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MoDA > Receptors And Ion Channels > Flashcards

Receptors And Ion Channels Flashcards

1
Q

What is the rINN name for the following drugs

a) butoxamine
b) clorgyline
c) amphetamine

A

a) butaxamine
b) clorgiline
c) amfetamine

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2
Q

What is 5-HT

A

5-hydroxytryptamine (serotonin)

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3
Q

Are steroid receptors membrane bound or cytosolic

A

They are cytosolic proteins

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4
Q

Give the five forces involved in the structure of a receptor in diminishing order of strength

A

Covalent bonds

Ionic bonds

Hydrogen bonds

Van der Waals Forces

Hydrophobic forces

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5
Q

How are large ligands believed to bind to receptors

A

Through a zipper interaction

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6
Q

Define agonist in terms of a receptor

A

An agonist binds to receptors and produces a response

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7
Q

Describe the approximate relationship between the size of the response and the concentration of agonist

What about when the response is plotted against the logarithm of the agonist concentration

A

Hyperbolic

Sigmoidal

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8
Q

What is the amount of a receptor that is bound by a given concentration of a drug governed by?

A

The affinity of the drug for the binding site

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9
Q

What is efficacy

A

The relationship between the amount of receptor occupied by a drug and the size of the response produced

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10
Q

True or false

An agonist has both affinity and efficacy

A

True

as they both binds to and activates a receptor to produce a response

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11
Q

True or false

Both antagonists and agonists display efficacy

A

False

both display affinity as antagonists bind but elicit no response

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12
Q

How is efficacy usually measured

What does this allow calculations of

A

On a log graph

EC50 - A measure of potency for agonists

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13
Q

What is EC 50

A

The concentration of the agonist that causes 50% of the maximum response

The response does NOT indicate the concentration of agonist occupying half of the receptors

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14
Q

What is potency

A

The concentration causing a particular magnitude of response (e.g. EC 50) - not to the size of the maximal response

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15
Q

What happens to the log concentration/response curve for an agonist in the presence of a competitive antagonist

A

It is shifted to the right in a parallel fashion

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16
Q

Can a maximal response be obtained if the agonist is in the presence of a competitive antagonist

Therefore what is another name of competitive antagonism

A

Yes, if enough agonist is added then the same maximal response is obtained

Surmountable antagonism

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17
Q

Does the addition of a competitive antagonist increase or decrease the EC 50

A

Increase

Maximal response remains the same

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18
Q

What is a structure activity series

A

A sequence of experiments to determine the relative potency of a group of structurally related compounds

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19
Q

What can be used to aid receptor classification

Give an example

A

In the case of ACh, two structure activity series can be seen and these help demonstrate the existence of two types of receptor, nicotinic and muscarinic receptors

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20
Q

Why can drugs with the same chemical formula offer different potencies

What does this demonstrate

A

Stereoisomers act differently

The complementarity of the interaction between drug and receptor

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21
Q

What is acetyl-β- methylcholine

What does its stereoisomer do

What does this mean for the racemate of acetyl-β-methylcholine?

A

Cholinergic agonist

Isomer has no affinity

Effectively reduces the concentration of the active isomer by half

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22
Q

What does isoprenaline do

What is the effect of its stereoisomer

What happens if you increase concentrations of the racemate

A

β- adrenoceptor agonist

Inactive isomer has affinity but no efficacy so acts as an antagonist

Simultaneously increases [agonist] and [antagonist]

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23
Q

What is the forward and backward reactions of the following know as:

D+R↔️DR

What does the rate of each equal?

A

Forward: K+1; rate =K+1[D][R]
Backwards: K-1; rate = K-1[DR]

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24
Q

What is the notation for the affinity constant of drug D

A

Ka (=k+1/k-1)

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25
Q

The higher the Ka, the ____ the affinity of D for R

A

Higher

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26
Q

What is Kd

How to work out Kd

A

The dissociation constant

1/Kd

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27
Q

What are the units of Ka

What about for Kd

A

M-1 or L/mol

M or mol/L

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28
Q

Describe D+R↔️DR in terms of α, where α is a fraction of receptors that combine with drug D

Therefore, what does Ka= in terms of α

Thus, what does it mean if α= 0.5

A

D + (1-α)↔️DR

α
————-
D

[D]= 1/Ka = Kd

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29
Q

Describe α in terms of Ka and [D]

α=?

A

[D] Ka
————-
1+[D]Ka

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30
Q

When α=0.5, [D]=1/Ka=Kd. What does this mean in reality?

A

The affinity constant is the reciprocal of the drug constant that produces 50% occupancy of the receptors

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31
Q

The affinity constant is the reciprocal of the drug constant that produces 50% occupancy of the receptors.

This is usually the concentration of an agonist that causes the half maximal response - true or false?

A

False

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32
Q

How can you measure the binding of a drug to its receptor directly

A

Using radioligand binding

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33
Q

What does the binding of a radio ligand consist of

A

Saturable component (specific binding to receptors) and amazing effectively linear non-saturable component (non - specific binding to non receptor material)

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34
Q

How is specific and non specific binding of radio ligands affected in the presence of a large excess of unlabelled ligand

A

Specific- almost completely abolished

Non- specific- almost unaffected

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35
Q

How can specific binding of radioligands be calculated

A

The difference between total binding and non specific binding in the presence of a large excess of non labelled ligands

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36
Q

Two of those

Specific binding sites always represent functional receptors

A

False

Conclusions from binding experiments must be supported by data about the functional behaviour of the putative receptor

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37
Q

How does the graph of specific binding and non specific binding differ on a chart of [radioligand] vs bound radioligand

A

Specific and total: rectangular hyperbola

Non specific: linear

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38
Q

Describe α in terms of B (specific binding at the radiolabelled concentration [D]) and Bmax (maximal specific binding)

A

α= B/Bmax

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39
Q

Describe the equation for the double reciprocal graph of the following equation

α= B/Bmax= [D]Ka/1+[D]Ka

How to calculate Ka and Bmax

A

1/B=1/[D] x 1/BmaxKa + 1/Bmax

1/Bmax= y intercept
-Ka= x intercept
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40
Q

What are the 2 axes for the Scatchard plot

How do you find out Ka and Bmax?

What does [D] refer to

A

B(x) vs B/[D] (y)

Gradient = -Ka
X intercept= Bmax

Free drug (NOT total concentration added)

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41
Q

Why is the Scatchard plot useful

A

Helps demonstrate situations where there maybe more than one binding site on a receptor

It can show the different affinities of each site

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42
Q

Can the different binding sites on a receptor affect the affinities of different binding sites

A

Yes - oxygen binding to haemoglobin - positive cooperativity

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43
Q

What graph is cooperativity seen in

A

A plot of frequency of channel opening vs agonist concentration

It is sigmoidal and NOT hyperbolic

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44
Q

What is the Hill plot

A

The equation relating binding to drug concentration can be modified to generate the Hill plot which reveals cooperativity

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45
Q

What are the axes of the Hill plot

A 
x= log[D]
y= Log B/(Bmax-B)
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46
Q

What indicated positive and negative cooperativity on a Hill plot

A

nH >1 is positive

nH <1 is negative

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47
Q

What does the nH =1 mean

In this condition, what does X=, if y=0

A

1:1 binding between drug and active site
No interaction between binding sites

LogKd

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48
Q

Describe a Hill plot line where there are multiple non interacting binding sites

A

nH <1 but line will not be straighten

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49
Q

When a fixed concentration of radioligand is used to describe the shape of the graph of ligand binding against log concentration of competing unlabelled drug

What do we need to know for this

A

Sigmoid

The concentration of unlabelled drug that displaces 50% of the specifically bound radio ligand

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50
Q

What is IC50?

A

The concentration of unlabelled drug that displaces 50% of the specifically bound radio ligand

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51
Q

What is the equation for the occupancy of receptors by unlabelled ligand α

When [U]=IC50, What does α=?

A

[U] x KU
———————————-
1+([U]xKU)+([L] x KL)

Where KU and KL are affinity constants for the binding of labelled and unlabelled drugs

α=0.5

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52
Q

Give an equation for KU, when [U]=IC50

KU=…

A

1+[L]KL
————
IC50

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53
Q

Is there a direct linear relationship between affinity and efficacy

A

This was thought to be true up until the 1960’s when it was believed that Kd=EC50

This was proved to be incorrect through experiments with Benzilylcholine mustard

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54
Q

What did experiments with BzCh reveal

Describe associated efficacy/ affinity graphs

A

The concept of ‘spare’ receptors

Affinity does not equal efficacy

Efficacy results from significant amplification of the response so is always left shifted from affinity
Both are sigmoidal

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55
Q

What does BzCh mustard (an antagonist) do to its receptor

What would be expected if the agonist response generated were directly proportional to receptor occupancy? What actually happens?

A

Irreversibly alkylates the muscarinic receptor

As progressive alkylation occurs thete should be a decrease in maximum response from the agonist with no change in apparent affinity of remaining receptors

With ACh, on the guinea pig ileum, only a fraction of the receptors need to be bound to to produce a maximal response

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56
Q

What happens as the amount of BzCh increases with the amount of ACh?

How can we estimate which percentage of receptors are spare?

A

At first maximal response is still attainable as BzCh is only affecting spare receptors
Once BzCh fills all spare receptors, maximal response is still just possible
Any extra BzCh results in a fall off of the maximal response

By measuring dose ratio at the point where maximal response is just attainable

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57
Q

What is the dose ratio for ACh in the guinea pig ileum

What does this mean

A

100

99% of the receptors are spare

58
Q

Why does it make sense for a receptor to have a low affinity for an agonist

What does this mean for the number of spare receptors

A

So the offset rate is high and the response is terminated quickly

The existence of spare receptors here increases the sensitivity of the tissue to the agonist

59
Q

How can you determine the affinity constant of an agonist from a log conc/ response curve

A

It is not possible because response is not directly proportional to receptor occupancy

60
Q

What does the dose ratio determining method assume

Why do we know this

A

Only have equal responses are produced by equal agonist

Antagonist affinities determined in this way are the same as those determined by direct binding

61
Q

What is the effect of adding a partial agonist alongside a full agonist

Why does this happen

A

Partial agonist acts like a competitive antagonist

By occupying receptors relatively ineffectually and preventing the full agonist from binding

62
Q

What does α= for drug D and antagonist A

A

α=

[D]K1
————————-
1+[D]K1 +[A]K2

63
Q

Give an example of drugs that don’t need to bind to receptors to have an effect

A

Ant acids - only change pH

Some diuretics only exert osmotic pressure

64
Q

What is the shape of a graph of bound receptors vs [D]

A

Hyperbolic

65
Q

What kind of bond is formed by an irreversible inhibitor

A

Covalent

66
Q

Which kind of inhibitor reduces Vmax

A

Irreversible

67
Q

Why can irreversible inhibitors still be surmountable

A

They may only block spare receptors so enough receptors are still present for a full response to occur

68
Q

Why do partial agonists act as inhibitors

A

Partial agonists require all receptors so its weaker effect blocks the more powerful effect that could be elicited by the full agonist

69
Q

What does the drug ratio (R)-1 of an antagonist (B) equal

What kind of antagonist is this for

A

R-1=[B] x Kb

Reversible antagonist

70
Q

What are the agonist, partial agonist and antagonist for μ-opioid receptors

A 
Morphine = full agonist
Buprenorphine = partial agonist 
Naloxone= competitive antagonist
71
Q

Define agonist

A

A substance that initiates a physiological response when combined with a receptor

72
Q

Define antagonist

A

A substance which interferes with/ inhibits the physiological action of another

73
Q

Define competitive antagonist

A

Bonds to the same site as the agonist but does not activate it, thus blocking the agonist’s action

74
Q

Define partial agonist

A

A substance that binds to and activates a given receptor, but only has partial efficacy at the receptor relative to a full agonist

75
Q

Define inverse agonist

A

A drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist

76
Q

Define biased agonism

A

AKA functional selectivity

Ligand dependant selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor

77
Q

V1=

A

C2 x V2

—————-
C1

78
Q

Should there be air in the intra-abdominal cavity?

What should you be thinking

A

No

This suggests a perforation

PEPTIC ULCERS

79
Q

What is the dose ratio

A

[D2]
—— = 1+[A]K2
[D1]

80
Q

How does K1 affect the dose ratio

A

Dose ratio is independent of K1

81
Q

What is the problem with dose ratio

A

We only have a single concentration of the antagonist to calculate affinity which is unsatisfactory experimentally

Normally multiple doses are used to compete with the agonist allowing a Schild regression to be generated

82
Q

What are the axes of the Schild regression

What can this be used to find

A

Log[antagonist]
y= Log[dose ratio-1]

X intercept = affinity of the competitive antagonist (if the slope is of unity)

83
Q

What are the 5 drug receptor families

Give an example for each

A
  1. Intracellular (NO or steroid receptors)
  2. Directly operated ion channels (nicotinic ACh receptor)
  3. Intrinsic enzyme activity receptors (eg RTK)
  4. Those linked to enzymes (eg EPO)
  5. GPCRs (eg β adrenoceptor or muscarinic ACh receptor)
84
Q

Which 2 groups can intracellular receptors be divided into

A

Those with enzymatic activity (eg soluble guanylyl cyclase

Those that bind to lipid soluble agonists eg steroids

85
Q

Describe the activity of soluble guanylyl cyclase

A

NO is released from endothelial cells to cross the PM and interact with soluble guanylyl cyclase, which converts GTP to cGMP

cGMP activates PKG, promoting smooth muscle relaxation

86
Q

How is cGMP broken down

How can this be inhibited

A

By cGMP phosphodiesterase

Sildenafil citrate

87
Q

What are the 3 domains of the steroid receptors

A

Lipid binding domain
DNA binding domain
Transcription activating domain

88
Q

Where do steroid receptors usually reside

Name an exception

A

In the cytoplasm but trans locates to the nucleus upon activation by ligand

Oestrogen receptor - May be located in the nucleus even in the absence of a ligand

89
Q

Describe the time period of steroid activity

Which other group of hormones work in this way

A

Effects typically appear after a lag and may persist for hours or days

Thyroid hormones

90
Q

What kind of communication do ligand gated ion channels allow

A

Fast communication between cells

91
Q

What is the best characterised ligand gated ion channel

How has it been studied

A

the nicotinic ACh receptor

Using the patch clamp technique

92
Q

Describe quantitively the behaviour of a nicotinic ACh receptor (nAChR)

A

In response to ACh, the channel opens for about 1ms, allowing passage of ~10,000 Na+ ions

Frequency of channel opening increases with increasing [agonist]

93
Q

What is the Hill coefficient for nAChR

A

2

94
Q

Describe the structure of the nAChR

A

Pentameter
2α, β, γ, and δ

α and its neighbour bind ACh and Both must be occupied to elicit a response

Each subunit has 4 hydrophobic stretches (M1-4)
M2 May form an α helix within the membrane and the 5 M2 regions apparently line the pore of the channel

95
Q

Is GC soluble or membrane bound

A

Both

Membrane bound GC is similar to soluble guanylyl cyclase function except the receptor is bound to the membrane

96
Q

Describe the structure of a membrane bound GC

A

Receptor is a dimer and binds molecules such as ANP

97
Q

How does ANP bind to membrane GC

A

Binds to the extracellular face of the receptor dimer which activates the guanylyl cyclase domain on the intracellular face

98
Q

What are RSKs

A

Receptor serine/ threonine kinases

Transmembrane proteins of the plasma membrane and Are characterised by extracellular ligand binding domains and cytoplasmic kinase domains

99
Q

What superfamily do RSKs belong to

Thus what roles are they involved in

A

Transforming growth factor β (TGF-β)

Physiological and pathological processes of the metres are in life including early embryogenesis, atherosclerosis and cancer

100
Q

What are the 2 sy types of RSKs

A

Type 1 and 2

Based on primary amino acid sequence - upon ligand binding a heteromeric complex of both types is formed and Type 2 phosphorylates and activates Type 1
Type 1 then plays a role in downstream signalling

101
Q

What do activated RSKs recruit

A

SMADs - when SMAD4 is recruited, a complex of activated SMADs and SMAD4 translocate to the nucleus and influence gene expression for cell proliferation

102
Q

What does every RTK have

Name 2 molecules that bind to them

What do all RTK do at some point

A

An intracellular catalytic domain and an extracellular regulatory domain

Insulin
EGF
PDGF

Activate the G protein Ras

103
Q

How many polypeptide chains do the receptors for the following contain
Insulin
EGF

A

Insulin: Contains two different peptide chains linked as a dimer (βα-αβ)

EGF: a single polypeptide chain

104
Q

Does dimerisation come before or after autophosphorylation in EGF RTK?

A

Dimerisation precedes auto phosphorylation

105
Q

Are RTK responses rapid

A

They can be fast or delayed

106
Q

Why are RTKs of interest to virologists

A

Several. Viral oncogenes encode mutated forms of either receptors or ligands

Eg v-erb encodes a truncated, constitutively active EGF receptor
V-sis encodes a PDGF chain

107
Q

How do RTKs and RSKs differ from receptors linked to soluble kinases

A

In receptors linked to soluble kinases, the kinase domain is encoded on separate genes from the transmembrane receptor but then associate together

108
Q

Give an example of receptors linked to soluble kinases

A

The EPO receptor

Signalling is facilitated by the JAK-STAT pathways - inducers of TFs

Disrupted JAK-STAT signalling May lead to many different disorders

109
Q

How many subunits do receptors of GPCRs have

A

1 of a size or 40-50kDa

110
Q

What do all GPCRs have

A

7 transmembrane α helices (N extracellular, c intracellular)

111
Q

Where is the GPCR’s ligand binding site

How does the receptor interact with the G protein

A

Usually buried within the transmembrane helices

Via the 3rd intracellular loop and C terminal tail

112
Q

How does cAMP control cell function

A

Through PKA

113
Q

How may GPCRs affect AC

A

Activate (β1-AR) - Gs

or

inhibit (α2 -AR) - Gi

114
Q

Describe the structure of G proteins

Where can the difference between Gi and Gs be found

A

Heterotrimers, consisting of an α subunit, a β subunit and a γ subunit

In the α subunit which binds and hydrolyses GTP

115
Q

What happens to a G protein when a GPCR is occupied by an agonist

A

The receptor forms a transient complex with Gs, which is occupied by GDP
GDP-GTP exchange promotes Gs release and causes a reduction in binding affinity of agonist to receptor

βγ is also released, while αs forms an active enzyme complex with AC

116
Q

How does G protein activity end

A

Agonist activates GTPase activity terminates the active state of αs and βγ recouples

117
Q

How does Cholera toxin act

A

Causes ADP-ribosylation of αs

This inhibits GTPase activity and causes sustained activity of AC

118
Q

How can the βγ complex be inhibitory

A

Through the mopping up of free αs

Can also have effects on AC (independent of αs)

119
Q

How does pertussis toxin work

A

ADP-ribosylation of αi and prevents activation of Gi in response to receptor stimulation

120
Q

Name a group of organists that stimulate the metabolism of inositol phospholipids in the plasma membrane

A

ACh (at mAChR)

Noradrenaline ( at α1 ARs)

Substance P

121
Q

Which G proteins activate phospholipase C

A

G11 and Gq

122
Q

What are the cleavage products of PIP2 and what do they Do

A

DAG - Stimulate membrane-bound PKC, which modifies properties of various proteins such as ion channels by phosphorylation

IP3- Causes the release of calcium from the endoplasmic reticulum

123
Q

How is IP3 metabolised

A

By phosphorylation to IP4 or by dephosphorylation successively to inositol

124
Q

Why is lithium used to treat bipolar disorder

A

That’s the uncompetitively inhibits the phosphatase that is responsible for converting IP1 to inositol thereby blocking recycling of inositol

125
Q

Overall what does it mean if a receptor is desensitised

A

Transduction mechanism is uncoupled

126
Q

What are the three processes involved in desensitisation

A

Uncoupling

Sequestration

Down-regulation

127
Q

Describe the uncoupling part of desensitisation

A

This is uncoupling of the receptor from its G-protein

Takes place over the course of seconds two minutes and is due to phosphorylation events at the receptor

128
Q

Describe the sequestration part of desensitisation

A

Receptors are removed from the plasma membrane by endocytosis and transferred to vesicles in the cytoplasm

This takes place over minutes

The receptors can be shuffled back to the plasma membrane but can also be destroyed in lysosomes this destruction can be elevated in the down regulation stage

129
Q

Describe the time regulation stage of desensitisation

A

Takes place over minutes two hours

The number of receptors available to be shuttled to and from the plasma membrane is reduced this is possibly due to reduced receptor synthesis by effect of PKA on mRNA stability

130
Q

Can sequestration or down-regulation in desensitisation take place without uncoupling

A

No

131
Q

What are the different types of desensitisation

A

Homologous and Heterologous

132
Q

Described a homologous desensitisation using the example of the β2adrenoreceptor

A

The adrenoreceptor can upon ligand
binding be phosphorylated by GRK (usually GRK2/3)

GRK phosphorylates sites at the end of the C terminal membrane which increases the infinity of the beta 2 adrenoreceptor for another protein called β arrestin

The binding of β arrestin to receptor uncouples the receptor from the α-subunit of Gs thus producing desensitisation

133
Q

How many GRKs are there

A

GPCR kinases - 7 types with 2,3,5 being the most important

134
Q

Why is it called homologous desensitisation

A

GRKS only work on agonist occupied receptors so does not affect any other receptors that might be present

135
Q

How does heterologous desensitisation work

A

Stimulation of β2 ARs increases cAMP, stimulating PKA

If the receptor is disproportionately stimulated, there will be a large rise in PKA activity, which is able to phosphorylate site on the β2- receptor itself

This phosphorylation uncouples the receptor from the α-subunit of Gs, thus rendering it ineffective

136
Q

Where does high levels of PKA phosphorylate the β2 receptor

A

At site on the third cytoplasmic loop and the first part of the C terminal domain

137
Q

Why is heterologous desensitisation of adrenoreceptors considered heterologous

A

PKA can also phosphorylate receptors with similar amino acid sequences so other receptors than in the β2 ARs can be desensitised without having first been stimulated by a ligand

138
Q

Can one GPC are couple to more than one G protein

A

Yes and can also be activated by multiple agonists

139
Q

What is the bias of an agonist

A

The degree by which the agonist activates different pathways

140
Q

What can β arrestin do for GPCRs

A

Recruitment of β arrestin blocks the G protein interaction but can now enable additional G protein independent signalling events

141
Q

Give an example of a drug that uses GPCR bias

A

Oliceridine
TRV130

μ-opioid receptor biased agonist that elicits robust G protein signalling, with potency and efficacy to morphine but with less β arrestin 2 recruitment and receptor internalisation thus having reduced adverse effects compared to morphine

MoDA (6 decks)

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