M&R Session 6 Flashcards

0
Q

How can signalling by secreted molecules be subclassified?

A

Paracrine
Endocrine
Synaptic

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1
Q

How can intracellular signalling occur?

A

Secretion of signalling molecules

Where adhesion proteins in adjacent cells are in contact

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2
Q

What is paracrine signalling?

A

Signal molecules act on adjacent cells

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3
Q

What is endocrine signalling?

A

Signal molecules enter the bloodstream and act on distal tissues

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4
Q

What is synoptic signalling?

A

Use of neurotransmitter as a signal molecule

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5
Q

How do hydrophilic signalling molecules work?

A

Bind to cell surface receptors

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6
Q

How do hydrophobic signalling molecules work?

A

Transported by carrier protein and bind to intracellular receptors in cytoplasm or nucleus

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7
Q

What is a receptor?

A

A molecule that recognises specifically a second molecule or family of molecules and in response brings about regulation of a cellular process

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8
Q

Describe an unbound receptor.

A

Functionally silent

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9
Q

What is a ligand?

A

A molecule that binds specifically to a receptor site

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10
Q

What is an antagonist?

A

A ligand which binds with the receptor site but does not cause activation

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11
Q

Does an antagonist switch off a receptor?

A

No. It prevent agonist binding therefore prevents switch on

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12
Q

What is an agonist?

A

A ligand which binds and causes activation of a receptor

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13
Q

What are the roles of receptors in cellular physiology?

A
Cell adhesion
Signalling by hormones/local chemical mediators
Neurotransmission
Modulation of immune response
Release of intracellular calcium stores
Control of gene expression
Cellular delivery
Sorting if intracellular proteins
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14
Q

How does the binding affinity at receptor sites compare to at enzyme sites?

A

Generally much higher

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15
Q

What accounts for the difference in affinity b/w receptor and enzyme binding sites?

A

Ligands generally have to travel much further than substrates and allosteric regulators for enzymes therefore are more diluted

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16
Q

What is KD?

A

The concentration of ligand required to half fill all available receptors

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17
Q

What are they comparative ranges of affinity for receptor and enzyme binding sites?

A
Receptor = 10^-9 M to 10^-6 M
Enzyme = 10^-6 M to 10^-3 M
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18
Q

How are receptors classified?

A

Specific agonist

Affinity to a series of antagonists

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19
Q

How are ACh receptors classified?

A

ACh
Nicotinic/muscarinic
Muscarinic into M1-M5 determined by the antagonists for which they have the highest affinity for

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20
Q

Give the antagonists which the receptors M1-M3 have the highest affinity for respectively.

A
M1 = Pirenzipine
M2 = Gallomine
M3 = Hexahydrosiladiphenol
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21
Q

How does an acceptor differ to a receptor?

A

An acceptor operates in the absence of ligand and ligand binding alone produces no response

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22
Q

Give two examples of acceptor molecules, explaining why they are not receptors.

A

Dihydrofolate reductase - functions in absence of methotrexate
Sodium channel - modulated by binding of other chemicals and functions w/out anaesthetic

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23
Q

What are membrane-bound receptors w/integral ion channels also called?

A

Classical ligand-gated ion channels

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24
Q

Describe the structure of nAChR.

A

5 subunits put -ve residues at mouth of channel

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25
Q

Give 5 examples of membrane-bound receptors w/integral ion channels.

A
nAChR
GABA receptor
Glycine receptor
Glutamate receptor
IP3 receptor
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26
Q

What ions do nAChR permit the passage of?

A

Sodium
Potassium
Calcium

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27
Q

What is the function of gamma amino butyric acid receptors?

A

Gated chloride channels which allow membrane hyperpolarisation

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28
Q

What ion movement do glycine receptors control?

A

Chloride

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29
Q

Give examples of glutamate receptors and state what ionic movement they control.

A

NMDA
Kainate
AMPA
All allow gated calcium entry

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30
Q

What does inositol 1,4,5-triphosphate allow?

A

Gated released of calcium from the ER

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31
Q

Give three examples of non-classical ligand-gated ion channels.

A

ATP-sensitive potassium channel
Purinoceptor
Ryanodine receptor

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32
Q

Describe the structure of ATP-sensitive potassium channels.

A

A channel pore with an ATP molecule on the intracellular side between 2 transmembrane domains

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33
Q

How does the structure of a purinoceptor relate to that of an ATP-sensitive potassium channel?

A

The same except for the shape of the channel pore and the location of the ATP molecule on the extracellular side

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34
Q

Describe the structure of a ryanodine receptor.

A

Four transmembrane domains with calcium and ryanodine linked to the first domain

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35
Q

Give two examples of membrane-bound receptors w/integral enzyme activity.

A

Atrial natriuretic peptide receptor

Dimeric growth factor receptor

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36
Q

What are ANP receptors directly linked to?

A

Guanylyl cyclase (GTP –> cGMP)

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37
Q

What are dimeric growth factor receptors directly linked to?

A

Tyrosine kinase

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38
Q

Describe the mechanism of dimeric growth factor receptors.

A

Allow phosphorylation of tyrosine for growth

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39
Q

Give some examples of the resultant molecules from activation of dimeric growth factor receptors.

A

Insulin
Epidermal growth factor
Platelet-derived growth factor

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40
Q

What is autophosphorylation?

A

Phosphorylation of the chain in the opposite subunit of a dimer - allows cross communication

41
Q

How does autophosphorylation facilitate the function of a tyrosine kinase-linked receptor?

A

The multiple phosphorylated a.a. residues give a specific site for binding which is recognised by transducing proteins which are allosterically activated/phosphorylated to regulated an intracellular event

42
Q

How are insulin receptors synthesised?

A

Alpha and beta chains are made together and cleaved extracellularly, held together in the membrane by sulphide bridges

43
Q

Describe the structure of insulin receptors in the plasma membrane.

A

Two tyrosine kinase domains intracellularly
Two transmembrane domains joined by a disulphide link (beta chains)
Two insulin binding domains linked to the two transmembrane domains by disulphide links (alpha chains) extracellularly

44
Q

Give three examples of membrane-bound receptors that signal through transducing proteins.

A

Coupled through GTP-binding regulatory proteins to enzymes/channels
Beta-adrenoreceptors activate the enzyme adenylyl cyclase via Gs
M2 stimulates potassium channel opening by Gi

45
Q

Where are binding domains found in GPCRs?

A

W/in the plane of the bilayer

46
Q

How many transmembrane receptors are there in membrane bound receptors that single through transducing proteins?

A

Seven

47
Q

Where are both beta-adrenoreceptors and M2 receptors found?

A

In the heart

48
Q

Describe the function of activating stimulatory/inhibitory receptors in receptors that use transducing proteins.

A

Receptor binding causes dissociation of GTP from alpha-s/i which acts in the target enzyme to stimulate/inhibit it

49
Q

Describe the mechanism of action of beta-adrenoreceptors.

A

Adrenaline binds–> G-protein subunit dissociation (alpha and beta move away)–> Gs-alpha binds to target enzyme adenylyl cyclase whilst it is combined with a new molecule of GTP –> cAMP produced

50
Q

What changes between intracellular receptors?

A

Their primary structure

51
Q

What do all hydrophobic signals use?

A

Similarity of sequence of intracellular receptors

52
Q

Describe the mechanism of intracellular receptor activation.

A

Binding of hormone –> huge conformational change –> inhibitory protein complex removed –> DNA binding site exposed

53
Q

What is the DNA binding site of an intracellular receptor also known as?

A

Zinc fingers

54
Q

What are intracellular receptors silent at rest?

A

The DNA site is blocked

55
Q

Describe the mechanism of amplification.

A

Single, v. low concentration signal molecule binds in one receptor –> small number of GPCR activated –> cAMP –> PKA –> emzyme –> products

56
Q

What is the magnitude of amplication by receptors?

A

x10^9

57
Q

Compare the activation and inhibition of receptors in hepatocytes.

A

Insulin stimulates glycogenesis

Glucagon stimulates glycogenolysis

58
Q

How is heart rate increased in cardiac pacemaker cells?

A

Noradrenaline binds to beta-1 adrenoreceptors

59
Q

How is heart rate decreased in cardiac pacemaker cells?

A

ACh binds to M2 muscarinic receptors

60
Q

How is the plasma membrane trafficked to its final position?

A

From the ER to the CSM via the exocytic secretory pathway

61
Q

What prevents the CSM being excessively ruffled?

A

Endocytosis of the membrane

62
Q

What is the pathway of vesicular transport of membrane?

A

Donor organelle –> membrane vesicle –> trafficked to destination –> fuse w/recipient organelle

63
Q

What is the function of pinocytosis?

A

Permits uptake of extracellular so lutes

64
Q

How does pinocytosis take place?

A

Invagination of the CSM to form a vesicle

65
Q

What is the function of phagocytosis?

A

Internalisation of particulate matter

66
Q

What is the mechanism of phagocytosis?

A

Receptors sequentially bind to ‘zip up’ around engulfed material

67
Q

Describe endocytosis.

A

Selective internalisation of molecules into cell by binding to specific cell surface receptors

68
Q

What is cholesterol uptake an example of?

A

Receptor-mediated-endocytosis

69
Q

Describe the structure of LDLs

A

Core of esterified cholesterol
Contain apoprotein B
Core covered by a phospholipid and cholesterol monolayer

70
Q

What do triskelions comprise of?

A

3 clathrin heavy chains
3 clathrin light chains
Always arranged in the same way

71
Q

What allows the coat structure to form vesicles instead of tubes and sheets?

A

The hexagon and pentagon structure

72
Q

Describe the mechanism of clathrin coating.

A

Clathrin coated pits form spontaneously –> protein coats prevent vesicle binding so must be removed –> uncoated by an ATP-dependent uncoating protein

73
Q

How do clathrin coated pits form spontaneously?

A

Association of more and more triskelions on cell face

74
Q

What happens to the clathrin triskelions removed by the uncoating protein?

A

Recycled back to newly forming clathrin coated pits

75
Q

What two mutations can occur which affect LDL receptor in hypercholesteroleamia?

A

Non functional receptor

Receptor binding normal but no internalisation

76
Q

What happens when there is no internalisation of LDL receptors?

A

LDL receptors are over the whole cell surface, not localised into pits
Deletion of C-terminal cytoplasmic domain prevents interaction w/clathrin coat

77
Q

What is the fate of the ligand and receptor in cholesterol uptake?

A

Ligand degraded

Receptor recycled

78
Q

What is CURL?

A

Compartment of Uncoupling of Receptor and Ligand

79
Q

What is the affect of the low pH in the endosome?

A

It decreases the affinity of the receptor for LDL

80
Q

What molecule allows uptake of ferric ions?

A

Transferrin

81
Q

Describe the uptake of ferric ions.

A

Ferrotransferrin binds to transferrin receptor in coated pits –> coated vesicles –> pH in vesicle decreases due to hydrogen-ATPase –> ferric ions released from CURL –> apotransferrin released by CURL in pH 5 vesicle –> neutral pH at cell surface causes dissociation of apotransferrin from receptor

82
Q

Why is it useful for the ligand to be recycled in ferric ion uptake?

A

It is a large molecule so you don’t want to use lots of energy having to make it

83
Q

What is the fate of the ligand and receptor in ferric ion uptake?

A

Ligand recycled

Receptor recycled

84
Q

What is the fate of the ligand and receptor in the endocytosis of insulin?

A

Ligand degraded

Receptor degraded

85
Q

What happens if insulin is high for a long time?

A

Receptors are removed to prevent overreaction but then it takes a few hours to synthesise replacements

86
Q

How does chronic hyperglycaemia lead to T2DM?

A

Vicious cycle arises as the body works v.hard to make enough receptors –> beta-cells give up –> T2DM

87
Q

What can cause insulin deficiency?

A

Genetic factors

Glucose toxicity

88
Q

What can cause insulin resistance?

A

Genetics

Environment

89
Q

What is the fate of the ligand and receptor in endocytosis of immunoglobulin?

A

Ligand transported

Receptor transported

90
Q

Describe the endocytosis of immunoglobulin.

A

Binds to receptor in coated pits –> coated vesicle –> uncoated vesicle –> endosome –> transfer vesicle –> bile canaliculi

91
Q

What is the endocytosis of immunoglobulin an example of?

A

Transcytosis of a large molecule across a cell

92
Q

How is IgA released?

A

Proteolytic cleavage of the receptor –> see small part of the ligand w/receptor

93
Q

How do membrane-enveloped viruses take advantage of receptor mediated endocytosis?

A

Fortuitous association w/cell receptors
Clathrin-coated pits
Unfolding hydrophobic domains in membrane fusion proteins in response to the acidic pH of the endosome
Insert membrane fusion proteins into endosome membrane –> membrane fusion and release of genomic RNA into cytosol
Use host machinery to replicate RNA and capsid proteins

94
Q

How do cholera and diphtheria toxins act?

A

Bind to GM1 ganglioside which is incorporated into the vesicle

95
Q

Do cholera and diphtheria bind to a receptor?

A

No

96
Q

Name three coat proteins.

A

Clathrin
COPI
COPII

97
Q

What are COP?

A

Family of coat proteins for vesicles from different organelles

98
Q

What shapes are COP made up of?

A

Squares and triangles

99
Q

Where is COPI from?

A

The ER

100
Q

Where is COPII from?

A

The Golgi apparatus