Strand 3 - Cell signalling Flashcards
1
Q
what is the first stage of signal transduction? (hint: involves the first messenger)
A
an extracellular signal molecule activates a membrane receptor
2
Q
what is the second stage of signal transduction
A
intracellular molecules are transduced via a certain pathway
3
Q
what is the third stage of signal transduction?
A
activating a cellular response
4
Q
give an example of an amine which is a first messenger
A
adrenaline
5
Q
give an example of a peptide/protein that is a first messenger
A
angiotensin 2
insulin
6
Q
give an example of a ligand gated ion channel (hint: think nervous system)
A
nicotinic ach receptor
7
Q
which subunits make up the nicotinic ach receptor
A
2 alpha
1 beta
1 delta
1 epsilon
8
Q
which ion is GABA A selective for?
A
Cl-
9
Q
which two substances activate GABA A receptors?
A
alcohol and anaesthetics
10
Q
name a muscarinic receptor which activates a potassium channel
A
GABA B
11
Q
what are metabotropic receptors connected to? and what does it do?
A
connected to a G protein
opens ion channels
12
Q
what do ionotropic receptors form in the membrane? what does this allow?
A
a pore
allows an ion to pass into a cell
13
Q
how many chains are G proteins made of? what are they?
A
3
alpha, beta, gamma
14
Q
the alpha subunit of a G protein has a …… binding site that binds…….
A
guanine
GTP/GDP
15
Q
does alpha GDP have a high affinity for the resting B-gamma or the active one?
A
resting
16
Q
the alpha subunit of a G protein hydrolyses GTP. what molecule does this activate?
A
adenyl cyclase
17
Q
in an inactive PKA molecule are the subunits bound together or not?
does the R subunit suppress the activity of the C subunit
A
yes and yes
18
Q
the R subunits in PKA have how many binding sites for cAMP?
A
2
18
Q
which 2 chains does PKA have?
A
catalytic and regulatory
18
Q
What does PKA catalyse the transfer of to serine or threonines on substrates?
A
ATP
19
Q
which cellular response is activated by cAMP in the kidney collecting duct?
A
water retention (vasopressin)
20
Q
which cellular response is activated by cAMP in the smooth/cardiac muscle?
A
relaxation of muscle / increase of heart rate (adrenaline)
20
Q
which cellular response is activated by cAMP in the colonic epithelium?
A
promotion of fluid/electrolyte secretion
21
Q
which cellular response is activated by cAMP in the pancreas?
A
promotion of the release of glucose in the blood (glucagon)
22
what is cAMP hydrolysed by?
phosphodiesterase
23
phosphodiesterases are inhibited by which substance?
caffeine
24
what does Beta adrenoreceptor kinase do to a beta adrenoreceptor?
what effect does this have on the affinity it has for adrenaline?
phosphorylates it
reduces affinity for adrenaline
25
what does the stimulatory alpha subnit stimulate in a G protein?
adenyl cyclase
26
what does the inhibitory alpha subnit inhibit in a G protein?
adenyl cyclase
27
which alpha subunit of a G protein does the cholera toxin act on?
the alpha stimulatory subunit
28
when cholera toxin binds to the alpha stimulatory subunit of a G protein what does it cause to happen to ADP?
what does this cause to happen to the alpha subunit in turn?
ADP ribosylation
hydrolysis of GTP = constant activation of alpha subunit
29
in the colon, the cholera toxin activates what?
what does this cause in turn to be excreted from the body?
PKA dependent Cl- channels
secretory diarhhoea
29
which **alpha** subunit of a G protein does pertussis toxin act on? and what does it prevent?
what does this increase therefore ?
the inhibitory alpha subunit - prevents activation by receptors and increases cAMP
30
what does pertussis toxin lead to in the airways?
whooping cough
31
which unique subunit do Gq proteins contain?
alpha q-11
32
what do Gq proteins allow hormones to do?
activate the amplifier enzyme phospholipase C
33
What does phospholipase C cleave to produce IP3 and DAG?
PIP 2
34
what does IP3 stimulate the release of from the ER?
Calcium
35
what does DAG recruit when it remains in the membrane?
Protein kinase C
36
how many Ca2+ does each calmodulin bind to ?
4
37
what doe the Ca2+/CaM complex activate?
CaM kinases
38
What do CaM kinases cause the contraction of in the body?
smooth muscle
39
which 2 residues do CaM kinases phosphorylate?
serine and threonine
40
What can PKCs potentiate the effect of which in turn mediates the desensitization via cf Beta- ARK?
IP3
41
What does alpha 1 adrenoreceptor cause the constriction of?
vascular smooth muscle
42
Which G protein causes blood pressure to increase?
Gq-PLC-IP3-CaMK
43
Which G protein causes blood pressure to decrease via vasodilation?
Gs-cAMP-PKA
44
which 3 subtypes (out of 1-5) of muscarinic receptors are Gq coupled stimulatory?
1, 3, 5
45
****which 2 subtypes (out of 1 to 5) of muscarinic receptors are Gi protein coupled **inhibitory?**
2 and 4
46
which 2 receptors are coupled with a Gi protein? (hint: one adrenergic and one muscarinic)
a2 adrenergic
M2 muscarinic
47
what is the function of the guanyl cyclase domains on guanyl cyclase receptors?
to convert GTP to cGMP
48
give an example of a response from an activated guanyl cyclase receptor?
vasodilation/ relaxation of vascular smooth muscle
49
what is the function of the Ser-Thr domains on Ser-Thr kinase receptors?
phosphorylation of target proteins
50
give an example of a response elicited by an **activated ser-thr kinase receptor?**
cell proliferation
51
what 2 things do tyrosine kinase domains in TKRs phosphorylate?
themselves and other proteins
52
give an example of a response caused by an activated **tyrosine kinase** receptor?
insulin mediated glucose uptake / storage in liver or muscles
53
tyrosine kinase associated receptors do not contain which type of domain?
kinase domains
54
what does the dimerization of tyrosine kinase associated receptors cause the activation of? Give an example
associated tyr kinases such as JAK2
55
give an example of a cellular response elicited by the activation of a tyrosine kinase associated response
EPO mediated increased production of blood cells
56
what do the tyrosine phosphatase domains dephosphorylate in tyrosine phosphatase receptors?
target proteins
57
give an example of a response elicited by the dephosphorylation of target proteins by tyrosine phosphatases
maturation of lymphocytes
58
what is glucose stored as in the liver and muscles?
glycogen
59
after a meal what happens to glucose absorption?
increases
60
what concentration is circulating glucose normally?
5mM
61
what does insulin promote the storage of? and as what?
glucose
stored as glycogen
62
what do the alpha cells of the pancreas produce?
glucagon
63
what do the beta cells of the pancreas produce? (2 things)
insulin and amylin
64
what do the gamma cells of the pancreas produce?
somatostatin
65
what is pro insulin activated by?
prohormone convertase 1 and 2
66
insulin is made up of ..... polypetide chains held together by ...... bonds?
2
disulphide
67
what is insulin stored in within B cells?
secretory granules
68
at what concentration of glucose is insulin at its highest concentration?
9 mM
69
Which GLUT transporter is expressed by B cells and is always open?
GLUT 2
70
in B cells, what is glucose phosphorylated to?
what is it phosphorylated by to generate ATP?
glucose - 6 - phosphate
by glucokinase
71
When is the Vm depolarised in B cells?
when glucose concentration is HIGH
72
when the Vm is depolarised in B cells which ion channel is open and which is closed?
K+ is closed
Ca2+ is open
73
into which vein is insulin released from the pancreas?
hepatic portal vein
74
in insulin release, P13K activation causes the activation of which protein kinase?
which GLUT channel does this then cause the translocation of to the PM?
PKB
GLUT 4
75
hepatic glucose uptake depends primarily on which GLUT channel?
GLUT- 4
76
if glycogen reserves are full, what is glucose metabolised to via oxidation?
fatty acids
77
when do the alpha cells of the pancreas secrete glucagon?
when blood glucose levels are low
78
what event can trigger glucagon release?
hypoglycaemia
79
during exercise, how does glucagon allow the skeletal muscle to indirectly metabolise glucose?
why is this necessary?
causes the translocation of GLUT-4 to the plasma membrane of skeletal muscle cells = GLUCOSE UPTAKE
because skeletal muscles do not have glucose receptors present on their PM
80
which 2 hormones can **promote glycogenolysis**?
glucagon and adrenaline
81
what do high levels of glucagon cause the release of from adipose tissue?
fatty acids
82
when glycogen has been depleted, what does glucagon stimulate the formation of?
what is this process known as
glucose
gluconeogenesis
83
in gluconeogenesis, what 2 things is glucose formed from?
lipids and amino acids
84
what is diabetes mellitus defined as?
the inability to regulate blood glucose
85
diabetes mellitus means blood glucose levels are consistently above what concentration?
7mM
86
what is the 'safe' range of blood glucose?
3-7mM
87
Type 1 diabetes is the failure to....., resulting in high levels of blood......
secrete insulin
glucose
88
type 2 diabetes is caused by what?
this results in high levels of...... in the blood?
resistance to insulin
glucose
89
type 1 diabetes is an autoimmune disease, mediated by which type of T cells?
CD8 cytotoxic T cells
90
which cells are destroyed in type 1 diabetes?
B cells
91
In type 1 diabetes mutations in caucasians, what is Asp57 substituted to in the HLA-DQ beta 1 chain?
( 3 AAs)
valine, alanine or serine
92
Which haplotypes are associated with type 1 diabetes?
HLA-DR3, HLA-DR4
93
In type 1 diabetes, why is the absorption capacity of the PCT overwhelmed, causing the increase of urine flow and therefore dehydration?
too high of a glucose concentration enters the glomerulus
94
why is weight loss associated with type 1 diabetes when no insulin is being made?
no insulin made = glucose not used by tissues = use fatty acids instead
95
when does ketoacidosis occur in type 1 diabetes, resulting in a coma or death?
in the presence of too many ketone bodies causing the decrease of pH = metabolic acidosis
96
what is a problem caused by continuous insulin injection into one site on the body?
fat deposition or lipohypertrophy
97
why do patients with type 1 diabetes need to change their insulin injection site often?
they have poor glycaemic control and therefore unpredictable insulin absorption (can get hyper/hypoglycaemic easily)
98
which combination of insulin forms would be used routinely to control glycaemia?
soluble insulin and glargine
99
which 2 events follow the hyperglycaemia stage in type 2 diabetes?
hyperinsulinaemia
Beta cell failure
100
which 2 molecules can lead to insulin resistance in type 2 diabetes?
IL-1 and DAG
101
Which of 2 drugs work by improving insulin secretion from the Beta cells of the pancreas?
gliclazide and GLP-1 agonists
102
what is soluble insulin used to treat?
is it rapid or slow onset?
hyperglycaemic emergencies only
rapid onset
103
give an example of a long acting insulin drug?
insulin zinc suspension
104
give an example of a very rapid and very short lived insulin analogue drug which is taken by diabetic patients before a meal?
insulin lispro
105
which slow acting, insulin analogue is taken by diabetic patients before a meal IN COMBINATION with a short acting form?
insulin detemir
106
give an example of an INSULIN ANALOGUE which is LONG ACTING
insulin glargine
107
which insulin drug targets the autoimmune reaction in type 1 diabetes?
teplizumab
108
which 2 drugs are used to routinely control glycaemia?
lispro and detemir
109
in type 2 diabetes, insulin resistance is caused by what?
the decrease of glucose uptake
110
what is hyperinsulinemia, in relation to the beta cells and insulin demand? (type 2 diabetes)
what does it lead to the decrease of?
the failure of the beta cells of pancreas to keep up with the peripheral demand of insulin
leads to the decrease of insulin secretion
111
what causes insulin resistance in liver and muscle in type 2 diabetes?
free fatty acids
112
when in excess, free fatty acids in type 2 diabetes are transformed to which second messenger?
DAG
113
DAG activates PKC. What does PKC phosphorylate on Ser residues which in turn attenuates the insulin receptor signal?
IRS-1
114
the expression of what enzyme is reduced in obesity (type 2 diabetes)?
adiponectin
115
what does the enzyme adiponectin improve by activating AMPK?
insulin sensitivity
116
what does the enzyme AMPK promote in liver and muscle?
lipolysis
117
which drug are AMPK activators used in for type 2 diabetes?
metformin
118
what is the nuclear receptor involved in adipocyte differentiation?
PPAR gamma
119
what does the receptor PPARy promote the secretion of?
anti-hyperglycaemic adipokines
120
which two interleukins are produced by adipocytes to attract macrophages to fat deposits?
IL-6 and IL-1
121
Which drug is an agonist for the PPARy receptor in diabetes type 2?
Pioglitazone
122
which drug can suppress glucose release from the liver, activate AMPK and increase lipolysis in liver?
metformin
123
give an example of a sulphonylurea drug which bind to receptors expressed on beta cell membranes (type 2 diabetes)
Gliclazide
124
which ion channel does gliclazide block in beta cells?
what does this cause the beta cell to do?
K+ channels
causes depolarization and opening of Ca2+ channels and insulin secretion
125
What can B3 agonists control in fat cells?
lipolysis
126
what do alpha 2 adrenoreceptor antagonists increase the secretion of? (type 2 diabetes treatment)
insulin
127
what do GLP-1 receptor agonists cause in beta cells?
increase insulin secretion from beta cells
128
what effect do SGLT-2 inhibitors have on the excretion of glucose in urine? what does this induce?
increase it and induce ketogenesis
129
what are some long term **disease** consequences of type 2 diabetes?
retinopathy, nephropathy, Coronary Artery Diseases
130
what does type 2 diabetes generate which cause damage to blood vessels? (2 things)
reactive oxygen species and AGEs
131
what do AGEs cross link with in type 2 diabetes causing inflammation and blood vessel damage?
collagen
132
which domain of NF-KB encodes the DNA binding and dimerization functions?
the rel homology domain (RHD)
133
what is the precursor protein for p50?
p105
134
what is the precursor protein for p52?
p100
135
is p50 part of the canonical or non-canonical p53 pathway?
canonical
136
name physiological 4 events that activate NF-KB
hypoxia, DNA damage, infection, physical stress
137
which 2 proteins involved in NF-KB signalling have regulatory functions but no catalytic activity?
IKB-alpha and IKK-gamma (NEMO)
138
p105 and p100 in the NF-KB family have ankyrin repeats in which terminals?
C terminals
139
in the non canonical p53 pathway, what does NIK kinase phosphorylate?
IKK alpha
140
in the non-canonical p53 pathway, the precursor p52 associates with what?
Rel-B
141
give examples of cellular events which NF-KB regulates?
cell death
cell proliferation
inflammation
angiogenesis
tumour metastasis
cell survival
142
when NF-KB control is lost in cancerous cells, the cells become abherrantly ...... instead of cytoplasmic
nuclear
143
the N terminal domain of p53 contains which two domains that are involved in apoptosis regulation?
sub-transactivation and a proline rich domain
144
in p53, what does the core domain bind to?
DNA sequences
145
in p53, which domain is contained within the C terminal domain?
tetramerization domain
146
does p53 suppress or promote tumour activity?
suppress
147
which molecule keeps p53 inactive?
Mdm2
148
does NF-KB promote or suppress cell survival?
promote
149
in cancer cells, p53 is ..... and NF-KB is abherrant
mutated
150
which cyclin can p53 repress?
D1
151
which molecule can induce senescence in a p53 dependent manner in the crosstalk pathway?
EZH2
152
in primary B cell chronic lymphocytic leukemia (CLL) cells, EZH2 expression is induced upon the stimulation of which CD ligand?
CD40L
153
Via EZH2 regulation, which 2 subunits of p53 can antagonize p53 mediated cell senescence?
p52 and RelB
154
regarding NF-KB and p53 crosstalks, which situation is most likely to happen in cancer cells? (hint: think antagonism
NF-KB antagonizes p53 functions
