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MODA > Dr Edwardson - Binding > Flashcards

Dr Edwardson - Binding Flashcards

0
Q

What effects can activation of a receptor have on a cell?

A
  • Changes in membrane permeability (and therefore membrane potential)
  • Generation of second messengers
  • Protein phosphorylation
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1
Q

What is a receptor?

A

A receptor is a signal transduce and usually respond to neurotransmitters, hormone and autacoids

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2
Q

How do drug receptor complexes form?

A
  1. Needs very close complementarity between surface topography of drug and receptor
  2. Energy barrier may be reduced by ‘induced fit’
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3
Q

Give an example of induced fit between and receptor and a substrate.

A

Glucagon and its receptor

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4
Q

Why are drug said to be selective but not specific?

A

Because they often interact with a number of receptors at different concentrations

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5
Q

What is the therapeutic index of a drug?

A

An indicator of how toxic a drug is compared to its effectiveness

Toxic dose / Therapeutic dose

(TD50/ED50)

TD50 - The dosage that would be toxic for 50% of the population
ED50 - The minimum dosage that would be effective for 50% of population

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6
Q

Why is a semi log plot used to plot a [drug] response curve?

A

Pseudo linear region
Competitive antagonist gives a parallel shift
(can accommodate large shifts)

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7
Q

What is efficacy?

A

The ability of a drug to activate a receptor

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8
Q

What is affinity?

A

The concentration of the drug to the proportion bound to the receptor

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9
Q

What is the difference between an agonist and an antagonist?

A

Agonist has both affinity and efficacy, whereas an antagonist only has affinity

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10
Q

Name an agonist, antagonist and the receptor type of smooth muscle.

A

Muscarine
Atropine
Muscarinic

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11
Q

Name an agonist, antagonist and the receptor type of striated muscle.

A

Nicotine
d-tubocurarine
nicotinic

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12
Q

What effect on the drug response curve will the use of racemate have, if only one of the isomers has affinity?

A

It will cause a parallel shift as the concentration of the effective isomer is half that of the racemate

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13
Q

What effect on the drug response curve will the use of a racemate have when one isomer is an agonist and the other an antagonist?

A

There will be a reduced gradient and right shift as you are both increasing the concentration of the effective isomer and that of the antagonist

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14
Q

What is the receptor occupancy equation?

A

a = [D]K1 / 1+[D]K1

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15
Q

What is the disassociation constant equal to?

A

50% occupancy!

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16
Q

What are the relative affinities of specific and non specific binding?

A

Specific has high affinity but low capacity

Non-specific has high capacity but low affinity

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17
Q

Why is Kd not equal to the EC50?

A

Because there is not a direct proportionality between receptor occupancy and effect

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18
Q

What is a Scatchard plot?

A

A graph of B (x axis) against B/[D] (y axis)

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19
Q

What information can you calculate from a Scatchard plot?

A

The Ka (- dy/dx) and the Bmax (the x intercept)

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20
Q

What does it mean if the Scatchard plot has two gradients?

A

That there are two receptors (with different affinities)

That it is a G protein coupled receptor (as these have two affinity states)

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21
Q

What is the receptor occupancy equation for when there are two ligands present?

A

a = [D]K1 / [D]K1 + [A]K2 + 1

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22
Q

What is the dose ratio?

A

[D]2 / [D]1 = 1 + [A]K2

where [D]2 / [D]1 is the dose ratio

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23
Q

What can be calculated from the Schild plot?

A

The logK2 (from the x intercept)

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24
Q

What is a Schild plot?

A

A graph of the log(Dose ratio - 1) against -log([antagonist])

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25
Q

What can be calculated from a radioligand binding graph?

A

Specific and non specific binding and the IC50

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26
Q

What equation can be used with the radioligand binding graph? And how is this equation different if the U and L are the same molecule?

A

Ku = 1 + [L]KL / IC50

If Ku = KL then….

K = 1 / (IC50 - [L])

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27
Q

What effect does addition of the unlabelled ligand have on the non specific binding

A

None

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28
Q

Why is there initially a maximal response upon the addition of a reversible inhibitor?

A

Because there is a receptor reserve present (not all of the receptors need to be stimulated in order to achieve a maximal response)

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29
Q

How does benzilylcholine mustard cause irreversible inhibition of the muscarinic ACh receptor?

A

By alkylation of the ACh binding site and of an allosteric site that stabilises its inactive state

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30
Q

Why is having a receptor reserve useful?

A

It allows a large response to a small receptor occupancy therefore increasing sensitivity

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31
Q

What is a partial agonist?

A

An agonist that cannot cause a maximal response

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32
Q

What is the Hill equation?

A

n.log[D] - log[Kdiss]

where n is a measure of cooperativity (the number of ligand needed to produce a response)

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33
Q

What can be calculated from a Hill plot?

A

The cooperativity (from the gradient)

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34
Q

What are the stages of affinity chromatography when purifying a receptor?

A

Receptor binds to substrate (which is bound to the gel bead)

Receptor is retained

Addition of excess substrate cause the dissassociation from the beads

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35
Q

What are the three structural types of ionotropic receptors

A

Pentameric (cys-loop family) - eg NAChR

Tetrameric - Glutamate receptor

Trimeric - P2X

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36
Q

What are the four receptor families?

A

The ligand gated ion channels

The G protein coupled receptors

Enzyme linked receptors

Receptors that bind to DNA

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37
Q

What are the features of the tetrameric ionotropic receptor ?

A

3 TM domains (M1, 3 and 4)

Re-entrant M2 domain

Extracellular N-terminus
Intracellular C-terminus

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38
Q

What are the structural features of the GPCRs?

A
  • 7 TM domains
  • Extracellular N-terminus
  • Intracellular C-terminus
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39
Q

How does cholera toxin work?

A

ADP ribosylation of the alpha subunit

Inhibits the hydrolysis of the GTP by alpha-s = persistent activation

This causes an increase in cAMP

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40
Q

How does pertussis toxin work?

A

ADP ribosylation of the alpha-i subunit

Prevents stimulation of alpha-i

Blocks inhibition of adenylyl cyclase = ^ cAMP

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41
Q

What are the relative affinities of the ligand when GTP is bound and unbound?

A

GTP bound = lower affinity for ligand

GTP unbound = higher affinity for ligand

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42
Q

Where does cAMP bind to PKA?

A

The regulatory domain

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43
Q

What is the role of AKAP in a signalling cascade?

A

It acts as scaffolding protein, anchoring the signalling molecules a membrane

This acts to organise the reaction chain

44
Q

What does production of IP3 cause and how?

A

It cause the release of Ca2+ from the ER via an IP3 receptor (needs 4 IP3 molecules to activate)

45
Q

What are the two mechanism by which desensitisation can occur?

A

Via a change in the coupling to G protein (a decreased response)

By internalisation of the receptor and their degradation

46
Q

What is the role of receptor desensitisation?

A

It allow cells to adjust their sensitivity to prevailing range of stimulation

47
Q

What is homologous receptor desensitisation?

A

It is when activation of the β2-receptor results in the recruitment of β-adrenoceptor kinase (βark)

βark then phosphorylate a site at the end of the C-terminal domain

This phosphorylation then increase the affinity of the β2-receptor for β-arrestin

The binding uncouples the receptor from the α-subunit thus causing desensitisation

48
Q

What does AlF4- do?

A

It mimics to gamma-phosphate of GTP and cause persistent activation of G proteins

49
Q

What is heterologous desensitisation?

A

This is when activation of the β2-receptor causes an increase in cAMP which in turn activates PKA

If there is a large rise in PKA (due to excessive stimulation) then PKA will then phosphorylate the β2-receptor at its C terminus and its 3rd cytoplasmic loop

This causes uncoupling of the a-subunit and thus prevents further stimulation

50
Q

What are the difference between homologous and heterologous desensitisation?

A

Homologous at high conc (requires greater stimulation to phosphorylate more sites)

Heterologous at low conc

Heterologous acts upon other receptors (PKA is less specific)

51
Q

Which protein domains interact with activated RTKs?

A

SH2 domains

52
Q

What class of drugs can be used to inhibit tyrosine kinases (selectively)?

A

Tyrphostins

53
Q

What protein are steroid receptors commonly complexed with when inactivated?

A

hsp90

54
Q

What are the four domains of a steroid receptor?

A

Transcription activating domain

DNA binding domain

Hinge domain

Steroid binding domain

55
Q

Which protein is an essential chaperone for steroid receptors?

A

hsp70

56
Q

What is hydrocortisone?

A

A glucocorticoid agonist and anti-inflammatory used for the treatment of asthma

57
Q

What is beclomethasone?

A

An immunosuppressive glucocorticoid agonist

58
Q

What is mifepristone?

A

A glucocorticoid antagonist used as an abortifacient

59
Q

What is fludrocortisone?

A

A mineralocorticoid agonist used as replacement therapy in Addison’s disease (replaces aldosterone)

60
Q

What is spironolactone?

A

A mineralocorticoid antagonist used as a diuretic

61
Q

What is estradiol?

A

An oestrogen agonist used in hormone replacement therapy

62
Q

What is ethinylestradiol?

A

An oestrogen agonist used as a contraceptive

63
Q

What is tamoxifen?

A

A oestrogen antagonist used in the treatment of breast cancer

64
Q

What is norethisterone?

A

A progesterone agonist used as a contraceptive

65
Q

What is mifepristone?

A

A partial agonist of progesterone used as an abortifacient

66
Q

What is danazol?

A

A progesterone antagonist used in the treatment of endometriosis, menorrhagia and gynacomastia (man boobs)

67
Q

What is stanazol?

A

an androgen agonist used as an anabolic agent

68
Q

What is flutamide?

A

An androgen antagonist used in the treatment of prostate cancer

69
Q

What is the MODA of local anaesthetics?

A

They block voltage-gated Na+ channels in all excitable tissues

70
Q

What is the general structure of a local anaesthetic?

A

Aromatic group–Ester of amide link–Tertiary amine

71
Q

Why are local anaesthetics selective to pain fibres?

A

They target fibres with small diameters and therefore block Type C fires and Type Aδ first

In addition to this they act upon fibres with a high rate of firing (pain fibres have this)

Pain fibres also has a long AP meaning there is an increased chance of binding

72
Q

What is the difference in the properties between a local anaesthetic with an ester link and one with an amide link?

A

The ester link is stronger and therefore a local anaesthetic with an ester link will have a longer half life

73
Q

What are the three states of a Na+ VGC?

A

Open
Closed
Inactivated

74
Q

Why is the pH of the solution surrounding the cell important for the action of local anaesthetics?

A

Because the local anaesthetics charge is important to action (may need to be uncharged to pass through the membrane)

75
Q

What is use dependence and what cause it?

A

Use dependence is when an increase in the rate of stimulation of a nerve fibre increases the effectiveness of a local anaesthetic

76
Q

Why is benzocaine not use dependent?

A

Because it is uncharged

77
Q

Which local anaesthetics show use dependence?

A

Lidocaine and novacaine

78
Q

Is the hydrophobic or hydrophilic pathway use dependent?

A

Hydrophilic

79
Q

Why is rate dependence important in Na+ channel blockers?

A

Because it determines which tissue the anti-dysrhythmic drugs act upon

Eg slow in/out = low frequency tissues

80
Q

What are TTX and STX? and where do they act?

A

Tetrodotoxin and satitoxin

They both bind to the outer mouth of the Na+ VGC pore to Glu residues

81
Q

What is batrachotoxin?

A

A Na+ VGC activator, causing it to activate at lower potentials = ^ excitability

82
Q

What is aconitine?

A

A Na+ VGC activator, causing it to activate at lower potentials = ^ excitability

83
Q

How does scorpion α toxin act?

A

It is a Na+ VGC activator, causing it to activate at lower potentials = ^ excitability

84
Q

What are the four types of Ca2+ channel? and where are they found?

A

L-type is found in smooth muscles and glands

N-type, P-type and T-type are found in nerve cells

85
Q

What are the three types of drugs used as Ca2+ blockers?

A

dihydropyrimidines, phenylalkylamines and benothiazepines

86
Q

What is nifedipine?

A

A dihydropyridine Ca2+ VGC blocker

87
Q

What is verapamil?

A

A phenylalkyamine Ca2+ VGC blocker

Class IV antidysrhythmic (reduces Ca2+ entry)

88
Q

What is diltiazem?

A

A benzothiazepin Ca2+ GVC blocker

89
Q

Upon which channel type do most Ca2+ VGC blockers act?

A

Upon L-type

90
Q

What is mibefradil

A

It is a benzimidazolyl tetraline Ca2+ VGC blocker that acts upon L and T-type channels

91
Q

What are the three modes of a Ca2+ VGC and how are these established?

A

0, 1 and 2

0 - Ca2+ antagonist
1 - no drugs
2 - Ca2+ agonist

92
Q

Which Ca2+ VGC blockers show use dependence and what are the implications of this?

A

Verapamil and diltiazem

This means that they are cardiac selective

93
Q

What feature of DHPs means that they are effective in the treatment of angina and hypertension?

A

They bind preferentially to the inactivated form of the channel

smooth muscles undergoes long periods of depolarisation

Therefore they are vascular selective

94
Q

What are the two main families of K+ channels?

A

VGCs and Inward rectifiers

95
Q

What are the features of K+ VGCs?

A

They have 6 TM segments
Functional channel is a tetramer
S4 is the voltage sensor
S5 and 6 form the selectivity filter

96
Q

What are the features of Kirs?

A

Tetramer of 2TM helices

Linked by a pore helix and a selectivity filter

97
Q

What are the three subfamilies of K+ channels?

A

Ca2+ activated
G protein-activated
ATP sensitive

98
Q

What is cromakalim?

A

A KCO used as an antihypertensive

99
Q

What is diazoxide?

A

A KCO used as an antihypertensive

100
Q

What is minoxidil?

A

A KCO used to treat baldness and hypertension

101
Q

What is the MODA of KCOs?

A

They act upon ATP-sensitive K+ channels in vascular smooth muscles

Inhibit ATP binding = channel stays open

= relaxation

102
Q

What are the negative side effects of KCOs as antihypertensive agents?

A

KCOs decrease glucose tolerance

Hyperglycaemia

103
Q

How do ATP sensitive K+ channels function in pancreatic cells?

A

ATP produced by metabolism cause the channel to close

This results in depolarisation

= Ca2+ enters
= insulin release

104
Q

What is tolbutamide?

A

A sulphonylurea used to treat diabetes by inhibiting the opening of the KATP channel

105
Q

What is glibenclamide?

A

A sulphonylurea used to treat diabetes by inhibiting the opening of the KATP channel

106
Q

How do sulphonylureas cause insulin release?

A

They bind to a site on the KATP (the sulfonylurea receptor) and decrease the opening of the channel leading to depolarisation

108
Q

What are the three types of SUR and where are they found?

A

SUR1 in β cells
SUR2A in the heart
SUR2B in blood vessels

109
Q

What are the properties of ion channels?

A

Voltage sensitive

Ion selective

Time depend (takes time to come to equilibrium with new membrane potential)

MODA (8 decks)

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