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Molecular Neuroscience I > 2 - ACh, glutamate, GABA and glycine > Flashcards

2 - ACh, glutamate, GABA and glycine Flashcards

1
Q

Acetylcholine is an ester of ____ and ____

A

Acetylcholine is an ester of acetic acid and choline

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2
Q

What is the formula for the synthesis of acetylcholine?

A

Choline + acetyl CoA Acetylcholine + coenzyme A

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3
Q

Where is the highest density of cholinergic interneurons found?

A

Caudate-putamen (part of basal ganglia), modulates movement control

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4
Q

ACh neurons in the brain stem are mostly ____

A

Motor neurons

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5
Q

what are three functions of basal forebrain cholinergic neurons?

A
  • Attention
  • Learning
  • Memory
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6
Q

Which divisions of the PNS are cholinergic neurons involved in?

A
  • Sympathetic (short preganglionic neuron)

- Parasympathetic (long preganglionic neuron)

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7
Q

The sympathetic nervous system serviced by what two type of cholinergic tissue receptors?

A
  • Adrenergic

- Muscarinic

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8
Q

The parasympathetic nervous system serviced by what type of cholinergic tissue receptor?

A

Muscarinic

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9
Q

Somatic neurons of the PNS are serviced by what type of cholinergic tissue receptor?

A

Nicotinic

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10
Q

What is ChAT?

A

Choline acetyl transferase,

The role of choline acetyltransferase is to join Acetyl-CoA to choline

Synthesized within the nerve terminal

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11
Q

What is CHT1?

A

Choline transporter 1

Transports choline into presynaptic terminal (reuptake) where it can be used to synthesize ACh again. Acetyl CoA is not reuptaken in this fashion as it is degraded into acetate by AChE

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12
Q

What is VAChT?

A

Vesicular acetylcholine transporter

Loads ACh into vesicles

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13
Q

What is AChE?

A

Acetylcholinesterase

Responsible for breaking acetylcholine into choline and acetate in the synapse

Extremely efficient

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14
Q

Which ACh receptor is fast and which is slow?

A

Muscarinic: Slow (metabotropic)
Nicotinic: Fast (ionotropic)

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15
Q

What subtype of muscarinic receptors are there and what are the associated G proteins?

A

M1, M3 and M5: Gq

M2, M4: Gi coupled

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16
Q

Are muscarinic/nicotinic receptors excitatory or inhibitory?

A

Muscarinic: mixed
Nicotinic: Excitatory

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17
Q

What type of muscles are nicotinic and muscarinic receptors found in?

A

Muscarinic: Smooth muscles
Nicotinic: Striated muscle

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18
Q

True or false? Nicotinic receptors are heteromeric?

A

False. Mostly heteromeric, but also homomeric (α7 subunits, present in CNS and characterized by high Ca permeability).

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19
Q

How many subunits do nicotinic receptors have? What type of subunits are found in the most common heteromeric nicotinic receptor?

A

5 subunits

9 different α subunits and 3 different β subunits

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20
Q

Name three subtypes of the nicotinic receptor subunits and their function

A

α7 - Most common
α5 - Controls nicotine intake
α7 - Working memory and attention in hippocampus
β2 - Sudden infant death syndrome (SIDS)

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21
Q

What is the distribution of muscarinic and nicotinic receptors in the brain?

A

More muscarinic receptors in newer parts of the brain (eg. forebrain) and nicotinic receptors more common in phylogenetically older areas

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22
Q

What three muscarinic receptors are coupled with the Gq protein?

A

M1, M3 and M5

stimulation activates protein kinase C by activation of phospholipase C (PLC) and inositol triphosphate (IP3)

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23
Q

What two muscarinic receptors are coupled with the Gi protein?

A

M2 and M4

Stimulation inhibits adenylyl cyclase

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24
Q

Stimulation of each muscarinic receptor subtype induces the transactivation of what?

A

Epidermal growth factor receptor (EGRF)

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25
Q

What is rapsyn?

A

A scaffolding protein responsible for clustering of cholinergic nicotinic receptors at neuromuscular junctions.

Necessary for muscle function, lack of rapsyn causes weakness, breathing difficulty and death within hours of birth (in mice)

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26
Q

What are acetylcholinesterase inhibitors?

A
  • Treatment of choice for alzheimers

- Irreversible inhibitors used as chemical weapons and pesticides

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27
Q

What are nicotinic agonists?

A
  • Treatment for Alzheimers, ADHD and schizophrenia (in trials)
  • Can be used as insecticide (killed the bees?)
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28
Q

What is a use for nicotinic antagonists?

A

Short acting muscle relaxants. Centrally acting antagonists are being considered to be used in treating drug addiction.

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29
Q

What are two uses for muscarinic agonists?

A
  • To reduce intraocular pressure when applied to the eye (to treat glaucoma)
  • Applied in certain cases of smooth muscle atonia (muscle weakness)
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30
Q

What are three uses for muscarinic antagonists?

A
  • Preventing motion sickness
  • Centrally acting muscarinic antagonists are useful for treating Parkinson’s disease
  • Atropine is useful to dilate pupils
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31
Q

What is the most abundant neurotransmitter in the nervous system?

A

Glutamate

32
Q

Why are there relatively few clinically drugs affecting the glutamatergic system?

A

Because of the great abundance of glutamatergic synapses in the brain

33
Q

What enzyme converts glutamate to GABA?

A

glutamate decarboxylase (GAD)

34
Q

What are the three types of ionotropic glutamate receptors?

A
  • AMPA
  • Kainate
  • NMDA
35
Q

Which of the three ionotropic glutamate receptors has endogenous ligands besides glutamate? How does this affect its activation?

A

NMDA receptors can also bind with glycine

The NMDA receptor is only activated in the presence of both glutamate and glycine

36
Q

Abnormal AMPA receptors can cause what three problems?

A
  • Neurodevelopment disorders
  • Neurodegenerative disorders (eg. ALS, Alzheimers)
  • Glioblastoma tumors
37
Q

Abnormal kainate receptors can cause what three symptoms?

A
  • Neuropathic pain
  • Fear memory
  • Epilepsy
38
Q

What is the general structure of an ionotropic glutamate receptor? (4)

A
  • Agonist binding site (extracellular)
  • Three transmembrane domains
  • Cytoplasm facing membrane loop forming the channel pore
  • Carboxy terminal (intracellular) is important for modifications such as phosphorylation or interactions with cytoplasmic proteins
39
Q

What is associated with an overabundance of glutamate?

A

Excitotoxicity of neurons, involving the activation of NMDA receptors. Prolonged elevation of intracellular calcium leads to mitochondrial damage and apoptosis

40
Q

What three NMDA receptor antagonists are used in therapy? Why are these often used as recreational drugs?

A
  • Ketamines (anasesthesia)
  • Dextromethorphan (cough suppressant)
  • Dizocilpine (MK-801) (stroke and Alzheimers’s prevention)

Psychotomimetic effects of NMDA antagonists make these popular recreational drugs

41
Q

Metabotropic glutamate receptors are divided into three groups (group I, group II and group III). Name the members of each group and their G protein

A

Group I (Gq)

  • mGluR1
  • mGluR5

Group II (Gi/Go)

  • mGluR2
  • mGluR3

Group III (Gi/Go)

  • mGluR4
  • mGluR6
  • mGluR7
  • mGluR8
42
Q

What is the venus flytrap (VFT) of mGlu metabotropic glutamate receptors?

A

The extracellular cleft of mGlu receptors that closes when bound to an agonist

These G protein-coupled receptors are (uniquely) dimers, a disulfide bonds links the two VFT parts

43
Q

Where is the mGluR1 receptor found?

A
  • Purkinje cells in cerebellum (eye movement)
  • Thalamus
  • Olfactory bulb
  • Hippocampus (spatial memory)
  • Glial cells
44
Q

Where is the mGluR2 receptor found?

A
  • Golgi cells in cerebellum

- Dentate granule neurons of the hippocampus (inhibition of Ca2+ channels)

45
Q

Where is the mGluR3 receptor found?

A
  • Thalamus and astrocytes
46
Q

What is the function of mGluR4(7)(8) receptors?

A
  • Presynaptic control of GLU and GABA release
47
Q

What does knockout of the mGluR7 gene do in mice?

A

Leads to rapid development of general epilepsy and death

48
Q

Where is the mGluR5 receptor found?

A
  • Sensory neurons
  • Retina amacrine cells
  • Astrocytes
49
Q

Where is the mGluR6 receptor found?

A
  • Postsynaptic on bipolar cells in the retina
50
Q

What does knockout of the mGluR8 gene do in mice?

A

Results in anxiety and weight gain

51
Q

What is the full name for GABA?

A

γ-aminobutyric acid

52
Q

How is the majority of GABA synthesized?

A

Synthesized from glutamate by glutamate decarboxylase (GAD)

53
Q

What is the most important inhibitory neurotransmitter in the mammalian brain?

A

GABA

54
Q

GABA is present in 20% of neurons, but also in non-neuronal tissues, especially in the ___?

A

Pancreas

55
Q

What are the two GABA receptors? Which is ionotropic/metabotropic?

A
  • GABAa receptor (ionotropic, postsynaptic)

- GABAb receptor (pre/postsynaptic, metabotropic)

56
Q

What is the structure of GABAa receptors?

A

Cys-loop, pentameric membrane proteins that operate as GABA-gated chloride channels

57
Q

GABAa-ρ receptors are found where and have what characteristic?

A

Found in the retina and are insensitive to GABAa antagonists bicuculine, barbiturates, benzodiazepines and steroids

58
Q

What is the structure of the GABAb receptor?

A
  • Comprised of two subunits, GABAb1 and GABAb2, inserted into the plasma membrane and coupled intracellularly
    -
59
Q

Which subunit of GABAb receptor contains the GABA binding domain in its extracellular N-terminal chain?

A

GABAb1

60
Q

What does GABAb2 do?

A

Does not bind GABA, but modulates within the transmembrane region.

61
Q

When stimulated, what does the GABAb receptor do?

A

Inhibits cAMP, increases potassium conductance and decreases calcium conductance.

62
Q

What is benzodiazepines action on GABAa receptors?

A

They act to increase affinity for GABA, they have no action in the absence of GABA.

63
Q

Knockout of the α1 and β2 subunits (most abundant subunits) of GABAa show what in mice?

A

The mice survive, showing there must be some compensatory mechanism

64
Q

Mice lacking one (heterozygous) or both γ2 alleles show what?

A

Both alleles: death due to lack of receptor clustering

Heterozygous: model for anxiety disorder

65
Q

What do agonists of GABAa do?

A

Act as anaesthetics and treatments for insomnia

66
Q

Baclofen, the only GABAb receptor agonist, is used for what?

A

Muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis

67
Q

Broadly, what is the function of glycine?

A

Mediator of synaptic inhibition, mostly in brain stem, spinal cord and retina

68
Q

Vesicular transport of glycine is not mediated by glycine transporters. What transporters do this?

A

GABA transporters

69
Q

What does Tetanus disease do?

A

Presynaptic block of glycine release

70
Q

Which neurotransmitter was found in space?

A

Glycine

71
Q

Subunits of glycine receptors assemble into what sort of complex?

A

Pentameric channels, thought to form rosette like arrangements surrounding a central ion pore.

72
Q

What are P and K on glycine receptors?

A

Positions of amino acid exchanges associated with the human neurological disorder hyperekplexia (exaggerated surprise) (acute startle response)

73
Q

In mice, the complete loss of the α1 subunit of glycine receptors is lethal. It is tolerated in humans. What does this suggest?

A

The loss of glycine receptors is effectively compensated in humans or subunit regulation substantially differs among these species.

74
Q

True or false? Glycine receptors have no pharmaceuticals that target them.

A

True

75
Q

Glycine has four amino acids that imitate it by being structurally similar. These range in potency. List them in order from strongest to weakest.

A

Glycine (strongest)

  • beta-alanine
  • taurine
  • L-alanine
  • Serine

Molecular Neuroscience I (8 decks)

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