M&R Session 7 Flashcards Preview

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Flashcards in M&R Session 7 Deck (93):
0

What tends to happens to cells if they do not receive extracellular signals?

They die

1

By what two mechanisms can cell surface receptors act?

Directly alter cellular activity
Transduction of initial binding event via other intracellular components

2

What cellular activity can be controlled by transduction of initial binding event?

Contraction
Secretion
Proliferation
Differentiation

3

What are the three superfamilies of cell-surface receptors?

Ligand-gated (receptor operated) ion channels
Receptors w/intrinsic enzymatic activity
GPCRs

4

Which superfamily of cell-surface receptors is heterogenous?

Receptors w/ intrinsic enzyme activity

5

Describe the mechanism of receptors w/intrinsic enzyme activity.

Ligand binding activates an enzyme
Enzyme phosphorylates the receptor itself and other substrates

6

Which superfamily of cell-surface receptors do insulin receptors belong?

Receptors w/intrinsic enzyme activity

7

How do GPCRs have specificity of action?

Each receptor subtype is specific for one/ limited number of endogenous ligands

8

What is an agonist?

A molecule that binds to a GPCR and activates it causing intracellular signal transduction events

9

What drugs are used to treat asthma?

Beta-2 adrenoreceptor agonists
E.g. Salbutamol, Salmeterol

10

What type of molecules are used for analgesia/anaesthesia?

Mu-opioid receptor agonists
E.g. Morphine, Fentanyl

11

What are antagonists?

Molecules that bind to a receptor but do not activate it; they block the effects of agonists

12

What type of molecules are used to treat hypertension?

Beta-adrenoreceptor antagonists
E.g. Propanolol, Atenolol

13

What are Haloperidol and Sulpiride examples of?

Anti-schizophrenic D2 dopamine receptor antagonists

14

What effect do antagonists have on certain mechanisms?

Damp-down hyper activation

15

Give the key features of GPCR structure.

300-1200 a.a. chain
7TMD
2 regions for ligand binding: in TMD or N-terminal region
Extracellular N-terminal
Intracellular C-terminal

16

What can drugs targeting GPCRs be used to treat?

Parkinson's disease
Congestive heart failure
Thrombosis
Benign prostatic hyperplasia
Acid reflux

17

What two types of mutation can occur to cause a disease associated w/signal transduction?

Loss of function
Gain of function

18

What causes retinitis pigmentosa?

Loss of function rhodopsin mutation

19

What causes nephrogenic diabetes insipidus?

Love of function mutation of V2 vasopressin receptor

20

What happens in a gain of function mutation?

Receptor becomes independent of ligand --> endocrine changes

21

What causes familial male precocious puberty?

LH receptor mutation

22

What stimuli can GPCRs respond to?

Light, odour, taste
Ions
Neurotransmitters
Hormones
Large glycoproteins

23

How do GPCRs cause a change in cellular activity?

Ligand binds --> conformational change --> GPCR activated --> interacts w/guanine-nucleotide binding protein --> activates G-protein --> GDP replaced by GTP on alpha-subunit

24

What is the structure of a guanine-nucleotide binding protein?

Heterotrimeric
Alpha, beta and gamma subunits

25

Why is a G-protein functionally dimeric?

Once the beta and game subunits are synthesised they stick together

26

What is the function of the alpha subunit of a G-protein?

Bind to guanine nucleotide
GTPase activity

27

When does GTP have a natural tendency to bind to the alpha subunit?

When the binding site is empty

28

How do you activate a G-protein?

Guanine nucleotide exchange by replacing GDP w/GTP

29

How do you turn off a G-protein?

Hydrolyse GTP

30

Which subunits can interact w/effector proteins?

Alpha
Beta-gamma

31

What effector proteins can the G-protein subunits interact with?

2nd messenger generating enzymes
Ion channels

32

What is amplification governed by?

Timer function of the G-protein unit

33

What is timer function?

Capacity of how long the signal can be passed on for by a GPCR

34

Why can efficiency of signal transmission be targeted therapeutically?

In different pathways it can be altered

35

What is the primary determinant of receptor G-protein selection?

The ~20 different G-alpha proteins in the human genome

36

Does a GPCR have its own unique G-protein combination?

No

37

How many possible G-alpha-beta-gamma protein combinations are possible in the human genome?

>1000

38

How is a specific cellular response brought about by a GPCR?

An extracellular signal working via a specific GPCR will activate a single/small sub-population of G-proteins and effectors in the cell

39

What is the ligand, G-protein and effector for beta-adrenoreceptors?

Adrenaline/NA
Gs-alpha
+ adenylyl cyclase

40

What is the ligand, G-protein and effector for alpha-2-adrenoreceptors?

Adrenaline/NA
Gi-alpha
- adenylyl cyclase

41

What GPCR, ligand and effector are used for Gq-alpha proteins?

Alpha-1-adrenoreceptors
Adrenaline/NA
+ phospholipase C

42

What ligand, GPCR and G protein are used to stimulate cyclic GMP phosphodiester Awe?

Light
Rhodopsin
Gt-alpha

43

What ligand acts at M2/4 muscarinic GPCRs?

ACh

44

What G-proteins are used for M2/4 muscarinic receptors?

Gi-alpha

45

What effector does Gi-alpha activation act on?

-adenylyl cyclase

46

What ligand, G-protein and effector do M1/3 GPCRs use?

ACh
Gq-alpha
+ phospholipase C

47

Which pathway do even numbered muscarinic receptors follow the same as?

Alpha-2-adrenoreceptors

48

Which pathway do odd numbered muscarinic receptors follow the same as?

Alpha-1-adrenoreceptors

49

Name two ADP-ribosylate specific G-proteins.

Cholera toxin
Pertussis toxin

50

What mechanism of action does cholera toxin use?

Eliminates GTPase activity of Gs-alpha
Irreversibly activates Gs-alpha

51

How does cholera toxin irreversibly activate Gs-alpha?

ADP-ribosylation of the unit prevents deactivation of Gs protein mediated signalling

52

Cells in which area of the body are infected by cholera toxin?

Small intestine

53

What happens to the toxin complex in both cholera and pertussis toxin action?

It binds to the cell and the emzyme is 'injected' into the cell

54

What type of cell does Bordetella pertussis bacteria colonise?

Tracheal epithelial

55

What characteristic symptom does pertussis toxin cause?

Whooping cough

56

By what method of action does pertussin toxin cause whooping cough?

Interferes w/ GDP-GTP exchange so Gi-alpha is irreversibly inactivated

57

How does pertussis toxin cause irreversible inactivation of Gi-alpha?

ADP-ribosylation of the subunit prevents Gi protein activation by GPCRs

58

What is PIP3?

A more phosphorylated form of the membrane phospholipid PIP2 that regulates a variety of processes - often survival signals

59

How is adenylyl cyclase regulated by agonist stimulation?

Ligand on receptor activates G-protein --> guanine nucleotide transfer --> activated Gs-alpha --> stimulates adenylyl cyclase --> secondary messenger cAMP formed

60

Which receptors are Gs coupled receptors?

Beta-adrenoreceptors
D1 dopamine receptors
H2 histamine receptors

61

Which receptors are Gi coupled receptors?

Alpha 2-adrenoreceptors
D2 dopamine receptors
My-opioid receptors

62

What does cAMP act on?

cAMP-dependent protein kinase A (PKA)
Epacs (GEFs)
Cyclic-nucleotide-gated ion channels (CNGs)

63

Describe the structure of PKA.

2 regulatory subunits sat in active site of 2 catalytic subunits

64

How does cAMP activate PKA?

Binds to regulatory subunits --> catalytic subunits dissociate exposing active site --> catalytic subunits phosphorylate specific target proteins in the cell that have serine or threonine residues

65

How is phospholipase C regulated by agonist stimulation?

Ligand on receptor activates G-protein --> guanine nucleotide transfer --> activated Gq-alpha --> stimulates PLC --> PIP2 into IP3 and DAG

66

Which part of the PIP2 molecule forms IP3?

Polar head group

67

Which part of the PIP2 molecule forms DAG?

Lipid moiety

68

What intracellular affect does IP3 have?

It releases calcium ions

69

What affect does DAG have?

Acts on PKC which can act on lots of different molecules to affect activity

70

Which receptors are Gq coupled receptors?

Alpha 1-adrenoreceptors
M1 muscarinic receptors
H1 histamine receptors

71

What is the advantage of signal amplification?

Modest concentration changes cause significant effects within cell

72

What affect does a few hundred molecules of adrenaline binding to cell surface beta-adrenoceptors have?

Glycogenolysis in the liver causing milimolar changes in blood glucose concentration

73

What magnitude of amplification does adenylyl cyclase itself cause?

Little

74

What follows activation of adenyly cyclase?

Lots of cAMP molecules released which activate PKA

75

Which two molecules cause ventricular mass to contract more forcefully?

Blood-borne adrenaline
Sympathetically released NA

76

Which receptors are activated to cause increased for of ventricular contraction?

Beta 1-adrenoreceptors

77

What is an increase in the force of contraction also called?

+ve inotropy

78

What causes an increase in the force of contraction?

VOCC phosphorylation by PKA --> each depolarisation allows in slightly more calcium than usual --> triggers CICR

79

What do sympathetically released NA and some blood-borne adrenaline interact with to cause vasoconstriction?

Alpha 1-adrenoreceptors

80

What causes bronchoconstriction?

Parasympathetic Ach action on M3-muscarinic receptors

81

What causes GI and GU smooth muscle contraction?

A variety of agents on GPCRs

82

What mechanism do all methods of regulation of smooth muscle tone utilise?

Gq-phospholipase C-IP3/Ca2+, DAG/protein kinase C pathways

83

What allows for coordinated increase in contractility of smooth muscle?

Utilisation of the same pathways

84

What often modulates neurotransmitter release in the CNS and PNS?

Pre-synoptic GPCRs

85

What is encephalin?

An endogenous ligand

86

What receptors do morphine and encephalin bind to?

Mu-opioid

87

Which subunit has most affect in the activation of mu-opioid receptors?

G-beta-gamma

88

What action does the g-beta-gamma subunit have?

Causes modulating inhibition of specific types of VOCC (very different to those in the heart)

89

What causes turned down neurotransmitter release?

Decreased calcium influx from specific VOCC modulating inhibition causing reduced vesicle docking

90

What allows for diversity in effector mechanisms of signal transduction?

Range of stimuli
Receptors
G-proteins
Effectors

91

What gives specificity of effector mechanisms in signal transduction?

Specific ligand-receptor interactions
Specific G-alpha subunits recruited coupled to particular effector pathways - different between cells but hard wired so that in the same cell type they have the same response

92

What benefit does amplification give to signal transduction?

Allows for gain of control on signalling pathways