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SMP - Neurophysio Exam 1 > Lecture 5 & 6 - Neurotransmitter Receptors > Flashcards

Lecture 5 & 6 - Neurotransmitter Receptors Flashcards

1
Q

What are 3 functions of NTs? Explain each and provide examples. Which function is the fastest?

A
  1. Neural signaling: mediate comms between neurons = AA NTs (faster than the 2 others)
  2. Trans-system modulators: modulate large populations of target neurons in multiple systems = biogenic amines
  3. Within-systems modulators: modulate info by neurons within systems (eg: within the basal ganglia system) = neuropeptides
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2
Q

What does allosteric modulation mean? Example?

A

Alteration of receptor activity (of binding site conformation) at a site distinct from the NT binding site

Eg: Benzodiazepines on GABAa receptors

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3
Q

Can a ligand be an agonist or antagonist?

A

YUP

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4
Q

How many subunits in an ionotropic NT receptor? Describe each.

A

5 subunits with each 4 transmembrane domains (20 crossing overs of the lipid bilayer)

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5
Q

How many subunits in a metabotropic NT receptor? Describe them.

A

2 subunits with 7 transmembrane domains each

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6
Q

What are the 2 types of ionotropic NT receptors based on their structure?

A
  1. Homomeric

2. Hetereomeric

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7
Q

Which are fastest: ionotropic or metabotropic NT receptors?

A

Ionotropic

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8
Q

What determines whether a particular ion will be able to go through an ion channel? What is this known has?

A

How that ion interacts with water = the ion’s sphere of hydration

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9
Q

What ion channel is activated by ATP?

A

P2X4

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10
Q

What is particular about glutamate ionotropic receptors?

A

They have 4-fold symmetry with a complex extracellular domain that translates the binding of glutamate to the opening of the channel and have evolved differently and during a different period of time than a lot of other ionotropic receptors

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11
Q

What % of clinical drugs act on GPCRs?

A

50%

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12
Q

What are orphan receptors? How many of them? Describe them.

A

Large component of the GPCR super family: greater than 100 orphan receptors = we do not know their ligand

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13
Q

What are the 6 components of the GPCR superfamily of receptors?

A
  1. Glutamate
  2. Frizzled/TAS2
  3. Rhodopsin
  4. Adhesion
  5. Secretin
  6. Orphan
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14
Q

Can G-proteins be stimulatory or inhibitory?

A

YUP

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15
Q

Which have more diverse postsynaptic effects: ionotropic or metabotropic receptors?

A

Metabotropic

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16
Q

Time frame of ionotropic synaptic transmission?

A

Milliseconds

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17
Q

Time frame of metabotropic synaptic transmission/effects?

A

Seconds to hours

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18
Q

What are 2 ions that a lot of ionotropic receptors are permeable to and cause hyperpolarization?

A
  1. Cl-

2. HCO3-

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19
Q

What are 2 ions that a lot of ionotropic receptors are permeable to and cause depolarization?

A
  1. Na+

2. Ca++

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20
Q

Describe the binding of NTs to receptors.

A

High degree of specificity

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21
Q

What determines whether the effect of an NT binding to a receptor will be excitatory or inhibitory?

A

Selectivity of the ion channel

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22
Q

What determines the length of the ion channel opening upon binding of the NT to the ionotropic receptor? What does this determine?

A

The kinetics of NT binding (for how long the NT binds)

This determines the duration of the effect

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23
Q

Can a single NT activate more than 1 receptor?

A

YUP

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24
Q

Can a single NT activate both ionotropic and metabotropic receptors?

A

YUP, most small ones do

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25
Q

What property describes the degree of specificity of an NT to a receptor?

A

The dissociation constant, Kd

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26
Q

What are the 5 ionotropic NT receptors?

A
  1. Cys-loop nicotinic ACh receptors (nAChRs)
  2. Serotonin type 3 receptors (5-HT3R)
  3. GABAaR and GABAcR
  4. Glycine receptors (GlyR)
  5. Glutamate ionotropic receptors: NMDA, AMPA, and Kainate
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27
Q

What are the 4 general features of ionotropic NT receptors?

A
  1. Pseudo symmetrical arrangement around a central ion-conducting pore
  2. Non-selective
  3. Ligand-binding sites at the interface of the subunits (between subunits)
  4. Exist in 3 states
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28
Q

What are the 3 possible states of ionotropic NT receptors? Describe each

A
  1. Resting: unliganded/closed
  2. Activated: liganded/open
  3. Desensitized: liganded/closed
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29
Q

What does the transition of the ionotropic receptor from the resting to the activated state dependent on?

A

Dose of agonist

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30
Q

When is the ionotropic NT receptor in the desensitized state?

A

When there is too much agonist

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31
Q

What is another name for ionotropic NT receptors?

A

Pentameric ligand-gated ion channels (pLGICs)

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32
Q

What does the anti-nausea drug ondansetron act on?

A

Binds to 5-HT3Rs and blocks it

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33
Q

Where are a lot of GlyRs found?

A

Spinal cord

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34
Q

How fast after ACh binding is the nAChR activated?

A

Instantaneously

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35
Q

How fast do neuronal nAChRs desensitize? What does this explain?

A

Rapidly (msecs-secs)

Explains nicotine addiction

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36
Q

Are all neuronal nAChRs the same? Why/Why not? Explain.

A

No, they are structurally diverse because multiple genes coding for these so different channels have unique properties, like:

  • Desensitization rates
  • Ca++ permeabilities
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37
Q

At what ratio does ACh bind its receptor?

A

2 ACh molecules : 5 molecules of receptor (pentameric)

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38
Q

Describe how ion current varies throughout receptor desensitization.

A

First the current is strong and reaches the peak current, and then decreases little by little

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39
Q

To what can we compare NT receptor desensitization? What is different?

A

Na+ VG channel inactivation

Desensitization is slower

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40
Q

Which causes stronger desensitization of AChRs: nicotine or cytisine? What does this explain?

A

Nicotine (explains addiction and abuse )

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41
Q

What ions go through nAChRs?

A

Na+/K+ mainly and some Ca++

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42
Q

What ions go through AMPA receptors?

A

Na+ and K+

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43
Q

What ions go through NMDA receptors?

A

Na+, K+, and Ca++

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44
Q

What ions go through Kainate receptors?

A

Na+

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45
Q

What ions go through 5-HT3 receptors?

A

Na+

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46
Q

What ions go through GABAa receptors?

A

Cl-

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47
Q

What ions go through Glycine receptors?

A

Cl-

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48
Q

What is a strong antagonist of GlyRs?

A

Strychnine poison

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49
Q

Why are nAChRs called Cys loop receptors?

A

Because they contain a disulfide bond between 2 Cys

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50
Q

What are the 2 families of ionotropic receptors based on? What does each contain?

A

Based on structural differences:

Family 1: nAChRs, GABAaRs, 5HT3Rs, GlyRs = N-terminal and C-terminal are both extracellular and 5 subunits each containing 4 transmembrane helices

Family 2: AMPA, NMDA, Kainate = N-terminal extracellular and C-terminal cytosolic and 4 OR 5 subunits each containing 3 transmembrane helices (completely transverse) plus 1 incomplete pore loop

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51
Q

What is the purpose of the cytosolic C-terminal of ionotropic glutamate receptors?

A

Contain sites for phosphorylation and binding of intracellular proteins

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52
Q

Why are NMDA receptors also permeable to Ca++ and the other glutamate receptors are not?

A

They have a voltage dependent Mg++ block

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53
Q

What are the 2 types of neuronal nAChRs?

A
  1. Pentahomomeric receptor

2. Pentaheteromeric receptor

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54
Q

Why don’t our muscles contract when we smoke a cigarette?

A

Because muscle nAChRs are different from neuronal ones and nicotine does not bind as well to these

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55
Q

What are the 4 genes that encode AMPA receptor subunits?

A
  1. Glu A1
  2. Glu A2
  3. Glu A3
  4. Glu A4
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56
Q

What is the ratio of NR1 and NR2 NMDA receptor subunits?

A

2:2

57
Q

What are the 7 genes encoding for NMDA receptor subunits? What are the 2 main ones?

A
  1. NR1
  2. NR2A***
  3. NR2B***
  4. NR2C
  5. NR2D
  6. NR3A
  7. NR3B
58
Q

What are the 5 genes encoding for Kainate receptor subunits?

A
  1. Glu R5
  2. Glu R6
  3. Glu R7
  4. KA1
  5. KA2
59
Q

What are the 6 genes encoding for GABA receptor subunits? How do these mix?

A
  1. Alpha 1-7
  2. Beta 1-4
  3. Gamma 1-4
  4. Delta
  5. Epsilon
  6. Rho

Mix in a very heterogenous fashion to produce many different types of GABAa receptors

60
Q

How many GABA molecules need to bind to the GABAa receptor to open the ion channel?

A

2

61
Q

What is picrotoxin?

A

GABAa receptor antagonist that induces seizures by blocking the ion channel

62
Q

How do benzodiazepines and barbituates affect the GABAa receptor?

A

They increase the flux of Cl- through the GABAa receptor channel in the presence of GABA

63
Q

What drugs can be used against epilepsy?

A

Barbituates

64
Q

How do steroids affect GABAa receptors?

A

They have the same interaction as benzodiazepines and other allosteric modulators

65
Q

Why are glutamate ionotropic receptors not very good drug targets?

A

They are expressed by all neurons so there would be a very wide range of side effects

66
Q

What are the 4 pathological processes in which glutamate is involved?

A
  1. Epilepsy
  2. Anxiety
  3. Addiction
  4. Ischemic brain damage
67
Q

What are the 3 physiological processes in which glutamate is involved?

A
  1. Neuroplasticity
  2. Neuronal development
  3. Learning and memory
68
Q

What are some mutations in the NR2A and B involved with?

A

Below 100 IQs

69
Q

What 2 areas of the brain are associated with addiction?

A
  1. Basal ganglia

2. Nucleus accumben

70
Q

Explain how glutamate is involved in ischemic brain damage.

A

NMDA receptors have a tendency to become over active when they lack O2 leading to Ca++ influx which will lead to further damage of brain cells (eg: apoptosis)

71
Q

How could brain damage in stroke victims be prevented?

A

Given NMDA receptor blockers during the acute phase of the stroke

72
Q

What type of ion channels are NMDA receptors?

A

Both ligand and voltage gated

73
Q

Describe the kinetics of the AMPA receptor.

A

FAST

74
Q

Describe the kinetics of the NMDA receptor.

A

SLOW

75
Q

What co-agonist is required for NMDA receptor activation?

A

Glycine

76
Q

How is the Mg++ block of NMDA receptors removed?

A

Initial depolarization to -30 mV

77
Q

How fast do AMPA and Kainate receptors desensitize? What is the mechanism?

A

Rapidly

Disruption of agonist binding domain dimer assembly

78
Q

How fast do NMDA receptors desensitize?

A

Slowly

79
Q

Are AMPA receptors permeable to Ca++?

A

Just a little

80
Q

Why is the NMDA receptor classified as a glutamate receptor and not glycine?

A

Because ambient levels of glycine usually saturate the binding sites on NMDA receptors under normal circumstances

81
Q

For what 2 conditions in the NMDA receptor used as a pharmacological target?

A
  1. Schizophrenia

2. Acute effects of ischemic event

82
Q

What is the 4th very rare type of ionotropic GluR?

A

DeltaRs

83
Q

What do Glu NR3A and B form when joined? How frequent are these?

A

Cl- ion channels, meaning they are inhibitory

Rare

84
Q

What are the 4 pathological processes in which NMDA receptors are involved?

A
  1. Stroke
  2. Seizures
  3. Traumatic CNS injury
  4. Neurodegenerative disorders
85
Q

What is a hypothesis for the cause of Huntington’s disease?

A

Too many NMDA receptors in the basal ganglia leading to the destruction of cells

86
Q

Describe the structure of a G protein and how it interacts with NT receptors.

A

Lipid modification on the alpha subunit and the beta-gamma dimer to hold it in close proximity to the NT receptor

87
Q

Describe the basal state of a G protein.

A

GDP bound to alpha subunit

88
Q

Describe the size of the subunits of the G protein.

A

Alpha subunit is much larger than the beta and gamma together

89
Q

Describe the 4 steps of operation of G proteins. Timeframe?

A
  1. Inactive NT receptor does not interact with G protein
  2. NT binding = G protein association and GDP exchange for GTP on alpha subunit
  3. Activated G protein splits and both alpha and beta-gamma subunits activate effector proteins
  4. Alpha subunit removes phosphate from GTP to terminate its own activity

Milliseconds

90
Q

Can G proteins directly activate ion channels?

A

Yes

91
Q

What is an example of a G protein directly activating an ion channel?

A

mAChR binding of ACh => G-protein activates K+ channel to hyperpolarize

92
Q

What can G proteins do once activated?

A
  1. Directly activate ion channels
  2. Activate membrane bound enzyme
  3. Activate second messenger cascades
93
Q

Effect of G alpha s activation?

A

Increase in intracellular cAMP

94
Q

Effect of G alpha i activation?

A

Decrease in intracellular cAMP

95
Q

What are 6 second messengers that can be activated/inhibited by G proteins?

A
  1. Ca++
  2. cAMP
  3. cGMP
  4. IP3
  5. Diacylglycerol
  6. Nitric oxide
96
Q

What is the function of the second messenger IP3?

A

Ca++ release from ER

97
Q

What is the function of the second messenger DAG?

A

PKC activation

98
Q

What is the function of the second messenger NO?

A

Guanylyl cyclase activation

99
Q

What is the function of the second messenger cAMP?

A

PKA activation

100
Q

What is the function of the second messenger cGMP?

A

PKG activation

101
Q

Effect of G alpha q activation?

A

PLC => DAG + IP3

102
Q

Norepi on alpha adrenergic 1-2 receptors: what G protein activated?

A

G alpha i

103
Q

Glutamate on mGluR: what G protein activated?

A

G alpha q

104
Q

Dopamine on D1 and D2 receptors: what G protein activated for each?

A

D1: G alpha s
D2: G alpha i

105
Q

What determine the output of a neuron?

A

Concentration and timing of NTs binding at its receptors

106
Q

ACh on muscarinic receptors: what G protein activated?

A

G alpha q

107
Q

GABA on GABAb: what G protein activated?

A

G alpha s OR

G alpha q

108
Q

Histamine on H1-3 receptors: what G protein activated?

A

G alpha s OR

G alpha q

109
Q

Serotonin on 5-HT1-2 and 4-7: what G protein activated?

A

G alpha s

110
Q

Norepi on beta-adrenergic 1-3 receptors: what G protein activated?

A

G alpha s

111
Q

What is an exogenous agonist to beta receptors? What is it used for?

A

Isoproterenol

Increase heart contractility

112
Q

What is an exogenous antagonist to beta receptors?

A

Propanolol

113
Q

What is an exogenous antagonist to alpha 2 receptors?

A

Phentolamine

114
Q

What do a lot of the names of beta adrenergic receptor antagonists have in common?

A

End in -olol

115
Q

What 2 types of adrenergic receptors do we have in the brain?

A
  1. Alpha2

2. Beta1

116
Q

What are the 8 metabotropic receptor subtypes?

A
  1. Glutamate
  2. GABAb
  3. Dopamine
  4. NE and EPI (adrenergic)
  5. Histamine
  6. Serotonin
  7. Purines
  8. Muscarinic
117
Q

What are the 3 classes of glutamate metabotropic receptors? Which G protein does each activate?

A
  1. Class I: G alpha q
  2. Class II: G alpha i
  3. Class III: G alpha q, i , and o
118
Q

What NTs bind purine metabotropic receptors?

A

ATP and GTP

119
Q

What drugs were given in the early treatment of Parkinson’s disease? Why?

A

Anti-muscarinic receptor drugs because patients have elevated levels of ACh in basal ganglia

120
Q

What 2 receptors are working against each other in the basal ganglia?

A

Metabotropic dopamine and muscarinic receptors

121
Q

Can metabotropic receptor subtypes for a single NT activate different G proteins? Examples?

A

YUP

Eg: glutamate metabotropic receptors

122
Q

Describe the concept of amplification with metabotropic NT receptors.

A

The activation of a single receptor with a single NT bound can result in the activation of many G proteins (same ones)

123
Q

What are the 2 MAIN types of voltage-gated calcium channels? Describe each.

A
  1. L-type (long-lasting): less sensitive, open slower, and remain open longer
  2. T-type (transient): more sensitive, open faster, and remain open for shorter periods of time
124
Q

Which VG calcium channels are high voltage gated?

A
  1. L type
  2. P/Q type
  3. N type
  4. R type
125
Q

Which VG calcium channels are low voltage gated?

A

T type

126
Q

Which VG calcium channels are expressed in the presynaptic terminal?

A
  1. P/Q type
  2. N type
  3. R type
127
Q

Which VG calcium channel is expressed in the postsynaptic terminal?

A

L-type

128
Q

Can VG calcium channels inactivate?

A

Yes

129
Q

What is EGTA? What does its effect demonstrate?

A

A molecule that chelates calcium and therefore inhibits inactivation of VG calcium channels because the inactivation is calcium-dependent

130
Q

How would an extracellular environment rich in Ba++ instead of Ca++ affect a calcium VG channel?

A

Ba++ would flow in the cell but Inactivation of the channel would be inhibited because the inactivation is calcium-dependent

131
Q

What is a method to test the functionality of different VG channel genes? 6 steps

A
  1. Dissect superior cervical ganglion near carotid bifurcation in rats
  2. Enzymatically dissociate and isolate the sympathetic neurons and place them on poly-lysine coated culture dish
  3. Intranuclear injection of cDNA plasmids encoding the protein of interest
  4. Wait 12-24 hours
  5. Use fluorescent die to determine which neurons have successfully expressed the gene
  6. Voltage clamp experiment on cells that express the gene and cells that didn’t
132
Q

What is voltage-dependent VG calcium channel inhibition? How can this be overcome?

A

The beta-gamma subunit of the G-protein binding the N type VG calcium channel will inhibit the channel when voltage is applied by having charge-charge interactions with the VG channel

A very large voltage (+100mV) will disrupt the interaction and the dimer will dissociate

133
Q

Does voltage-dependent VG calcium channel inhibition happen pre or post synaptically?

A

Both

134
Q

How can metabotropic receptors produce long-term changes?

A

By regulating gene expression

135
Q

What other neuronal receptors are involved in long term effects?

A

Tyrosine kinase receptors

136
Q

What is the orthosteric binding site?

A

The site where the NT binds

137
Q

What is cystisine?

A

nAChR agonist

138
Q

How many serotonin receptors? Which is the only ionotropic one?

A

7

5HT-3R

SMP - Neurophysio Exam 1 (13 decks)

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