Neurotransmitters 1 Flashcards

1
Q

Fast, reliable, and bidirectional mode of communication throughout the CNS

A

Electrical synapses/gap junctions

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2
Q

Electrical synapses/gap junctions allow what type of molecules to pass from one cell into another? What type of passage?

A

Ions and small molecules (

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3
Q

What proteins form the electrical synapse/gap junction? Be specific in the makeup.

A
  • Connexins, ~20 of them
  • 6 connexins form 1 connexon
  • 2 connexons align to form a channel
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4
Q

What are electrical synapses important in? List 4.

A
  1. Embryonic stem cells
  2. Retina
  3. Auditory system
  4. Cortex
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5
Q

What regulates an electrical synapse? List 4.

A
  1. Cytosolic pH
  2. Cytosolic calcium
  3. Phosphorylation
  4. Voltage
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6
Q

This is caused by mutations in one connexin

A

The most common form of inherited deafness in Caucasian populations (DFNB1)

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7
Q

What do electrical synapses allow?

A

Allow groups of similar neurons to be synchronized e.g. hormone-secreting neurons in hypothalamus - get burst of hormone secretion; neocortical interneurons; cells of adrenal medulla

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8
Q

Explain the membrane potentials in pre and post-synaptic neurons

A
  • Potential in downstream neuron won’t go as high
  • Signal will be degraded
  • Signal is less intense, more spread out
  • Not faithfully transmitter. Quick, but can’t keep doing this forever
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9
Q

Do electrical synapses have a synaptic delay?

A

Yes, ~0,1 msec

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10
Q

What is the predominant mode of signaling?

A

Chemical synapses

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11
Q

Which type of synapse (electrical or chemical) is faster?

A

Electrical synapses. (Chemical are not quite as fast)

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12
Q

2 key features of a chemical synapse

A
  1. Synaptic vesicles

2. Receptors on post-synaptic ending

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13
Q

What is the major different in contact of pre and post synaptic membranes in chemical and electrical synapses?

A

Electrical synapse-connected by desmosomes, no synaptic cleft, touching each other
Chemical synapse-no direct contact with each other, 2-4x bigger membrane space, contain synaptic cleft ~20 nm

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14
Q

In vesicular release for major neurotransmitters, an action potential propagates down an axon and does what to the presynaptic terminal?

A

Depolarizes it

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15
Q

What is the consequence of depolarization of the presynaptic terminal in vesicular release?

A

Opens voltage gated Ca2+ channels

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16
Q

What is the difference in intracellular and extracellular concentration of Ca2+ ?

A

[Ca2+] outside = mM (10^-3)
[Ca2+] inside = uM (10^-6)

much smaller inside

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17
Q

What initiates fusion of synaptic vesicles with plasm membrane in vesicular release?

A

Influx of Ca2+. After depolarization, calcium voltage gated channels open and calcium ions enter down their electrochemical gradient. (Equilibrium potential for Ca = ~100 mV)

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18
Q

After fusion of synaptic vesicles with plasma membrane, vesicle content is released into this very small region

A

Synaptic cleft

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19
Q

What type of receptors on post-synaptic cells do released transmitters act on?

A

Ligand gated ion channels or receptors that use G proteins (GPCRs)

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20
Q

True or false: Transmitters can only act on receptors on the post-synaptic cell

A

FALSE. They can also act on receptors on the pre-synaptic terminal

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21
Q

What inactivates transmitter? List 4.

A

Na+ dependent reuptake, degradation and/or diffusion, or glial metabolism

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22
Q

Vesicular membrane must be retrieved. What two events facilitate this?

A

Exocytosis followed by endocytosis

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23
Q

Pre-synaptic vesicles contain more than one kind of vesicle. Release from these types has a different Ca2+ dependence and occurs at a different place

A

Large dense core vesicles (LDCVs)

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24
Q

Calcium is a crucial player of vesicle release. What are two of its sources?

A
  1. Usually comes across the synaptic plasma membrane to start release
  2. Can also be liberated from intracellular space
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25
Q

3 benefits of chemical synapses

A
  1. Amplification of signal
  2. Integration of inputs
  3. Makes use of different receptors
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26
Q

How do different receptors create a variety of post-synaptic effects?

A

Ligand gated ion channel-response is RAPID

Other receptors link to signaling pathways that alter morphology, receptor localization, gene transcription- response is SLOWER

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27
Q

Major mode of release

A

Vesicular release

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28
Q

Most prevalent vesicle, lined up at synapse

A

Small clear synaptic vesicles (SSVs)

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29
Q

These vesicles are less numerous and not as localized

A

Large dense core vesicles (LDCVs)

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30
Q

What type of chemical mediators are released by diffusion (non vesicular release)

A

Lipid mediators like anandamide/endocannabinoids, neurosteroids, and gasses like NO

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31
Q

What type of chemical mediators are released by transport?

A

Hydrophilic molecules (via carriers or pores)

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32
Q

There are over a hundred different neurotransmitters known. They are split into what two groups?

A

Smal molecules and peptides

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33
Q

List 5 biogenic amines that fall under small molecules group of neurotransmitters

A
  1. Dopamine
  2. Epinephrine
  3. Norepinephrine
  4. Serotonin
  5. Histamine
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34
Q

List 4 amino acids that fall udner small molecules group of neurotransmitters

A
  1. Glycine
  2. Glutamate
  3. Aspartate
  4. GABA
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35
Q

What store small molecule transmitters?

A

Small clear synaptic vesicles (SSVs)

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36
Q

What store peptides?

A

Large dense core vesicles (LDCVs)

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37
Q

Which neurotransmitter is present in both types of vesicles?

A

ATP

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38
Q

Which type of neurotransmitter group is most abundant?

A

Peptides, far outnumber small molecule transmitters

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39
Q

List and describe the three main features major neurotransmitters share

A
  1. Localization (substance must be present at presynaptic site, usually made by that neuron)
  2. Release (must be released in response to presynaptic depolarization, release dependent on extracellular Ca2+)
  3. Receptor (on postsynaptic cell, mimicry, given exogenously, get same affect with same amount of substance)
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40
Q

List the 3 approaches for inactivation and which transmitters employ them

A
  1. Enzymatic degradation- ACh, peptides
  2. Reuptake- Dopa, norepi, epi, serotonin, GABA, glycine, glutamate
  3. Diffusion- Important for all
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41
Q

List the three important catecholamines

A

Dopamine, epinephrine, norepinephrine

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42
Q

Why use vesicles? (3)

A
  1. Concentration of transmitter- makes it high enough to affect receptor following release into synaptic cleft
  2. Separates transmitter pool from metabolic pool and from degradative enzymes- Glu, Gly, GABA, ACh, catchecholamines
  3. Essential part of biosynthetic pathway for some transmitters (peptides, norepi and epi)
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43
Q

What is the importance of having vesicles recycle multiple times?

A

If synaptic vesicles simply fused with presynaptic membrane, the terminal would enlarge and supply of vesicles would be depleted.

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44
Q

Where are synaptic vesicles proteins synthesized?

A

ER and Golgi, cannot be replenished quickly

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45
Q

The recycling process of synaptic vesicles is fast. ~1 min. List the steps (5)

A
  1. Budding from endosome - exocytosis
  2. Docking - exocytosis
  3. Priming
  4. Fusion of calcium (1msec)
  5. Budding with endoome- endocytosis (10-20 sec)
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46
Q

Vesicles nearby, but not at the terminal

A

Reserve pool

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47
Q

Some reserve pool vesicles are even further away form terminal, often tethered to actin cytoskeleton by this molecule

A

Synapsin (on surface)

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48
Q

This type of vesicle is siting right next to plasma membrane at active zone.

A

Docked vesicles

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49
Q

This type of vesicle is not ready to be released quickly

A

Docked vesicles

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50
Q

An ATP-dependent, multi-step biochemical change has occurred so that this type of vesicle can response to an increase in intracellular Ca2+

A

Primed vesicle

51
Q

Form the “readily releasable pool” of vesicles, quickly fusing with the plasma membrane

A

Primed vesicle

52
Q

Occurs when calcium concentration is elevated by opening of calcium channels, energetically very unfavorable

A

Fusion (of membranes)

53
Q

Studies on mutations affecting membrane trafficking in yeast identified these common set of proteins

A

SNARE complex

54
Q

What forms the SNARE complex? [# of helices]

A
  • VAMP/synaptobrevin (vesicular or V-SNAREs) [1]

- Syntaxin [1] and SNAP-25 [2] (target or T-SNAREs on presynaptic membrane)

55
Q

Before docking, the trans-SNARE complex is not assembled. What proteins organize the trans-SNARE complexes?

A

Sec/Munc Proteins - act as break to control

56
Q

This protein acts as a clamp, controlling the “zipping” together of the SNARE complex helices

A

Complexins (Ca enters and binds synaptotagmin, causes release of complexin, zippering is completed)

57
Q

The zipping together of the SNARE complex provides enough energy to force the bilayer fusion of what?

A

The synaptic vesicle and plasma membrane lipid bilayers

58
Q

True or false: The SNARE complex is Ca2+ sensitive

A

FALSE. It is not Ca2+ sensitive

59
Q

Ca2+ binding protein and sensor; triggers Ca2+ dependent SV release

A

Synaptotagmin

60
Q

What binds calcium channels directly?

A

Syntaxin - is at the site of greatest Ca2+ concentration during action potnetial

61
Q

Ca2+ influx is through what type of channels?

A

Voltage gated channels (triggers release in less than a msec)

62
Q

What does Ca2+ binding to synaptotagmin allow?

A

Final zippering of helices

63
Q

These proteases disrupt the process of vesicle fusion by cleaving VAMP/synaptobrevin, syntaxin, or SNAP-25

A

Clostridial toxins/Botulinum toxins

64
Q

Prevents release of inhibitory transmitters from interneurons by cleaving synaptobrevin, causes over excitation of skeletal muscle, tetanic contractions

A

Tetanus toxin

65
Q

Prevents ACh release at neuromuscular junction, causes flaccid paralysis

A

Botulinum toxin B

66
Q

After release of neurotransmitter, the SNARE complex needs to be taken apart. What set of proteins disassemble it?

A

NSF (N-ethylmaleimide sensitive factor) and SNAPs (soluble NSF accessory proteins, alpha, beta, and gamma)

67
Q

Unraveling the cis-SNARE complex is ATP- independent/dependent

A

ATP-DEPENDENT. NSF uses 3-6 ATPs to disrupt each SNARE complex.

68
Q

The average neuron has 10^6-7 vesicles. How many are at any given terminal?

A

50 vesicles

69
Q

This synaptic vesicle protein generates electrochemical gradient

A

Proton pump or V-ATPase

70
Q

These are examples of vesicular transmitter transporters (3)

A

VGLUT, VMAT, AChT

71
Q

Acetylcholine (ACh) is the neurotransmitter at these receptors throughout the autonomic nervous system and brain

A
  1. Nicotinic AChR (ligand-gated ion channels)
  2. Skeletal neuromuscular junction
  3. Muscarinic AChR (7 transmembrane domain, second-messenger mediated)
72
Q

The only enzyme unique to ACh synthesis; soluble, cytoplasmic enzyme; not rate limiting

A

Choline Acetyltransferase (ChAT)

73
Q

What limits ACh synthesis?

A

Choline availability

74
Q

Neurons do not make choline. Choline comes from what two sources?

A

Hydrolysis of ACh or phosphatidylcholine

75
Q

What is rate limiting step in ACh synthesis?

A

Choline uptake at plasma membrane

76
Q

Cholinergic neurons have a high affinity for choline via what type of uptake system?

A

Na+ dependent uptake system (CHT1)

77
Q

Acetyl CoA combines with Choline in the first step of ACh synthesis. What is source of acetyl CoA?

A

Comes from pyruvate generated by glucose metabolism (used in cytosol by ChAT

78
Q

This moves acetylcholine form cytosol into synaptic vesicle

A

Vesicular ACh Transporter (VAChT)

79
Q

Charge of ACh

A

positive charge

80
Q

Transport of ACh is driven by a _____ set up by the ______

A

Proton gradient, V-ATPase proton pump

81
Q

V-ATPase proton pump uses energy from ATP to

A

acidify synaptic vesicles

82
Q

Uphill/downhill transport of ACh is driven by uphill/downhill flux of protons

A

Uphill of ACh, downhill of Protons (1-2 H+ leave granule as 1 ACh+ enters)

83
Q

How many molecules of ACh does each synaptic vessicle store?

A

6000 molecules

84
Q

What is also stored in the same vesicles and released with ACh?

A

ATP

85
Q

This exteremly fast enzyme is critical for inactivation of ACh

A

Acetylcholinesterase (AChE)

86
Q

Sources of ACHE (3)

A
  1. Neurons
  2. Target cells (muscle)
  3. Glia
87
Q

Choline generated by AChE is retrieved by

A

Plasma membrane choline transporter (CHT1) = exclusively cholinergic

88
Q

CHT1 is stored with VAChT in synaptic vesicles; very little on cell surface until what event?

A

Exocytosis of vesicles containing ACh

89
Q

____ gradient established by _____ drives choline retrieval

A

Na+ gradient; Na+/K+ ATPase

90
Q

CHT1 resembles what type of transporters?

A

Na+ dependent glucose transporters, NOT other neurotransmitter transporters

91
Q

These types of inhibitors are key ingredients in many pesticides (DTT) and nerve gases (e.g. sarin)

A

Acetylcholinesterase inhibitors (inhibit ACh inactivation)

92
Q

What is a common result of many snake venoms?

A

AChR blockade

93
Q

The major excitatory neurotransmitter

A

Glutamate

94
Q

What percentage of neurons in CNS use glutamate as a neurotransmitter?

A

90%

95
Q

Glutamate in synaptic vesicles is a small/large percentage of total Glu

A

Small: 1-20%

96
Q

Asymmetrical contacts often on dendritic spines

A

Excitatory synapses

97
Q

Glutamate is often used to make (4)

A

proteins, glutathione, GABA, glutamine

98
Q

Glue does/does not pass the blood-brain barrier

A

Does not. needs to be made locally

99
Q

Carbon backbone of brain glutamate comes from ____, which is converted into ______

A

Blood glucose, converted into alpha-ketoglutarate

100
Q

To be used asa neurotransmitter, Glu must be concentrated in

A

Synaptic vesicles

101
Q

Glutamate concentrations in cytosol vs. synaptic vesicle

A

Much higher in synaptic vesicle:
Cytosolic [Glu] = low mM
SV [Glu] = 60-250 mM

102
Q

This transports Glu into SV

A

VGLUT (vesicular glutamate transporter). Glutamatergic neurons have VGLUT1 or VGLUT2.

103
Q

Two important characteristics of VGLUT

A
  1. H+/glutamate antiporter

2. NOT Na+ dependent

104
Q

Two factors that drive entry of Glu into SV

A

High concentration of H+ and positive charge in SC

105
Q

VGLUTs are activated by _____ and inhibited by ______

A

Activated by Cl-, inhibited by ketone bodies (links Glu neurotransmission to metabolic state)

106
Q

Inactivation of Glu is by this process

A

Reuptake into surrounding glia and pre and post synaptic neurons

107
Q

Volume of synaptic clef is about 100 x larger/smaller than volume of a single SV

A

larger

108
Q

Glu is removed from cleft by this family of transporters

A

EAAT or EATT 1-5 (excitatory amino aid transmitter transporters)

109
Q

Certain EATTs are expressed in _____ and others in ____

A

Glial cells and nerve terminals (EATTs differ in structure from catecholamine transporters)

110
Q

Concentration of glial EAATs surrounding glutamatergic synapse is very low/high

A

high- allows for rapid binding of Glu

111
Q

Uptake of Glu is driven by?

A

Na+ gradient

112
Q

Explain how EAATs are Glu symporters

A

3 Na+ and 1 H+ enter with Glutamate; 1 K+ exits cell; costs 1 ATP for each Glu taken up

113
Q

Glial cells use this ATP-depdendent cytosolic enzyme to convert Glu into Gln and export it

A

Glutamine synthetase (NOT found in neurons)

114
Q

Glutamine release from glial cell (astrocyte) is taken up by neuronal transporter and is driven by

A

Na+ gradient and membrane potential

115
Q

This enzyme converts Glutamine that is taken up by pre-synaptic terminal to Glutamate

A

Glutaminase

116
Q

This cycle accounts for almost half of the glutamate turnover

A

Glutamate-glutamine cycle

117
Q

Disruption of this enzyme in astrocyte rapidly impairs glutamatergic neurotransmission

A

Glutamine synthetase

118
Q

Each subunit (monomer) of EAAT functions independently/dependently

A

independently

119
Q

Neurons generally use more than one/only one transmitter

A

MORE THAN ONE.

120
Q

True or false: the transmitter used by a given neuron can change

A

True.

121
Q

EAAT forms

A

trimers

122
Q

In EAAT structure, glutamate sits between ______ and interacts with ______

A

Two hairpin loops, interacts with TMDs 7 and 8

123
Q

Why may you see convulsant effects in ketogenic diet or fasting?

A

Ketone bodies (acetoacetate and beta hydroxybutyrate) compete with choride binding site on VGLUT. As result, glutamate can’t get transferred into vesicle, and thus less Glu is arriving at postsynaptic cell.