Molecular Medicine > Unit 1 - Signal Transduction > Flashcards

Unit 1 - Signal Transduction Flashcards

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1
Q

Molecular

A

activation of enzyme, generation/synthesis of metabolite and its degradation

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2
Q

cellular

A

number of mitochondria regulated in a cell may divide, split, fuse

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3
Q

tissue/organ

A

no of cells or cell types are tightly regulated

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4
Q

4 levels of regulation in living organism

A

molecular

cellular

tissue/organ

organism (neuro-endocrine)

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5
Q

main mechanims of integration of the levels of regulation

A

HPA axis

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6
Q

what is the target of regulation

A
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7
Q

definition of signal transduction

A

process linking the signal-activated receptor and the biological response

there is a common logic in the structure of signal transducers and in the mode of their function

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8
Q

how is regulation initiated and and how does it flow

A

initiated by the signal (information) reaching the cell or formed within the cell

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9
Q

EC signal molecule → receptor protein → IC signalling proteins → target proteins

A
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10
Q

what can a signal be, based on their origin

A

from environment - pin, temp, light, smell

from organism - hormones, cytokines, metabolites

from within the same cell - DNA damage, ROS

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11
Q

what can a signal be if chemical

A
  • proteins - GH
  • peptides - insulin, neuropeptides
  • AAs, derivatives - thyroxine, dopamine, epinephrine
  • lipids - PGs, platelet activating factor
  • ions - Ca2+, Cl-
  • nucleotides - adenosines with specialised receptors on their surface
  • gases - nitric oxide (produced by endothelial cells – trigger smooth muscle relaxation and vasodilation)
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12
Q

types of signal transmission

A
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13
Q

what is the significance of ligand binding

A

specificity

amplification

co-ordination of response - the same receptor may be present on a number of cells

cell specific response - by regulating the number and function of receptors

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14
Q

example of disease that involves a cell-specific response

A

type 2 diabetes

autoinhibitory receptors are present on cells become inactivated and unresponsive

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15
Q

types of receptors

A

cell surface/transmembrane receptors

nuclear receptors

cytosolic receptors

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16
Q

receptors for what hormone are present on a wide variety of cells

A

cortisol

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17
Q

amplification system

A

Uniform response of cell

e.g. If a cell triggers lipid degradation, whole lipid synthesis across the cell has to shut down and lipid degradation must occur

Net 0 effect - what 1 process achieves, the other will undo

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18
Q

allosteric regulation

A
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19
Q

interconversion cycle

A

NOTE: enzyme specific - some are active phosphorylated, some are active dephosphorylated

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20
Q

Akt/Protein Kinase P interconversion cycle - 1st mechanism

A

inactive Akt → Akt by 2 mechanisms:

FIRST

phosphorylated serine 473 interacts with the linker between the kinase and pH domains

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21
Q

2nd mechanism in Akt/protein kinase P interconversion cycle

A

phosphorylated serine 477 and threonine 479 result in the displacement of the pH domains

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22
Q

enzyme cascade

A
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23
Q

acceptors

A

all signal transduction pathways culminate to control of function of proteins (mostly enzymes, ion channels, transporters), which are involved directly in formation of biological response

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24
Q

2 categories of acceptors

A

control of protein amount

gene expression

protein degradation

protein stabilisation (tumour suppression gene P53)

control of existing proteins

without covalent modification of the protein (P) - Allosteric activator binds to an allosteric enzyme complex

with covalent modification of the protein - reversible and irreversible (cleavage of 3 forms of enzymes e.g. digestive enzymes involved in cleavage of trypsinogen to inter trypsin)

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25
tumour suppression gene P53
regulated by protein stabilisation
26
mechanisms of hormonal regulation
27
4 types of membrane bound receptors
ion channel enclosing receptors 7 transmembrane domain receptors 1 hydrophobic domain receptors (R with enzyme activity, R with no enzyme activity)
28
ligands that activate membrane bound receptors
hydrophilic
29
signalling via ion channel-enclosing receptor example
nicotinic ACh receptor
30
structure of nicotinic ACh receptor binding results in
pentamer (2 x α, β, γ, δ) subunits surround a central pore 2 Ach binding sites from the pore their binding is co-operative and leads to channel opening channel is selective for divalent cations (+ve) - Na+ and Ca2+ hyperpolarisation with AP triggered
31
ION CHANNEL-ENCLOSING RECEPTORS GABA, glycine, ACh, glutamate, serotonin 1. receptors 2. amplification systems 3. acceptors 4. biological response
1. on the plasma membrane 2. channel-transmitted ions 3. membrane ion channels (e.g. VG Na+ channels) 4. membrane depolarisation, hyperpolarisation, muscle contraction etc
32
glycine ion selectivity
Cl- HCO3-
33
GABA ion selectivity
Cl- HCO3-
34
ACh ion selectivity
Na+ K+ Ca2+
35
glutamate ion selectivity
Na+ K+ Ca2+
36
serotonin ion selectivity
Na+ K+
37
ION CHANNEL-ENCLOSING RECEPTORS IP3, cGMP, cAMP, ATP 1. receptors 2. amplification system 3. acceptors 4. biological response
1. on IC membranes 2. channel-transmitted ions 3. myosin, membrane ion channels 4. muscle contraction, depolarisation, hyperpolarisation, activating of energy producing metabolic pathways also
38
IP3 ion selectivity
Ca2+
39
cGMP ion selectivity
Na+ K+
40
cAMP ion selectivity
Na+ K+
41
ATP ion selectivity
K+
42
overview of signalling system of ion channel-enclosing receptors
43
example of signalling via 7-transmembrane domain receptors
β adrenergic receptors
44
structure of 7 transmembrane domain receptors
amino terminal lies on EC side carboxyl-terminal is in the cytosol ligand sits in a pocket formed by transmembrane helices upon R activation, the R binds a G protein (GPCRs) 3rd TM domain recognises the G protein
45
amplification system of G-protein activated adenylate cyclase
46
how does protein kinase A regulate the acceptor
PKA when activated by cAMP can penetrate the nuclear membrane It can then phosphorylate CREB When phosphorylated, it is ACTIVE and helps to initiate gene expression
47
acceptors of protein kinase A
* enzymes * structural proteins - troponin, myosin light chain kinase * ion channels - IP3-sensitive Ca2+ channel * transcription factors (cAMP response element binding protein - CREB)
48
**biological responses induced by adenylate cyclase system** in what structures is it present
Liver adipocytes muscle adrenal cortex T cell Olfactory cells crypt cells SM cells
49
biological responses induced by adenylate cyclase system LIVER
glycogenolysis glyconeogenesis glucolysis gluconeogenesis lipid synthesis β oxidation cholesterol synthesis
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biological responses induced by the adenylate cyclase system ADIPOCYTES
lipid breakdown
51
biological responses induced by the adenylate cyclase system adrenal cortex
synthesis of many steroid hormones ACTH regulated aldosterone secretion
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biological responses induced by the adenylate cyclase system OLFACTORY CELLS
sensitivity to odorants
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biological responses induced by adenylate cyclase system CRYPT CELLS
Cl- secretion
54
biological respones induced by adenylate cyclase system SM CELLS
inhibition of contraction
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biological responses induced by adenylate cyclase system MUSCLE
glycogenolysis
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biological responses induced by adenylate cyclase system T CELL
proliferation death
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Amplification system - G protein activated phospholipase C
IP3 = **ion channel**
58
catalytic rxn of PLC
PLC can be activated via G proteins or by Tyr phosphorylation membrane bound phosphatidyl 4, 5 bisphosphate is hydrolysed to membrane bound diacyl-glycerol and cytosolic ionositol 1, 4, 5-trisphosphate
59
activation of PLC?
via G proteins or by Tyr phosphorylation
60
amplification of G protein activated PLC
61
targets of calcium
calcium activates protein by directly binding or binding to a calcium-activated regulatory subunit
62
acceptors that are directly activated by Ca2+
tissue transglutaminase protein kinase C phospholipase A2 calpain DNases
63
calcium-sensing regulatory subunits functions
calmodulin regulated proteins glycogen phosphorylase kinase, muscle contraction, calmodulin regulated protein kinase
64
AAs associated with PKC
Ser Thr
65
targets of PKC
**cell surface receptors** - EGF, insulin, CD3 **enzymes** - raf1 kinase, GAP-p21 ras **ion channels** - Na/H+ exchange **proteins in cell cycle control** - DNA topoisomerase **nuclear factors** - NFκB **proteins in cytoskeleton** - MARCKS
66
PLC-induced biological responses
liver glycogenolysis (adrenaline α1, vasopressin) thrombocyte aggregation (PAF, thromboxan) thrombocyte serotonin secretion mastocyte histamine secretion (IgE) pancreas digestive system enzyme secretion (cholecystokinin) insulin secretion adrenal chromaffin cell adrenaline secretion adrenal cortex aldosterone secretion (Ang II) SM contraction (PGE2) cell proliferation differentiation programmed cell death
67
signalling system via 7-transmembrane domain receptors
68
signalling through 1-hydrophobic domain receptors carrying enzymatic activity - give an example
receptor tyrosine kinases (in their C terminus) - insulin receptor
69
receptor tyrosine kinase how many present how do the domains differ what are the receptors for
58 in humans, in 20 sub-families ***_1_*** transmembrane region variable EC ligand binding domain IC tyrosine kinase domain receptors for growth and survival factors - drive cell proliferation, cell survival, cell differentiation
70
GOF mutation in TK receptor
GOF ⇒ constitutively active in the absence of their ligand they will drive constant cell proliferation, cell survival making these cells resistant to drugs
71
ligands of TK receptors induce
RTK dimerisation, leading to activation
72
what do the phosphorylated tyrosines act as
docking sites for signal transducing proteins
73
phosphotyrosine residues act as binding sites for
enzymes and adaptor proteins
74
what are adaptor (scaffold) proteins
proteins with platforms to bind multiple proteins ability to bring protein complexes together proteins with SH2 (Src homology domain 2) and PTB (phosphotyrosine binding) domains can dock on phosphorylated tyrosines of RTK the type of adaptor protein determines the downstream signalling and the biological response
75
3 main signal transduction pathways induced by RTKs
76
what is Ras what amplification cascade does it activate
a small GTPase, similar to G proteins activates the MAPK amplification cascade
77
Ras activating enyme
Raf (Ser/thr kinase)
78
RAS signalling drives
cell division
79
Ras and cancer
Ras (HRAS, NRAS, KRAS) one of the most frequently mutated oncogenes in human cancers
80
what is Ras unable to do
single subunit protein so not able to replace GDP with GTP hence GEF protein helps with this - removes GDP and replaces it with GTP
81
Ras pathway
Grb2 (scaffold) binds to P-Y via its SH2 domain Grb2 has 2 SH3 domains, which bind Sos Sos = guanine nucleotide exchange factor that activates Ras Ras activates Raf Raf is a serine threonine kinase and activates mitogen activating protein kinases
82
how and what does Ras induce
83
3 main Ras proteins in the body
KRAS NRAS HRAS
84
Ras mutations and cancer
GOF - affects GTP binding
85
phosphatidyl ionositol 3 kinase pathway - how is it activated
by RTKs (PLC is seen both with 7 TM receptors but also RTKs)
86
what does PI3K phosphorylate
the membrane lipid phosphatidyl ionositol 2-phosphate
87
structure of PI3K
regulatory and catalytic subunit both subunits have multiple protein binding motifs and recognition motifs (SH2, SH3) 1 of the most frequently mutated pathways in human cancers
88
phosphatidyl ionositol 3 kinase pathway
89
FoxO
blocks cell signalling Forkhead transcription factor regulates expression of Bim
90
GLUT4
glucose uptake into cells activated by Akt
91
GSK3
glycogen synthase kinase Akt inhibits GSK3 metabolic adaptation leads to glycogen metabolism, **cell cycle progression**
92
mTOR
metabolic adaptation protein synthesis for cell proliferation (activated by Akt)
93
Bad, Bim
cell survival Akt inhibits Bad, Bim, Bax (which are all pro-apoptotic)
94
what does activated Akt do
regulates receptors via phosphorylated serine and/or threonine residues on them
95
what are inhibitors of PI3K used to treat
chronic lymphocytic leukaemia
96
PI3K and Akt are
proto-oncogenes (GOF ⇒ constitutively active - Drive proliferation, drug resistance)
97
signalling system of receptor tyrosine kinases
98
3 groups of signal transduction pathways
membrane bound receptors cytosolic receptors nuclear receptors
99
types of membrane bound receptors
ion channel-enclosing receptors 7-TM receptors (β adrenergic) 1 hydrophobic domain receptors (with or without enzyme activity)
100
requirement for IC receptors
ligands must be membrane permeable
101
examples of IC receptor ligands
steroid hormones lipophilic vitamins small molecules e.g. NO and H2O2
102
example of cytosolic receptor what is its ligand
soluble guanylate cyclase receptor receptor for NO
103
functions of NO
regulation of SM relaxation platelet aggregation neurotransmission
104
where does the synthesis of NO occur
in endothelial cells, neuronal cells and macrophages
105
enzymes that produce NO what are their isoforms
nitric oxide synthases (NOS) neuronal NOS endothelial NOS inducible NOS \*\* expression is not restricted to these tissues
106
how is the synthesis of NO controlled
by hormones, cytokines, bacterial endotoxins VIA 1. regulating the IC Ca2+ level (eNOS, nNOS) 2. regulating the synthesis of NOS on gene level (iNOS)
107
soluble guanylate cylcase-induced signalling
108
what are nuclear receptors
transcription factors - intitiate gene transcription
109
nuclear receptors intitiating gene transcription
110
what are class I nuclear receptors
inactive receptor located in cytosol
111
what complex keeps the receptor inactive
HSP complex
112
what happens when the hormone binds to the nuclear receptor
dissociation of heat shock proteins dimerisation translocation to the nucleus
113
what family does the class I NR belong to
**steroid receptor family** * progesterone - PR * oestrogen - ER * glucocorticoid - GR * androgen - AR * mineralocorticoid - MR
114
nature of changes in gene transcription mediated by steroid receptors
relatively slow in onset yet result in long-term changes in gene expression
115
where are class II nuclear receptors found
retained in the nucleus even when no ligand is bound
116
ligand binding to class II nuclear receptors causes
dissociation of corepressor protein recruitment of coactivator protein recruitment of additional proteins including RNA polymerase to the NR/DNA complex to transcribe DNA into mRNA resulting in biological response
117
examples of class II nuclear receptors
retinoic acid receptor retinoid X receptor thyroid hormone receptor vit D receptor (VDR) peroxisome proliferator-activated receptor (PPAR)

Molecular Medicine (7 decks)

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