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Cell Signalling Flashcards

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1
Q

What are the stages of signal transduction?

A
  1. An extracellular signal molecule activates a membrane receptor
    2.That in turn alters intracellular molecules to be transduced via a certain pathway
  2. That then activates a cellular response
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2
Q

What is the first messenger?

A

The extracellular signal molecule.

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3
Q

What is the second messenger?

A

The intracellular signal molecules.

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4
Q

What are transducers?

A

In-between the first and second messenger system, membrane proteins act as transducers, converting the message of extracellular signals into intracellular messenger molecules that trigger a response.

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5
Q

What kind of chemicals can serve as extracellular signalling molecules (first messenger)?

A

Amines
Peptides & Proteins
Steroids
Other small molecules

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6
Q

Where are receptors located?

A

Cell surface receptors.
Intracellular (nuclear) receptors.

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7
Q

What are cell surface receptors?

A

*Membrane receptors for hydrophilic signalling molecules
*Activate a wide variety of intracellular “signal transduction” pathways
*FAST RESPONSE
*Co-ordinates gene regulation

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8
Q

What are intracellular (nuclear) receptors?

A

*Most receptors for hydrophobic signalling
molecules
*Act as transcription factors in
nucleus to regulate gene transcription.
*SLOW RESPONSE

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9
Q

What are the 4 main classes of receptors?

A
  • Ligand-gated ion channels
  • G-protein coupled receptors
  • Enzyme-linked receptors
  • Nuclear receptors
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10
Q

Which receptors are cell surface receptors?

A

*Ligand-gated ion channels (ionotropic receptors)
* G-protein-coupled receptors (metabotropic)
*Kinase-linked receptors.

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11
Q

What does ionotropic mean?

A

Forming an ion channel pore.

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12
Q

What does metabotropic mean?

A

Indirectly linked with ion channels on the plasma membrane through signal transduction pathways.

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13
Q

Which receptors are ionotropic?

A

*Nicotinic acetylcholine receptor
*The y-amino buytyric acid (gaba)A receptor

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14
Q

What are nicotinic acetylcholine receptor?

A

Ligand gated ion channel that mediates effects of acetylcholine (ACh) on muscle.

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15
Q

How do nicotinic acetylcholine receptors work?

A
  • Binding of acetylcholine opens a channel and allows Na+ entry
  • Binds nicotin
  • Electrical event (inward Na+ current) triggers response
  • Calcium may also enter from this channel
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16
Q

What are the y-amino buytyric acid (gaba)A
receptor?

A

*Ion channel selective for Cl- ions.
*It is a inhibitory receptors.
*Important role in CNS.

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17
Q

What is the y-amino buytyric acid (gaba)A
receptor activated by?

A
  • Benzodiazepines
    *Alcohol
    *Anaesthetics
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18
Q

What is an example of metabotropic receptors?

A

Muscarinic acetylcholine receptor.
Gaba B.

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19
Q

What are muscarinic acetylcholine receptors?

A

ACh also activates Muscarinic receptor.
More sensitive to muscarine than nicotine.

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20
Q

What is the common structure of all G protein coupled receptors?

A
  • Receptors that activate G proteins all have 7 transmembrane domains
  • At least 800 genes encode G protein coupled receptors
  • Activated by many molecules
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21
Q

What is the function of G protein coupled receptors?

A

*Play a huge role in the regulation of cell function

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22
Q

What are the sub-units of G-protein coupled receptors?

A
  • G proteins consist of three polypeptide chains, a, B and Y.
  • In nature there are at least 16 a subunits, 5 b and 11 y.
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23
Q

What is the By subunit within the G-protein coupled receptors?

A

The B and Y subunits bind tightly to each other effectively forms a single by subunit.

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24
Q

What is the structure of the a subunit within the G-protein coupled coupled receptors?

A

The a subunit has a guanine nucleotide binding site that binds GTP or GDP.
The a-subunit can hydrolyse GTP.

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25
Q

What is the affinity for BY subunit of a-GDP?

A

a-GDP has high affinity for by (resting conditions).

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26
Q

What is the affinity for BY subunit of a-GTP?

A

a-GTP has low affinity for by.

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27
Q

What are the stages of the G protein cycle?

A
  1. Unstimulated cell
  2. Adrenaline binding to b-adrenoceptor
  3. Allows b-adrenoceptor/G protein interaction
  4. Allows GDP / GTP exchange
  5. Allows a subunit liberation
  6. Free a subunit activates AC
  7. Unbinding of adrenaline/GTP hydrolysis
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28
Q

What is PKA?

A
  • PKA is a tetrameric protein with two types of polypeptide
    chains
  • Catalytic (C) and regulatory (R)
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29
Q

What is the structure of inactive PKA?

A

Subunits bound together and R subunit suppresses activity of C subunit.

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30
Q

What is PKA (Protein Kinase A) activated by?

A

cAMP.

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31
Q

How does cAMP activate Protein Kinase A (PKA)?

A
  • R subunits have 2 binding sites for cAMP.
  • cAMP binding allows the subunits to dissociate.
  • Catalytic subunits become active phosphorylate other proteins.
  • PKA catalyzes transfer of ATP to specific serine or threonine residues on substrate proteins.
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32
Q

What is the function of the cAMP / PKA pathway?

A
  • The cAMP / PKA pathway is present in virtually every cell
  • One of most important mechanisms that allow hormones/neurotransmitters to evoke responses in target cells
  • Many proteins are phosphorylated by PKA
  • Many physiological responses are mediated by cAMP / PKA
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33
Q

How is the signal transduction terminated?

A
  • Removal/inactivation of signal
  • Removal/inactivation of receptor
  • Inactivation of activated signalling proteins
  • GTP hydrolysis
  • dephosphorylation
  • Degradation/removal of second messengers
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34
Q

How do we remove the 2nd messenger form the cAMP / PKA pathway?

A
  • cAMP is hydrolysed by phosphodiesterase (PDE)
  • When hormone is removed, PDE rapidly clear cAMP from the cell
  • Unbinding of cAMP from R subunit increases affinity for C subunit
  • Protein reassembles into tetramer and are inactivated
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35
Q

What is PDE inhibited by?

A
  • PDEs are inhibited by caffeine. Interfering with a “switch off” mechanism prolongs the time on and indeed prolongs a cellular response.
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36
Q

What are the stages of Desensitization of receptor?

A

(1) Protein phosphorylation leads to cellular response
(2) PKA phosphorylates b-ARK and increases activity
3) b-ARK phosphorylates b-adrenoceptor and reduces affinity for adrenaline
(4) Reduced affinity leads to reduced cellular response despite sustained stimulation

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37
Q

What is b-ARK?

A

b-adrenoceptor kinase.

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38
Q

What is dephosphorylation?

A

Removal of phosphate.

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39
Q

What effect does the alpha-s subunit have on adenylyl cyclase?

A

Alpha-s subunit activates AC.

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40
Q

What effect does the alpha-i subunit have on adenylyl cyclase?

A

Alpha-s subunit inhibits AC.

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41
Q

What kinds of adrenoceptors couple to the G-s protein?

A

b-adrenoceptors
Vasopressin receptor
A2A /B adenosine receptors

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42
Q

What kinds of adrenoceptors couple to the G-i protein?

A

a2 adrenoceptors
m and d opioid receptors
A1/3 adenosine receptors

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43
Q

What is the purpose of GTP being bound to G proteins?

A
  • Signalling via G proteins depends upon exchange of GDP for GTP
  • Active a subunit has GTP bound
  • Hydrolysis of GTP leads to inactivation
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44
Q

What is the effect of the cholera toxin on G proteins?

A
  • Cholera toxin (CTx) acts on as subunit and causes ADP-ribosylation
  • This prevents hydrolysis of GTP
  • Causes persistent activation of a subunit
  • Causes over-activation of PKA-dependent Cl- channels
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45
Q

What effect does the pertussis toxin on the alpha-i subunits?

A
  • In this case locks subunit into inactive configuration
  • Prevents activation by receptors
  • Prevents inhibitory control over AC / PKA
  • Again leading to increased levels of cAMP and PKA
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46
Q

What can the pertussis toxin lead to?

A

In airway leads to symptoms of whooping cough

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47
Q

What do G protein contain the alpha-q11 subunit?

A
  • Allow hormones/neurotransmitters to activate amplifier enzyme Phospholipase C (PLC)
  • Underlies autonomic effects of acetylcholine
  • Histamine H1 receptor responses
  • Responses due to increased internal Ca2+
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48
Q

What kinds of autonomic effects does the alpha-q11 subunit have?

A

salivary secretion
bronchial smooth muscle contraction

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49
Q

What kinds of histamine H1 receptor responses is the alpha-q11 responsible for?

A

G.I. smooth muscle contraction
Allergies

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50
Q

What are G-q proteins responsible for?

A

Gq proteins stimulate phospholipase C (PLC)

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51
Q

Describe the stages of the phosphoinositide breakdown.

A

*G-q protein stimulate phospholipase C.
*PLC cleaves PIP2, into IP3 and DAG.
*IP3 travels through the cytosol to stimulate calcium release from the ER.
*DAG remains in the hydrophobic part of the membrane where is recruits Protein Kinase C (PKC).

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52
Q

What is PIP2?

A

A membrane phosphate.

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53
Q

What is IP3?

A

Inositol 1,4,5-triphosphate.
It is the soluble part of PIP2.

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54
Q

What is DAG?

A

Diacylglycerol

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55
Q

What happens to IP3 after it travel through the cystol?

A

IP3 is a second messenger that stimulates Calcium release from ER.

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56
Q

Describe the process of IP3 being the second messenger that stimulates calcium release from the ER.

A
  • IP3 enters the cytoplasm
  • Binds to receptors on ER
    *Promotes release of stored Ca2+
  • Also promotes Ca2+ influx from extracellular fluid
  • Resultant increase in intracellular free Ca2+ promotes cellular responses
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57
Q

What happens to calcium ions after the influx?

A

Calmodulin, CaM, binds 4 Ca2+ ions.

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58
Q

What are the functions of Ca2+-CaM?

A
  • Activates PDE (the enzyme that degrades cAMP)
  • Activates CaM kinases (CaMKs)
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59
Q

What happens once the Ca2+-CaM complex actiavted the CaM kinase?

A
  • CaMKs phosphorylate Serine and Threonine residues on substrate proteins
  • CaMKs are involved in smooth-muscle contraction.
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60
Q

What are the effects of DAG?

A
  • Remains in the plasma membrane
  • Presence of DAG increases the activity of Ca2+-dependent protein kinase
  • Evokes cellular responses by phosphorylating other proteins.
  • PKCs can control the effects of IP3
  • Mediates desensitization
  • Regulates cell shape, cell proliferation and transcription factor activity
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61
Q

Why does DAG stay in the plasma membrane?

A

DAG is hydrophobic.

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62
Q

What is the most important thing DAG phosphorylates to get a cellular response?

A

Proteins kinase C (PKC).

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63
Q

What is the function of alpha1-adrenoceptors

A
  • It causes vascular smooth muscle tone contraction (‘vasoconstriction’)
  • Makes blood pressure to increase
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64
Q

Which complex do alpha1-adrenoceptors work via?

A

Gq-PLC-IP3-CaMK

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65
Q

What is the function of beta2-adrenoceptors?

A
  • Cause relaxation of vascular smooth muscle (‘vasodilation’)
  • Makes blood pressure to decrease
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66
Q

What complex do beta2-adrenoceptors work via?

A

Gs-cAMP-PKA

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67
Q

Which G protein are muscarinic receptors coupled with?

A

Gi and Gq

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68
Q

What activated muscarinic receptors?

A

ACh

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69
Q

What effect do 1-3-5 coupled Gq muscarinic receptors?

A

Slimulation

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70
Q

What effect do 2-4 coupled Gi muscarinic receptors?

A

Inhibition

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71
Q

What are some examples of enzyme linked receptors?

A
  • Receptor guanylyl cyclases
  • Receptor serine/threonine kinase
  • Receptor tyrosine-kinase
  • Tyrosine kinase-associated receptors
  • Receptor tyrosine phosphatase
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72
Q

What is the Receptor Guanylyl Cyclase?

A

Contain 2 Guanylyl Cyclase domains which convert GTP to cGMP-cGMP which activates downstream kinases

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73
Q

What is the mechanism of signalling for the Receptor Guanylyl Cyclase?

A

1) Binding of ANP induces a conformational change in the receptor that causes receptor dimerization and activation.
2) The Guanylyl cyclase activity of the receptor generates cGMP.
3) Increased concentrations of cGMP activates other signalling molecules determining the response

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74
Q

What is an example of a response the receptor Guanylyl Cyclase?

A

Relax vascular smooth muscle and dilate blood vessels (vasodilation).

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75
Q

What is the Receptor Serine/Threonine kinases?

A

Contain Serine-Threonine kinase domains which phosphorylate target proteins (similar to PKA).

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76
Q

What is the mechanism of signalling for the Receptor Serine/Threonine kinases?

A

1) first messenger binds to receptor Type II
2) Receptor Type I then binds forming a ternary complex with Type II and first messenger.
3) Type II receptor phosphorylates Type I, activating the Ser-Thr Kinase activity of Type I
4) Type I then phosphorylate target proteins

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77
Q

What is an example of a response to the signalling of the Receptor Serine/Threonine kinases

A

cell proliferation

78
Q

What is the Receptor Tyrosine Kinases (RTKs)?

A

Contain tyrosine kinase domains which phosphorylate themselves/other proteins.

79
Q

What is the mechanism of the Receptor Tyrosine Kinases (RTKs)?

A

1) Binding of 2 molecules of insulin causes the receptor to dimerise.
2) Then they use their cytoplasmic tyr kinase activity to phosphorylate each-other at multiple tyrosine residues creating “phosphotyrosine motifs”.
3) These motifs recruit intracellular signalling molecules leading to the response

80
Q

What is an example of a response to the signalling of the Receptor Tyrosine Kinases (RTKs)?

A

Insulin mediated glucose uptake and storage in liver and muscles

81
Q

What are Tyrosine kinase-associated receptors?

A

The receptors do not contain kinase domains. Instead tyrosine kinase proteins are associated non-covalently with the cytoplasmic domains.

82
Q

What is the mechanism of signalling for Tyrosine kinase-associated receptors?

A

1) Binding of first messenger to the receptor, induce a conformational change that cause dimerization of the receptor
* 2) The dimerization causes activation of the associated Tyr kinases.
* 3) These kinases then phosphorylate tyrosine residues on both themselves and the receptor, creating “phosphotyrosine motifs”.
* 4) These motifs recruit intracellular signalling molecules leading to the response

83
Q

What is an example of a response the the signalling by Tyrosine kinase-associated receptors?

A

EPO mediated increased production of blood cells

84
Q

What is the Receptor tyrosine phosphatase?

A

The receptors contain tyrosine phosphatase domains and deposphorylate target proteins

85
Q

What is the mechanism of signalling for the Receptor tyrosine phosphatase?

A

1) CD45 binding to the receptor inducing a conformational change that activates the Tyr phosphatase activity of the receptor.
2) Target proteins are dephosphorylated by
Tyr phosphatase activity
3) This cause the regulation of downstream cell-signalling events

86
Q

What is an example of a response to the signalling of the Receptor tyrosine phosphatase?

A

Maturation of lymphocytes

87
Q

What happens to glucose in the body?

A
  • Glucose absorbed from GI tract
  • Enters circulation
  • Used to fuel metabolism in many tissues
  • Brain can only use glucose
88
Q

How is glucose stored in the body ?

A

The body stores glucose as glycogen
Main sites of glucose storage are muscle and liver

89
Q

What happens to the body after you have a meal?

A
  • Increased glucose absorption after meal
  • Would increase glucose concentartion in circulation
  • May stimulate metabolism
  • Increase O2 demand
90
Q

What happen in your body between meals?

A
  • Between meals glucose absorption minimal
  • Would lower glucose concentration in circulation
  • May limit metabolism
  • Reduce O2 demand
  • Mammals maintain metabolism between meals
  • When glucose is scarce it is released from glycogen
91
Q

What is the normal circulating glucose concentration?

A

5mM

92
Q

What promotes glucose storage as glycogen?

A

Insulin

93
Q

What promotes glucose release from glycogen?

A

Glucagon

94
Q

What is the pancreas?

A

An endocrine organ critical to digestion.
Contains a small group of cells called Islets of Langerhans.

95
Q

What is the function of the endocrine pancreas?

A

Secrete hormones into the bloodstream

96
Q

How many islets of Langerhans are in the pancreas?

A

Approx. 3 million

97
Q

How big are the Islets of Langerhans?

A

Each islet ~0.1 mm in diameter

98
Q

What are the 3 main cell types in each islet?

A

*α cells
* β cells
* γ cells

99
Q

What percentage of Islets of Langerhans are α cells?

A

15 – 20%

100
Q

What percentage of Islets of Langerhans are β cells?

A

65 – 80%

101
Q

What percentage of Islets of Langerhans are γ cells?

A

3 – 10%

102
Q

What is the function of α cells?

A

Produce glucagon.

103
Q

What is the function of β cells?

A

Produce Insulin and amylin

104
Q

What is the function of γ cells?

A

Produce somatostatin

105
Q

How is insulin produced?

A
  • Synthesised within pancreatic islet β cells as a polypeptide
  • Polypeptide chain is processed within Golgi to give pro-insulin which is biologically inactive
  • Pro-insulin is activated by prohormone convertase 1 and 2 remove 33 amino acids (C chain)
106
Q

What is the structure of insulin?

A

2 polypeptide chains heldtogether by disulphide bridges

107
Q

How many amino acids are present in the A chain of insulin?

A

30 amino acids

108
Q

How many amino acids are present in the B chain of insulin?

A

21 amino acids

109
Q

Where is insulin stored?

A

Stored within secretory granules of theβ cells together with some pro-insulin and the C peptide

110
Q

What is the first phase of insulin secretion?

A

Release of insulin stored within secretory granules

111
Q

What is the second phase of insulin secretion?

A

Synthesis/secretion of new insulin.

112
Q

What is insulin broken down by?

A

Insulin degraded by insulinase.

113
Q

Why is the effect on tissues of insulin rapidly reversible?

A

Because plasma half life is ~6 mins.

114
Q

What is the function of the C chain in insulin?

A

C chain is stable.
Provides an indicator of insulin secretion.

115
Q

How is glucose transported into the beta-cell?

A
  • β cells express a type 2 glucose transport system (GLUT2)
  • This system is hormone-insensitive
    and therefore always active
  • Intracellular glucose concentration is therefore strongly influenced by circulating glucose concentration.
116
Q

What happens to glucose once it enters into the beta-cell?

A

In the β cells glucose is phosphorylated to glucose 6-P by glucokinase and metabolised by glycolysis and mitochondrial oxidation to generate ATP/ADP

117
Q

What is the concentration of ATP depend on?

A

[ATP] is determined by circulating glucose level

118
Q

How are B-cells affected by ATP?

A
  • β cells express a ATP-sensitive K+ channel
  • These channels are open at normal levels of ATP
  • High levels of ATP close channel
  • Since these channels set the membrane potential (Vm) – channel closure causes depolarization
  • ATP-sensitive K+ channels therefore allows external glucose to set Vm
119
Q

How do ca2+ channels work in Beta cells?

A
  • These channels are closed at normal membrane potentials
  • Membranes of cells normally essentially impermeable to Ca2+
  • Depolarization opens voltage-gated Ca2+ channels
  • Depolarization therefore increases membrane permeability to Ca2+
120
Q

What happens when Beta cells are exposed to low glucose?

A
  1. Normal internal ATP
  2. K+ channels are open
  3. Vm is hyperpolarized
  4. Ca2+ channels are closed
  5. β Cell does not secrete insulin
121
Q

What happen when Beta cells are exposed to high glucose?

A
  1. High glucose
  2. High internal ATP
  3. K+ channels close
  4. Vm is depolarized
  5. Ca2+ channels open
  6. β Cell secrete insulin
122
Q

What happen to insulin after it is released from the pancreas?

A
  • Blood from pancreas drains into the hepatic portal vein
  • Liver therefore first organ to be exposed to insulin
  • Portal circulation transports glucose from gut to liver
123
Q

What is the major site of glucose?

A

Liver is major site of glucose storage.

124
Q

What is the structure of a dimeric receptors?

A

Each receptor consists of 2 subunits α and β.

125
Q

What is the function of the dimeric receptor?

A
  • Insulin binding promotes receptor dimerization and activation
  • Once the receptors dimerise, then the 2 subunits phosphorylate each other at multiple tyrosine residues
126
Q

What is the function of amino acid 960 on the insulin receptor beta-subunits?

A

Required for substrate binding

127
Q

What is the function of amino acid 1146, 1150, 1151 on the insulin receptor beta-subunits?

A

Phosphorylation leads to kinase activity

128
Q

What is the function of amino acid 1293, 1294, 1336 on the insulin receptor beta-subunits?

A

Attenuates kinase activity

129
Q

What is the function of amino acid 1316, 1322 on the insulin receptor beta-subunits?

A

Maybe associated with growth signal

130
Q

What is the process of insulin receptor signalling?

A
  1. Insulin binding causes receptor dimerisation/activation.
  2. Active receptors phosphorylate IRS-1.
  3. IRS-1 activates PI3K.
  4. Cellular response to insulin.
131
Q

What is another function of IRS-1?

A

IRS-1 also activates MAPK cascade, resulting in stimulating cell growth and survival

132
Q

What effect does glucose have on the liver?

A
  • In unstimulated cells GLUT4 is not in plasma membrane
  • Plasma membrane therefore has low glucose permeability
  • Insulin promotes hepatic glucose uptake
  • Insulin activates PI3K
  • Which then activates protein kinase B (PKB)
  • Which evokes the translocation of GLUT4 to the plasma membrane
  • And thus allows glucose uptake into the hepatocyte
133
Q

How does insulin promote glycogen synthesis?

A

Activates glycogen synthase

134
Q

What happens when glycogen reserves are full?

A

Glucose is metabolised to fatty acids.
They are then stored as fat.

135
Q

How does insulin promote the use of glucose as metabolic substrate?

A
  • In the absence of insulin cells have a low permeability to glucose
  • Metabolic needs generally met by oxidation of fatty acids
  • Insulin stimulation increases glucose permeability
  • Switches cell to use glucose as source of metabolic energy
136
Q

What is the major exception of insulin promoting the use of glucose as a metabolic substate?

A
  • The brain
  • CNS cells can take up glucose independently of insulin
  • Do not metabolise fatty acids
137
Q

What are the effects of insulin?

A

*Promotes uptake and storage of glucose
*Promotes metabolic utilisation of glucose
*Promotes storage of fat
*Promotes synthesis of new protein

138
Q

When is glucagon released?

A

Pancreatic alpha cells secrete glucagon in
response to low glucose concentration.

139
Q

What is glucagon?

A

Single polypeptide chain (29 amino acids)

140
Q

Where is glucagon stored?

A

Secretory granuled

141
Q

What is hypoglycaemia?

A

Low BSL

142
Q

What is hyperglycaemia?

A

High BSL.

143
Q

What is glycogenolysis?

A

Glucose release from liver

144
Q

Which G-protein-coupled receptor is involved in glycogenolysis promoted by glucagon?

A

Glucagon receptor is a G protein-coupled receptor (7 transmembrane domains)

145
Q

How does glucagon promote the release of glucose?

A
  • Glucagon receptor is couple to Gs and activates the cAMP / PKA-dependent signalling pathway
  • Adrenaline can also activate this pathway via β adrenoceptors
146
Q

Why is glucagon important during starvation?

A
  • During starvation blood glucose must be maintained as brain is entirely dependent upon glucose. *Hypoglcemia strongly induces glucagon release
  • Once glycogen stores are depleted, glucagon stimulates the formation of glucose from lipids and amino acids
  • This takes place via complex metabolic processes in liver and kidney-gluconeogenesis
  • Glucagon will promote lipid and protein degradation to fuel gluconeogenesis in order to maintain glucose for brain metabolism
147
Q

What causes the production of glucagon?

A

Hypoglycemia
Vigorous exercise
Raised level of amino acids

148
Q

What are the effects of glucagon?

A

Promotes glucose release from glycogen stores (mainly liver)
Promotes gluconeogenesis to convert lipids and amino acids in glucose

149
Q

What is Diabetes mellitus?

A

Inability to regulate blood glucose

150
Q

What is Type 1 diabetes?

A
  • Caused by a failure of insulin secretion
  • Characterised by high [glucose]
  • Has sudden onset
  • Usually develops early in life
151
Q

What is Type 2 diabetes?

A
  • Caused by insulin resistance in tissues
  • Insulin present in circulation but [glucose] remains elevated
  • Has gradual onset
  • Associated very strongly with obesity
152
Q

What is the type 1 diabetes pathogenesis?

A
  • Type 1 diabetes is caused by destruction of β cells
  • Involves autoimmune mechanism (CD8 cytotoxic T cells mediated)
  • Total failure of insulin secretion
153
Q

What genes are associated with type 1 diabetes?

A
  • HLA-DR3
    *DR4
154
Q

What are the Symptoms of type 1 diabetes?

A

*Tissues cannot accumulate and store glucose
Tissues cannot use glucose as metabolic fuel
*Body cannot store excess energy as fat
*Reduced synthesis of protein
*Weight loss

155
Q

How does diabetes lead to Dehydration, excessive urine production and thirst?

A
  • High Glucose concentration enters glomerular filtrate and overwhelms glucose absorbing capacity of proximal convoluted tubule
  • Increased fluid osmolarity in tubules
  • More water is secreted from cells into the proximal convoluted tubule
    *Increased urine flow – diuresis
  • Water reabsorption is reduced
156
Q

What are the problems with repeatedly injecting insulin?

A
  • A major effects of insulin is to promote the deposition of fat
  • Cells close to site of insulin injection exposed to high insulin concentration
  • If same site used again and again will promote deposition of fat around injection site (lipohypertrophy)
  • Important to change site frequently toavoid this
157
Q

What forms of insulin are used in therapy?

A
  • Animal insulin (porcine/bovine)
  • Human insulin
  • Human insulin analogue
158
Q

What kinds of human insulin are used in therapy?

A
  • Soluble insulin
  • Isophane insulin
  • Insulin zinc suspension
159
Q

What are the characteristics of Soluble insulin?

A

Rapid and short lived

160
Q

When is soluble insulin used?

A

Used intravenously in emergency treatment of hyperglycemic emergencies

161
Q

What are the characteristics of isophane insulin?

A

Tends to form precipitates.
Intermediate acting

162
Q

What are the characteristics of Insulin zinc suspension?

A

Tends to form precipitates.
Long acting

163
Q

What kinds of insulin analogues?

A

*Insulin Lispro
* Insulin glargine & detemir

164
Q

What is Insulin Lispro?

A

A modified insulin (analogue) obtained by switching a Lys28 and Pro29

165
Q

What are the characteristics of Insulin Lispro?

A

Very rapid and very short lived.
Normally taken from patients before a meal

166
Q

What is Insulin glargine?

A

A modified insulin (analogue) obtained by mutating Asn21 in Gly and by adding 2 Arg at the end of the B chain

167
Q

What is Insulin detemir

A

A modified insulin (analogue) obtained by mutating Thr 30 (deletion)

168
Q

What are the characteristics of Insulin glargine & detemir?

A
  • Long-acting.
  • Forms a micro-precipitate at the physiological pH of subcutaneous tissue
  • Slowly absorbed
169
Q

What is type 2 diabetes?

A

*Insulin resistance
*Decrease in Glucose uptake
*Insulin pathway defects

170
Q

What are the stages of developing type 2 diabetes?

A
  1. Genetic and environmental predisposition
  2. Insulin resistance
  3. Hyperinsulinemia
  4. Diabetes
171
Q

What are the types of Type 2 diabetes therapy?

A

Thiazolidinediones
Metformin
Sulphonylureas

172
Q

What is Thiazolidinediones?

A
  • Agonist of nuclear receptor PPAR-γ
  • Promotes expression and secretion of anti-
    hyperglycaemic adipokines
    -Increase lipolysis
  • Increase action of insulin by sensitizing cells to its action
  • Collectively reduce insulin-resistance in liver
173
Q

What is Metformin?

A
  • Suppress glucose release from liver
  • Activate AMPK
  • increase lipolysis in liver and muscles and
  • Improving insulin receptor signalling
  • Suppress glucose release from liver
  • Useful in obese type 2 patients
174
Q

What is Sulphonylureas?

A
  • Bind to sulphonylurea receptors expressed on membranes of β cells
  • Block ATP-sensitive K + channels in β cells
  • K + accumulates inside cells
  • β cells depolarize
  • Ca++ channels open and allow insulin secretion by exocitosis
175
Q

How is the NF-kB pathway activated?

A

Ligand attaches to extracellular receptor.
IKK kinase becomes lkB complex.
lkB is phosphorylated.
lkB is ubiquinated.
NF-kB translocate to nucleus.

176
Q

What is RHD?

A

The Rel Homology Domain (RHD) encodes the DNA binding and dimerisation functions of NF-kB

177
Q

What are p100 and p105?

A

Precursors for p50 and p52.
They contain ankyrin repeats in their C-termini that allow them to function as IkB inhibitors

178
Q

What are the inhibitors of NF-κB?

A

IκBα
IκBβ
IκBε
Bcl-3.

179
Q

What is the structure of IkB?

A

Contain ankyrin repeat motifs (ANK) in their C termini.
PEST domain.

180
Q

What is a PEST domain?

A

Rich in:
proline (P)
glutamate (E),
serine (S)
threonine (T).

181
Q

What is Bcl-3?

A

A nuclear coactivator for the p52 NF-κB subunit.

182
Q

What are The three core subunits of the IkB kinase (IKK) complex?

A

IKK-alpha and IKK-beta
Regulatory subunit called the NF-kB essential modifier
NEMO binding subunit

183
Q

What are the parts of the NEMO-binding domain?

A

CC1 and CC2, coiled coil regions 1 and 2
ZF, zinc finger domain
Whatever LZ is

184
Q

What are the major regions on the kinase complexes alpha and beta?

A

Kinase domain
LZ
HLH, helix–loop–helix domain, homo/eterodimerization domain
NBD: NEMO binding domain

185
Q

What is the NF-kB responsible for?

A

Proliferation
Survival
Tumour promotion
Cell death
Inflammation

186
Q

What triggers the NF-kB pathway?

A

Stress
Carcinogens
Tumour promoters
Cancer therapies
Genetic alteration

187
Q

What is the structure of p53?

A

N-terminal domain
The core domain
The c-terminal domain

188
Q

What is the N-terminal domain?

A

Contain a sub-transactivation domain and a proline rich domain which may be involved in regulation of apoptosis

189
Q

What is the core domain?

A

Bind to specific DNA sequences

190
Q

What is the The c-terminal domain?

A

Contains the tetramerization domain and another DNA binding site within the regulatory region.

Cell Biology and Disease (6 decks)

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