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Biomed year 2 sem 1 > BMS2002 - cell signalling > Flashcards

BMS2002 - cell signalling Flashcards

1
Q

3 stages of signal transduction

A
  1. reception - EC signal activates membrane receptor
  2. transduction via amplifiers, second messangers, pathways
  3. response
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2
Q

responses from signal transduction

A

transport protein->altered ion transport
metabolic enzyme -> altered metabolism
gene regulatory protein -> altered gene expression
cytoskeletal protein -> altered shape or movement
cell cycle protein -> altered cell growth and division

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3
Q

first messengers are..

A

chemicals that can serve as extracellular signalling molecules

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4
Q

examples of second messengers

A

amines, peptides/proteins, steroids, other small molecules (aas, ions, gasses)

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5
Q

cell surface receptors

A

bind EC molecules -> wide range of IC signal transduction pathways
FAST response

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6
Q

intracellular nuclear recdptors

A

bind molecules that can freely pass membrane by diffusion
often act as transcription factors
SLOW response

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7
Q

4 main classes of receptors

A
  1. ligand gated ion channels
  2. GPCRs
  3. Enzyme-linked
  4. Nuclear
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8
Q

nicotinic acetylcholine receptor

A

ligand gated ion channel
binds Ach -> channel opens -> Na+ in
binds nicotine
electrical event -> response
calcium can also enter

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9
Q

y-amino buytyric acid gabaA receptor

A

ion channel Cl-
inhibitory receptor
activated by benzodiapines, alcohol, anaesthetics

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10
Q

muscarinic acetylcholine receptor

A

indirectly links with membrane ion channels (signal transduction pathways)
more sensitive to muscarine than nicotine

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11
Q

ionotropic receptors

A

form an ion channel pore
e.g. nictotinic Ach receptor, gabaA

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12
Q

metabotropic receptors

A

indirectly linked with membrane ion channels via signal transduction pathways - often g protein mediated

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13
Q

GPCR mechanism

A
  1. unstimulated cell
  2. adrenaline binds beta adrenoreceptor
  3. b adrenoreceptor - G protein interaction
  4. GDP/GTP exchange
  5. alpha subunit liberation
  6. Free a subunit activates AC -> camp -> PKA activation
  7. unbinding of adrenaline/ GTP hydrolysis -> unstimulated cell
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14
Q

cAMP activates

A

PKA

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15
Q

PKA..

A

catalyses transfer of ATP to specific serine/threonie residues on substrate proteins

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16
Q

physiological responses mediated by cAMP/PKA

A

Kidney collecting duct - activated by vasopressin -> water retention
Vascular smooth/cardiac muscle- activated by adrenaline -> relax/increase HR
Colonic epithelium- various factors -> fluid/electrolyte secretion
Pancreas - glucagon-> release of glucose into blood

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17
Q

b-ARK

A

beta adrenoreceptor kinase

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18
Q

steps of desensitization of receptor

A
  1. protein phosphorylation -> cell response
  2. PKA phosphorylates b-ARK -> increases activity
  3. b-ARK phosphorylates b-adrenoreceptor -> reduced affinity for adrenaline
  4. reduced affinity -> reduced cellular response (even if sustained stimulation)
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19
Q

Gs

A

stimulates AC
- couples with b-adrenoreceptors, vassopressin receptor, A2a/B adenosine receptors

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20
Q

Gi

A

inhibits AC
- a2 adrenoreceptors, m & a opiod receptors, A1/3 adenosine receptors

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21
Q

how does cholera toxin target G-proteins

A

cholera toxin activates a s subunit -> ADP dephosphorylation -> conformational change to cause permanent binding to GTP -> constant signalling -> continuous cAMP production
- in colon: activation of PKA-dependent Cl- channels -> lose water and Na+/Cl-
-> secretory diarrhoea

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22
Q

how does pertussis toxin affect g-proteins

A

acts on alpha I subunit -> forces subunit to remain inactive -> prevents activation of AC/PKA -> phosphorylation -> symptoms of whooping cough

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23
Q

Gq pathway

A

Gq stimulates PLC -> cleaves PIP2 into IP3 and DAG
IP3 -> Ca2+ release from ER
DAG-> recruits PKC -> regulates cell shape/proliferation/ transcription factors, mediates desensitization

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24
Q

blood pressure control

A

alpha1- adrenoreceptor -> vasoconstriciton -> increase blood pressure
beta2-adrenoreceptor -> vasodilation -> decrease blood pressure

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25
Q

Receptor Guanylyl Cyclases mechanism of signalling

A

ANP binds -> receptor dimerization and activation -> generates cGMP -> activates other signalling molecules

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26
Q

Receptor serine/threonine kinases mechanism of signalling

A

first messenger binds to receptor type 2 -> receptor 1 then binds, forms complex with all three units -> type 2 phsphorylates type 1 -> activates ser-thr kinase activity of type 1 -> type 1 phosphorylates target proteins

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27
Q

Receptor tyrosine kinases (RTK) mechanism of signalling

A

binding of two insulin molecules -> receptor dimerises -> phosphorylate eachother -> creates phosphotyrosine motifs -> recruit intracellular signalling molecules

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28
Q

Tyrosine kinase-associated receptor mechanism of signalling

A

first messenger binds -> dimerization of the receptor -> activation of tyr kinases -> these phosphorylate tyr residues on themselves and on the receptor -> these motifs recruit intracellular molecules

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29
Q

Receptor tyrosine phosphatase mechanism of signalling

A

CD45 binds -> activates tyr phosphorylase activity -> dephosphorylates target protein -> regulation of downstream cell-signalling events

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30
Q

how is glucose stored?

A

as glycogen, mostly in muscles and liver

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31
Q

after a meal

A

increased glucose absorption -> increased glucose conc in circulation -> can stimulate metabolism and increase o2 demand
abundant glucose stored as glycogen

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32
Q

between meals

A

absorption is minimal -> reduced glucose conc -> may limit metabolism and reduce o2 demand

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33
Q

pro-insulin

A

converted by prohormone convertase -> removes C peptide -> left with 2 polypeptide chains held by disulphide bridges

34
Q

two phases of insulin secretion

A

first: release of insulin stored in secretory granules (rapid, transient)
second: synthesis and secretion of new insulin (slower, sustained)

35
Q

insulin circulates..

A

freely - v little plasma protein binding

36
Q

insulin is degraded by

A

insulinase, mainly in liver/muscle/kidneys

37
Q

Glucose transporters on beta cells

A

GLUT2
- system is hormone-insensitive (always active)
- glucose -> ATP

38
Q

beta cells K+ channels

A

ATP sensitive - open at normal levels, closed at very high levels of ATP
-> control membrane potential
-> external glucose can set membrane potential

39
Q

beta cells VG Ca2+ channels

A
  • opened by depolarisation -> makes cells permeable to calcium
    -> depolarisation increases membrane permeability to Ca2+
40
Q

Beta cell exposed to normal glucose

A

normal glucose -> normal internal ATP -> K+ channels open -> Vm is hyperpolarised -> Ca2+ channels closed -> b cell doesnt secrete insulin

41
Q

beta cell exposed to high glucose

A

high glucose -> high internal ATP -> K+ channels close -> depolarised Vm -> Ca2+ channels open -> b cells secrete insulin

42
Q

insulin is released from the (1) into the (2)

A
  1. pancreas
  2. hepatic portal vein
43
Q

insulin receptors

A

dimeric: alpha and beta subunits
- insulin binding -> dimerization -> activation
- receptor dimerises -> subunits phosphorylate eachother at multiple tyrosine residues

44
Q

insulin receptor signalling

A

insulin binds receptor -> receptor dimerization + activation -> receptor phosphorylates IRS-1 -> P13K activation -> cellular responses to insulin

45
Q

insulin promoting glucose uptake by liver

A

insulin induces P13K activation -> P13K activates PKB -> induces translocation of GLUT4 to plasma membrane -> GLUT4 allows glucose entry

46
Q

insulin promoting glycogen synthesis

A

insulin activates PKB -> activates GSK-3 -> activates glycogen synthase -> glycogen synthesis

47
Q

insulin promotes fat deposition in adipocytes

A

insulin allows glucose into cell via GLUT4 -> glucose metabolised to glycerol
- insulin inactivates lipase
- excess fatty acids in the cell

48
Q

insulin promotes synthesis of new proteins

A

insulin receptor -> P13K -> TORC1 -> protein synthesis
- when amino acids are abundant, insulin stimulates their incorporation into proteins

49
Q

2 things that promote insulin release

A
  1. hyperglicemia
  2. raised levels of amino acids
50
Q

4 effects of insulin

A
  1. promotes uptake and storage of glucose
  2. promotes metabolic utilisation of glucose
  3. promotes storage of fat
  4. promotes synthesis of new protein
51
Q

glucagon is secreted by (1) in response to (2)

A
  1. pancreatic alpha cells
  2. low glucose concentration
52
Q

glycogenolysis

A

glucose release from liver

53
Q

glycogenolysis signalling pathway

A

glucagon activates AC -> cAMP activates PKA -> activates phosphorylase kinase A -> phosphorylase A
(adrenaline can also activate this pathway by b-adrenoreceptors)

54
Q

gluconeogenesis

A

glucose formation from lipids and amino acids stimulated by glucagon

55
Q

3 things that stimulate glucagon release

A
  1. hypoglucemia
  2. vigorous exercise
  3. raised levels of amino acids
56
Q

3 effects of glucagon

A
  • glycogenolysis
  • gluconeogenesis
  • ketogenesis
57
Q

Diabetes mellitus

A

inability to regulate blood glucose

58
Q

blood sugar levels in diabetes

A

> 7mM (5mM is normal)

59
Q

pathogenesis of T1DM

A

environmental factors/genetic predisposition -> autoimmune destruction of beta cells (CD8+ mediated) -> severe insulin deficiency -> hyperglycaemia

60
Q

genes associated with T1DM

A

HLA-DR3/DR4

61
Q

no insulin ->

A

glucose not used as metabilic fuel -> rapid weight loss
-> fatty acids -> ketone bodies -> decreased pH -> metabolic acidosis -> acidic coma

62
Q

hyperglycemia and dehydration

A

high conc of glucose enters glomerular filtrate -> overwhelms PCT glucose absorbing capacity
-> increases fluid osmolarity in tubules
-> more water secreted from cells into PCT
-> water reabsorption is reduced
-> urine flow is increased
-> dehydration, excessive urine production, thirst

63
Q

problems with injecting insulin therapy

A
  • exogenous insulin into general circulation, natural insulin into portal circulation
  • lipohypertrophy (fat deposition around repeated injection site as insulin promotes fat deposit) -> unpredictable rate of insulin absorption
64
Q

soluble insulin

A

rapid/short lived
IV in emergencies

65
Q

isophane insulin

A

intermediate acting
tends to form precipitates

66
Q

insulin zinc suspension

A

long acting
tends to form precipitates

67
Q

insulin lispro

A

insulin analogue
v. rapid/short lived
normally taken before a meal

68
Q

insulin glargine and detemir

A

insulin analogue
long acting, slowly absorbed
normally taken before a meal in combo with short-acting
forms a micro-precipitate at physiological pH

69
Q

teplizumab

A

drug to target autoimmune reaction in diabetes type 1

70
Q

pathogenesis of T2DM

A
  1. genetic and environmental predisposition (lifestyle, obesity)
  2. insulin resistance
  3. hyperinsulinemia -> beta cells try to compensate for peripheral resistance
  4. beta cells fail to keep up -> hypoinsulinemia
  5. diabetes: total failure of insulin
71
Q

diabetes 2 and free fatty acids (FFA)

A

excess FFA are transformed into DAG -> activate PKC -> phosphorylate IRS-1 -> attenuates insulin receptor signal
-> insulin resistance in muscle and liver

72
Q

diabetes 2 and adipokines

A

released by adipocytes
can be pro- or anti-hyperglycaemic
adiponecting (anti-hg) is reduced in obesity

73
Q

diabetes 2 and inflammation

A

adipocytes produce IL-6 and IL-1 -> attract macrophages to fat deposits
reduction of cytokines can improve insulin sensitivity

74
Q

diabetes 2 and PPARy

A

nuclear receptor involved in adipocyte differentiation, promotes secretion of anti-hyperglycemic adipokines
mutations cause diabetes

75
Q

Thiazolidinediones for T2DM

A

PPARy agonist
promotes secretion of anti-hyperglycaemic adipokines -> increases lipolysis
sensitize cells to insulin
collectively reduces insulin resistance in liver/perpheral tissues

76
Q

Metformin for T2DM

A

supresses glucose release from liver
activates AMPK
increase lipolysis in muscles and liver -> improve insulin receptor signalling
suppress glucose release from liver

77
Q

Sulphonylureas for T2DM

A

bind sulphonylurea receptors on beta cell membranes
block ATP sensitive K+ channels on b cells -> K+ accumulates insise -> cell depolarises -> Ca2+ channels open -> allow insulin secretion y exocytosis

78
Q

macro complications of T2DM

A

hyperglycemia -> macrovascular disease -> damage to medium/large blood vessels -> coronary heart disease, cerebrovascular disease, peripheral vascular disease

79
Q

micro complications of T2DM

A

hyperglycemia -> microvascular disease -> damage to small blood vessels -> retinopathy, nephropathy, neuropathy

80
Q

ROS generation

A

from excess glucose and FFA
-> micro- and macro-vascular complications of T2DM

81
Q

AGE generation

A

from excess sugar molecules and proteins
-> vessel damage

82
Q

AGE effect on blood vessels

A

AGE crosslinks with collagen
-> basal membrane of endothelium thickens
-> traps LDL and IgGs
-> oxidation, complement activation, inflammation
-> vessel damage

Biomed year 2 sem 1 (7 decks)

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