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chem141 > Receptors And Signal Transduction - Done > Flashcards

Receptors And Signal Transduction - Done Flashcards

1
Q

What is the role of receptors?

A

To provide a communication system between cells, tissues and organs - essential in a complex organism

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2
Q

What is the difference between the sympathetic and parasympathetic nervous systems?

A

Parasympathetic - normal body function, cranial region

Sympathetic - fight or flight, spinal region

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3
Q

Describe the structure of a typical nerve cell

A
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4
Q

What’s the gap between neutrons and target cells?

A

100Å

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5
Q

What are the secondary effects of a neurotransmitter binding?

A

Binding leads to either:

A flow of ions across the cell membrane

Switching enzymes within the cell on/off - protein kinases

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6
Q

Give an example of a prostaglandin

A

Alprostadil

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7
Q

Give an example of a neuropeptide

A

B - endorphin

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8
Q

How do hormones travel such great distances?

A

They are released into the circulatory system by glands

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9
Q

Do chemical messengers that bind to receptors undergo a chemical reaction?

A

No - different to enzymes

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10
Q

What 2 processes happen after an induced fit at a receptor?

A

Signal amplification and signal transduction must then occur to produce an observable biological effect

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11
Q

What are the 3 types of membrane bound receptors involved in triggering signal transduction? How fast do they work?

A

Ion channel receptor - milliseconds

G-protein coupled receptors - seconds

Kinase-linked receptors - minutes

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12
Q

How many protein subunits doe an ion channel have?

A

5 protein subunits

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13
Q

How does signal amplification work in ion channels?

A

Relatively mall number of neurotransmitter molecules - opens a few ion channels - several thousand ions mobilised

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14
Q

What’s the difference in subunits between ion channels l and ll?

A

Ion channel l has
2 alpha
1 beta
1 gamma
1 sigma

Ion channel ll
3 alpha
2 beta

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15
Q

What receptor are the l and ll ion channels controlled by?

A

Ion channel l - nicotinic cholinergic receptor

Ion channel ll - glycine receptor

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16
Q

Where are the binding sites located on ion channel l & ll?

A

Ion channel l - 2 binding sites on alpha subunits

Ion channel ll - 3 binding sites on alpha subunits

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17
Q

How many loops/chains does the alpha subunit have, intracellular or extra-cellular?

A

1 lengthy extracellular N-terminus chain
1 lengthy C-terminus extracellular chain
1 extracellular loop

1 intracellular loop
1 variable intracellular loop

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18
Q

Where is Transmembrane receptor subunit 2 always facing?

A

TM2 faces the central pore of the ion channel

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19
Q

How does the structure of the TM2 subunit contribute to opening/closing of the ion channel?

A

TM2 is a kinked alpha helix, so one from each protein subunit changes conformation on binding to allow ions to pass through

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20
Q

How do ligand gated and voltage gated ion channels differ?

A

Ligand gated - controlled by a chemical messenger

Voltage gated - sensitive to the potential difference that exists across a cell membrane - membrane potential
- important drug targets for local anaesthetics
- opens when membrane is depolarised.

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21
Q

What % of marketed drugs act at G-protein coupled receptors and how are they activated?

A

30%

Activated by hormones and slow-acting neurotransmitters
-response time measured in seconds

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22
Q

Describe how the general mechanism in g-protein coupled receptors

A

1 - resting state - inner binding site is closed

2 - once messenger binds, receptor changes conformation and G-protein binds to newly opened inner site - allosteric

3 - G-protein becomes destabilised and fragments into monomer and dimer.

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23
Q

How many transmembrane domains does G-protein coupled receptors?

A

7

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24
Q

What chain is external in G-protein coupled receptors N or C - terminus?

A

N - terminus

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25
Q

What ligands bind to G-protein coupled receptors?

A

Monoamines - dopamine, histamine, noradrenaline, acetylcholine

Nucleotides

Lipids

Hormones

Glutamate

Ca2+

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26
Q

Where are the G-protein coupled receptor ligand’ binding sites?

A
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27
Q

What are the three classes of G-protein coupled sub receptors?

A

Class A - rhodopsin like receptors

Class B - secretin like receptors

Class C - metabotrophic glutamate like and pheromone receptors

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28
Q

What class of G-protein coupled sub receptors is the most important in drug discovery /development?

A

Class A - rhodopsin like

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29
Q

Define divergent evolution

A

Various receptor subtypes diverge from a common evolutionary branch - eg. Dopamine subtypes D2,D3 and D4

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30
Q

Define convergent evolution

A

Receptor subtypes found in separate branches - eg. D1A, D1B and D5 are convergent to D2, D3 and D4

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31
Q

Why is greater similarity of receptors a problem for medicinal chemists?

A

Possible selectivity issue

Design of selective drugs is paramount to reduce side effects

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32
Q

What receptor subtypes are found in heart muscle?

A

Beta1 adrenergic receptors

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33
Q

What receptor subtypes are found in fat cells?

A

Beta3 adrenergic receptors

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34
Q

What receptor subtypes are found in bronchial muscle?

A

Alpha1 and Beta2 adrenergic receptors

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35
Q

What receptor subtypes are found in the GI-tract?

A

Alpha1, Alpha2 & Beta2 adrenergic receptors

36
Q

Why do kinase-linked receptors not require G-proteins?

A

Because they activate enzymes directly

37
Q

What’s the key kinase-linked receptor type?

A

Tyrosine kinase receptors are important receptors

38
Q

What cofactor is required for kinase linked receptors?

A

ATP - to provide necessary phosphate group

39
Q

How does signal amplification occur in kinase linked receptors?

A

Active site remains open for as long as messenger molecule is bound - several phosphorylation reactions take place

40
Q

What ligands activate kinase linked receptors?

A

Polypeptide hormones, growth factors and cytokines

41
Q

What can a loss of function of kinase linked receptors cause?

A

Developmental defects or hormone resistance

42
Q

What can an overexpression of kinase linked receptors?

A

Malignant growth disorders

43
Q

Describe the structure of kinase-linked receptors

A
44
Q

What reaction does tyrosine kinase catalyse?

A

Phosphorylation of tyrosine residue

45
Q

Describe how the epidermal growth factor (EGF) receptor works

A
46
Q

What’s the purpose of phosphorylation of tyrosine residues?

A

Phosphorylated regions act as binding sites for further proteins and enzymes - resulting in activation of signalling proteins and enzymes

  • message carried into the cell
47
Q

How does the insulin receptor work?

A

Receptor already exists as a tetramer

Insulin binds (opening active site) and then phosphorylation occurs

48
Q

How does the growth hormone receptor work?

A

GH binds and dimerisation occurs
2 kinases bind - form tetramer - and activates kinase enzymes

Phosphorylation occurs

49
Q

What are the general principles of intracellular receptors?

A

50 members of this group directly regulate gene transcription
- nuclear hormone receptors or nuclear transcription factors

Response time - hours or days

Chemical messengers must be hydrophobic and must cross cell membrane

Example - steroids and steroid receptors

50
Q

Describe how a messenger triggers or inhibits the start of transcription

A

Messenger passes through surface membrane

Binds to a receptor and dimerises

Co-activator protein binds to dimer - then transcription is either triggered or inhibited, affecting the eventual synthesis of a protein

51
Q

What role do zinc ions have in intracellular receptors?

A

They stabilise and determine the conformation of the DNA binding region

52
Q

Describe the signal transduction pathway for Gs - protein coupled receptor

A

1 - Alpha subunit binding pocket binds guanosine diphosphate (GDP)

2 - Neurotransmitter binds receptor - opens intracellular binding site

3 - G-protein now binds and changes shape - GDP released

53
Q

What does the alpha subunit + or - activate?

A

cGMP phosphodiesterase

54
Q

What do alpha s and i subunits activate?

A

Adenylate cyclase

55
Q

What does the alpha q subunit activate?

A

Phospholipase C

56
Q

What does the alpha o subunit activate?

A

Ca2+ ion channels

57
Q

What does the alpha i subunit activate?

A

K+ ion channels

58
Q

What pathway follows once adenylate cyclase is activated?

A

Adenylate cyclase —> cAMP —> PKA

59
Q

What two pathways follow after phospholipase C is activated?

A

Phospholipase C —> IP3 —> Ca2+

Phospholipase C —> DAG —> PKC

60
Q

Describe the process by which adenylate cyclase is activated

A

1 - alpha subunit binds to adenylate cyclase

2 - binding opens the active site and ATP is converted to cAMP - signal transduction

3 - GTP in alpha subunit hydrolysed to GDP by alpha subunit

4 - GDP causes a change in shape of alpha subunit - weaker binding to enzyme so subunit departs - closing adenylate cyclase active site.

5 - alpha s subunit recombines with Beta-gamma dimer to reform Gs protein

61
Q

What’s the benefit of the adenylate cyclase active site staying open as long as ås subunit is bound?

A

Several hundred ATP converted before ås - GTP is deactivated
- signal amplification

Cyclic AMP becomes secondary messenger - enters cell cytoplasm with message

62
Q

What is protein kinase A?

A

A serine-threonine kinase

63
Q

What activates PKA?

A

Cyclic AMP - need ATP

64
Q

What does PKA do?

A

Catalyses phosphorylation of serine and threonine residues on protein substrates, turning the enzyme on

Phosphate provided by ATP

65
Q

PKA subunit C phosphorylates 3 enzymes, what are those enzymes?

A

Glycogen synthase - inactivates, stops glycogen production

Phosphorylase kinase - activates

Inhibitor - activates inhibitor of phosphtase which stop Phos-a going back to Phos-b

66
Q

What does phosphorylase kinase cause?

A

It phosphorylates phosphorylase kinase b to phosphorylase a

Converts glycogen to glucose-1-phosphate

67
Q

What causes glycogen metabolism?

A

Triggered by adrenaline in liver cells

ås subunit binds adenylate cyclase - produces cAMP from ATP
cAMP activates PKA…

68
Q

What is the coordinated effect?

A

Activation of glycogen metabolism & inhibition of inhibition of glycogen synthesis

69
Q

How does the Gi-protein differ to the Gs-protein?

A

åi subunit inhibits adenylate cyclase

Adenylate cyclase is under dual control - depends on dominant alpha subunit

70
Q

What are the key points to do with signalling cascade involving cAMP?

A

Explains signal amplification through the molecular ‘relay runner’ - G-protein

Explains how the message delivered reaches enzymes within the cell

71
Q

Give the roles of the beta-gamma dimer

A

Can activate adenylate cyclase

Regulation by dimer becomes more important where more receptors are activated

Higher conc of dimer are required for same effect as monomer

Control other enzymes

72
Q

What is phosphorylation involved in?

A

Key in the (de)activation of enzymes

Also involved in desensitisation of G-protein linked receptor

73
Q

Where does the åq subunit come from?

A

A Gq-protein - same splitting mechanism as Gs and Gi

74
Q

What does the åq subunit do?

A

It activates / deactivates phospholipase C (membrane bound enzyme)
-reaction catalysed for as long as åq subunit is bound, signal amplification

Brake and accelerator effect

75
Q

Describe the Gq-protein effect on phospholipase C (PLC)

A

1 - åq subunit with GTP bound binds to PLC

2 - PIP2 bound splits into IP3 and DG, phosphate is lost from GTP

3 - GDP formed, reaction stops as åq subunit moves away / unbinds

76
Q

What properties does Diacylglycerol have?

A

DG is hydrophobic so remains in cell membrane when formed

77
Q

What does DG activate? What happens next?

A

Protein kinase C (PKC)

PKC then moves to cell membrane from cytoplasm and catalyses phosphorylation of serine and threonine residues of enzymes

78
Q

What effects does Diacylglycerol induce?

A

Tumour propagation

inflammatory response

Contraction or relaxation of smooth muscle, etc.

79
Q

How does IP3 differ to DG?

A

IP3 enters the cytoplasm as its hydrophilic

80
Q

What is the action of IP3?

A

IP3 activates calcium stores, activating protein kinases through Ca2+ ions and calmodulin with Ca2+ bound

81
Q

What happens to IP3 and DG once their tasks have been completed?

A

They are recombined through a complex synthesis - cannot be linked directly

82
Q

What do lithium salts treat and how is this achieved?

A

Used to treat manic depression

Interfere with the complex synthesis for IP3 and DG recombination

83
Q

What’s the benefit of phosphorylating kinase-linked receptors?

A

Each phosphorylated region can bind to a specific signalling protein or enzyme

84
Q

What does Guanylate cyclase do and why’s it special?

A

It opens Na+ channels in kidney

Special as it acts as both a receptor and enzyme

85
Q

What biological effect does Ca2+ cause?

A

Smooth muscle and cardiac muscle contraction

86
Q

What biological effect does PKC cause?

A

Tumour propagation & inflammatory response

87
Q

What biological effect does GAP have?

A

GTPase-activating proteins

chem141 (12 decks)

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