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Flashcards in M&R Session 6 Deck (101):
0

How can intracellular signalling occur?

Secretion of signalling molecules
Where adhesion proteins in adjacent cells are in contact

1

How can signalling by secreted molecules be subclassified?

Paracrine
Endocrine
Synaptic

2

What is paracrine signalling?

Signal molecules act on adjacent cells

3

What is endocrine signalling?

Signal molecules enter the bloodstream and act on distal tissues

4

What is synoptic signalling?

Use of neurotransmitter as a signal molecule

5

How do hydrophilic signalling molecules work?

Bind to cell surface receptors

6

How do hydrophobic signalling molecules work?

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

7

What is a receptor?

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

8

Describe an unbound receptor.

Functionally silent

9

What is a ligand?

A molecule that binds specifically to a receptor site

10

What is an antagonist?

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

11

Does an antagonist switch off a receptor?

No. It prevent agonist binding therefore prevents switch on

12

What is an agonist?

A ligand which binds and causes activation of a receptor

13

What are the roles of receptors in cellular physiology?

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

14

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

Generally much higher

15

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

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

16

What is KD?

The concentration of ligand required to half fill all available receptors

17

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

Receptor = 10^-9 M to 10^-6 M
Enzyme = 10^-6 M to 10^-3 M

18

How are receptors classified?

Specific agonist
Affinity to a series of antagonists

19

How are ACh receptors classified?

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

20

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

M1 = Pirenzipine
M2 = Gallomine
M3 = Hexahydrosiladiphenol

21

How does an acceptor differ to a receptor?

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

22

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

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

23

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

Classical ligand-gated ion channels

24

Describe the structure of nAChR.

5 subunits put -ve residues at mouth of channel

25

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

nAChR
GABA receptor
Glycine receptor
Glutamate receptor
IP3 receptor

26

What ions do nAChR permit the passage of?

Sodium
Potassium
Calcium

27

What is the function of gamma amino butyric acid receptors?

Gated chloride channels which allow membrane hyperpolarisation

28

What ion movement do glycine receptors control?

Chloride

29

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

NMDA
Kainate
AMPA
All allow gated calcium entry

30

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

Gated released of calcium from the ER

31

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

ATP-sensitive potassium channel
Purinoceptor
Ryanodine receptor

32

Describe the structure of ATP-sensitive potassium channels.

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

33

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

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

34

Describe the structure of a ryanodine receptor.

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

35

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

Atrial natriuretic peptide receptor
Dimeric growth factor receptor

36

What are ANP receptors directly linked to?

Guanylyl cyclase (GTP --> cGMP)

37

What are dimeric growth factor receptors directly linked to?

Tyrosine kinase

38

Describe the mechanism of dimeric growth factor receptors.

Allow phosphorylation of tyrosine for growth

39

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

Insulin
Epidermal growth factor
Platelet-derived growth factor

40

What is autophosphorylation?

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

41

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

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

How are insulin receptors synthesised?

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

43

Describe the structure of insulin receptors in the plasma membrane.

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

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

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

Where are binding domains found in GPCRs?

W/in the plane of the bilayer

46

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

Seven

47

Where are both beta-adrenoreceptors and M2 receptors found?

In the heart

48

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

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

49

Describe the mechanism of action of beta-adrenoreceptors.

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

What changes between intracellular receptors?

Their primary structure

51

What do all hydrophobic signals use?

Similarity of sequence of intracellular receptors

52

Describe the mechanism of intracellular receptor activation.

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

53

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

Zinc fingers

54

What are intracellular receptors silent at rest?

The DNA site is blocked

55

Describe the mechanism of amplification.

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

56

What is the magnitude of amplication by receptors?

x10^9

57

Compare the activation and inhibition of receptors in hepatocytes.

Insulin stimulates glycogenesis
Glucagon stimulates glycogenolysis

58

How is heart rate increased in cardiac pacemaker cells?

Noradrenaline binds to beta-1 adrenoreceptors

59

How is heart rate decreased in cardiac pacemaker cells?

ACh binds to M2 muscarinic receptors

60

How is the plasma membrane trafficked to its final position?

From the ER to the CSM via the exocytic secretory pathway

61

What prevents the CSM being excessively ruffled?

Endocytosis of the membrane

62

What is the pathway of vesicular transport of membrane?

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

63

What is the function of pinocytosis?

Permits uptake of extracellular so lutes

64

How does pinocytosis take place?

Invagination of the CSM to form a vesicle

65

What is the function of phagocytosis?

Internalisation of particulate matter

66

What is the mechanism of phagocytosis?

Receptors sequentially bind to 'zip up' around engulfed material

67

Describe endocytosis.

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

68

What is cholesterol uptake an example of?

Receptor-mediated-endocytosis

69

Describe the structure of LDLs

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

70

What do triskelions comprise of?

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

71

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

The hexagon and pentagon structure

72

Describe the mechanism of clathrin coating.

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

73

How do clathrin coated pits form spontaneously?

Association of more and more triskelions on cell face

74

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

Recycled back to newly forming clathrin coated pits

75

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

Non functional receptor
Receptor binding normal but no internalisation

76

What happens when there is no internalisation of LDL receptors?

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

77

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

Ligand degraded
Receptor recycled

78

What is CURL?

Compartment of Uncoupling of Receptor and Ligand

79

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

It decreases the affinity of the receptor for LDL

80

What molecule allows uptake of ferric ions?

Transferrin

81

Describe the uptake of ferric ions.

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

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

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

83

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

Ligand recycled
Receptor recycled

84

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

Ligand degraded
Receptor degraded

85

What happens if insulin is high for a long time?

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

86

How does chronic hyperglycaemia lead to T2DM?

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

87

What can cause insulin deficiency?

Genetic factors
Glucose toxicity

88

What can cause insulin resistance?

Genetics
Environment

89

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

Ligand transported
Receptor transported

90

Describe the endocytosis of immunoglobulin.

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

91

What is the endocytosis of immunoglobulin an example of?

Transcytosis of a large molecule across a cell

92

How is IgA released?

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

93

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

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

How do cholera and diphtheria toxins act?

Bind to GM1 ganglioside which is incorporated into the vesicle

95

Do cholera and diphtheria bind to a receptor?

No

96

Name three coat proteins.

Clathrin
COPI
COPII

97

What are COP?

Family of coat proteins for vesicles from different organelles

98

What shapes are COP made up of?

Squares and triangles

99

Where is COPI from?

The ER

100

Where is COPII from?

The Golgi apparatus