

(Slide 34)

43
Q

Regarding glutamate receptors, how can they contribute to schizophrenia?

A

By hypo-functioning glutamate receptors or decreased glutamatergic function at NMDA receptors

(Slide 35)

BM324: Fundamental Pharmacology (15 decks)

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