Hormone Action Flashcards
(140 cards)
1
Q
signals are received by cell ____, and passed on to _____, where it is _____, ultimately resulting in ___ or ___
A
receptors
chain of signaling proteins
exponentially amplified
on or off state
2
Q
the 2 main classes of hormones, based in signalling pathway:
What types of hormones are associated with each?
A
- cell-surface receptor pathways (hydrophilic)
2. intracellular receptor pathways (hydrophobic)
3
Q
basic structure of a cell surface receptor:
A
outer ectodomain (amino end) hydrophobic transmembrane domain (crosses plasma membrane)
cytoplasmic domain (carboxyl end)
4
Q
how many AA are needed at least to cross the cell membrane?
A
25
5
Q
Characteristics of the ectodomain:
A
NH2 end
rich in cysteine (for S-S bonds)
Often glycosylated
6
Q
The transmembrane domain usually has a ___ ___ strucutre
A
alpha helix
7
Q
the ectodomain can also break off and serve as ____ ____ ___. Give an example:
A
hormone binding protein
ex: GH receptor can act as GH binding protein in circulation
8
Q
What is a possible trigger of Graves disease?
A
TSH receptor ectodomain can induce antibodies -> bind to receptor and mimic TSH -> hyperthyroidism
9
Q
an activated cytoplasmic domain will induce a ____ ____. How is this done?
A
signal cascade (passing of the signal)
signal passed by phosphorylating proteins, or binding proteins => conformation changes
10
Q
What AA are common sites for phosphorylation? Why?
A
Serine
Threonine
Tyrosine
Have a polar hydroxyl group that is replaced by phosphate group
11
Q
What is the phosphate donor in the phosphorylation cascade?
A
ATP
12
Q
Many signaling proteins are ____, which are activated by _____
A
kinases
phosphorylation
13
Q
What causes signal amplification?
A
activation of kinase -> can phosphorylate many more kinases -> phosphorylate even more kinases (chain rxn/ripple effect)
14
Q
True/False: once an activated protein in the signal cascade has phosphorylated the next messenger, it becomes inactive since it loses the phosphate group.
A
False; stays active until inactivated (phosphorylates using ATP, not its own phosphate group)
15
Q
How do you reverse phosphorylation?
A
phosphatase
16
Q
Advantages of using protein phosphorylation for signal transduction:
A
- rapid (don’t need to synth/degrade proteins)
- reversible: easy to reset with phosphatases
- easy signal passing: Tyr, Thr, Ser make binding sites for other proteins
17
Q
____% of all cell proteins are phosphorylated
A
10%
18
Q
True/False: tyrosines are more abundantly phosphorylated than serine or threonine
A
False: phosphorylated Ser and Thr is 100:1 compared to Tyr
19
Q
What is special about tyrosine phosphorylation?
A
at beginning of cascade; serve as DOCKING SITE for downstream signal proteins
20
Q
What are the AA sequence that mediates docking to phosphorylated tyrosines?
A
SH2, SH3 domains (highly conserved; essential)
21
Q
Types of cell surface receptors? (3)
A
- G protein coupled
2. Tyrosine kinase (intrinisc or recruited TK activity)
22
Q
What are the 2 types of tyrosine kinase receptors?
A
intrinsic TK activity
recruited TK activity
23
Q
Describe the structure on an intrinsic TK activity receptor
A
inactive intracellular catalytic domain (attached)
binding of dimer signal molecule -> 2 halves of receptor dimerize -> TK activated
24
Q
Describe the structure on a receptor with recruited TK activity
A
catalytic domain unattached
binding of signal molecule -> 2 halves of receptor dimerize and recruit (summon) intracellular TK -> activated
25
The general process when a signal binds in a G protein coupled receptor:
1. signal binds
2. G protein activated
3. G protein -> membrane enzyme
4. membrane enzyme activated
26
How many times does a TK cell surface receptor cross the membrane?
once
27
what are 3 examples of ectodomain types that may be coupled with TK domains?
cysteine rich domain
immunoglobulin-like domain
fibronectin-type III-like domain
28
examples of intrinsic TK activity receptors:
EGF, insulin, IGF-1, NGF, PDGF, Eph
29
What holds together the insulin receptor?
disulfide bonds
30
Structure of insulin receptor:
hetero-tetrameric
| 2 alpha, 2 beta chains, S-S bonds
31
The insulin receptor is formed from _____, through formation of _____ and _____
precursor protein
| disulfide bonds, cleavage
32
What cells are highest in insulin receptors?
adipocytes, hepatocytes
33
Cells have between ____ to ___ insulin receptors per cell
100 to 200,000
34
the insulin receptor is similar in structure to the ____ structure
IGF-1 receptor
35
insulin binds to the ____ subunits of the insulin receptor, which causes ______ on the ___ subunits
alpha
| autophosphorylation, beta
36
What pathways does insulin binding trigger?
PI-3 kinase pathway -> enhances glucose transport
MAPK pathway
37
3 main steps in sequence of events when insulin binds to receptor:
1. autophosphorylation of intracellular domain
2. IRS-1 and IRS-2 dock -> get phosphorylated
3. activate 2 pathways (PI-3 and MAPK)
38
IRS stands for:
insulin receptor substrates
39
What are the ultimate effects of the PI3-K pathway? (2)
maintaining active glycogen synthase -> glycogen synth
more GLUT4 (transporter) moved to surface -> more glucose uptake
40
IRS -1 is activated by the insulin receptor through _____. Then, active IRS-1 will _____ by binding to _____.
phosphorylation
| activate PI-3K by binding to its SH2 domain
41
What is the function of PI-3K?
convert PIP2 (membrane phospholipid) into PIP3
42
___ bound to PIP3 will be activated by ______. Then, it will phosphorylate ______ on a ____ residue, causing it to go (active/inactive).
PKB
PDK1
GSK3, Serine
Inactive
43
What is the role of GSK3?
phosphorylate (inactivate) glycogen synthase
44
When GSK3 is INACTIVE, and PKB is ACTIVE, this indicates a (fed/fasting) state
fed
45
When GS is phosphorylated, and IRS-1 is not phosphorylated, this indicates a (fed/fasting) state
fasting
46
The main enzymes involved in the insulin response/glycogen synthesis pathway:
What is the effect of phosphorylating them?
```
PI-3K (activated)
PKB (activated)
PDK-1
GSK3 (inactivated)
GS (inactivated)
```
47
What is MAPK? What is its role?
mitogen activated kinase - target regulatory genes of cell division (c-fos, c-jun)
48
The MAPK pathway:
| _____ is phosphorylated on its ____ residues by the receptor. ____ docks by binding with its ___ domain.
IRS-1
Tyrosine
Grb2, SH2
49
What happens in the MAPK cascakde after Grb2 binds to IRS-1?
Sos (sons of seven less) bind to Grb2, then bind/activate to Ras
50
How is Ras activated in the MAPK pathway?
binds to Sos (bound to Grb2), GDP replaced by GTP
51
Activated Ras (in MAPK pathway) will _______
bind/activate Raf-1
52
What is the role of Raf-1 in the MAPK pathway?
phosphorylate/activate MEK (on 2 Serines)
53
What is the role of MEK in the MAPK pathway?
phosphorylate/activate MAPK on Thr and Tyr
54
What does activated MAPK do?
move into nucleus, phosphorylate/activate transcription factors (like Elk1)
55
How does Elk1 transcription factor function?
activated -> join SRF in nucleus -> stimulate transcript/translation of genes needed for cell division
56
How does insulin affect synthesis in the body? What enzymes increase for this purpose?
muscle: more glycogen synth
liver: more FA and glycogen synth
adipose: more TG synth
increase in: glycogen synthase, acetyl-coA carboxylase, lipoprotein lipase
57
what cell process/enzyme decrease in presence of insulin?
glycogen breakdown; glycogen phosphorylase
58
What enzyme is required for glucose uptake in the liver?
glucokinase
59
defects in insulin receptor or pathway leads to ______. What symptoms does this present?
insulin resistance syndromes
| impaired glucose metabolism, raised insulin concentrations
60
the different severities of insulin resistance syndromes:
mild: Type A insulin resistance
Medium: Rabson-Mendenhall syndrome
Severe: Leprachaunism/Donahues syndrome (IUGR, dead <1 yr)
61
recruited TK activity receptors are characterized by _____ and ______
4 alpha helices
| similar structure of ectodomain
62
the ___ domain in recruited TK receptors can vary, but _____ region is conserved and is involved in ______
cytoplasmic
Box 1
triggering cell division
63
Examples of recruited TK kinase activity receptors:
GH
PRL
Leptin
64
GH has ____ binding sites, and binds sequentially to ___ molecules.
2
| 2
65
____ of the cytoplasmic regions of GH will initiate signal transduction
dimerization
66
The majority of recruited TK activity receptors have ____ dimer formation, except: ______
heterodimer or oligomers
| GH, PRL, EPO
67
Describe the process of GH binding to the receptor
1. binds to receptor 1
2. binds to receptor 2 -> form dimeric complex with them both
3. dimer complex recruit/activate JAK2
68
how many different JAKs are there?
4
69
What pathways are activated by the GH binding?
MAPK -> gene regulation
JAK2-STAT - gene regulation
JAK2-PI-3 -> insulin-like metabolic effects
70
How does MAPK Pathway differ in GH vs. insulin pathway?
in GH: not dependent on IRS-1 (via Shc)
71
How many different STAT regulatory proteins are there?
4
72
How are STATs activated?
1. recruited JAKs will cross-phosphorylate (activated)
2. they phosphorylate the tyrosines on receptor
3. STATs can dock (via SH2 domain)
4. JAKs phosphorylate the STATs
5. STATs dissociate, dimerize (via SH2)
6. go to nucleus, form transcription complex (bind/affect gene regulation proteins)
73
What does STAT stand for
signal transduction and activation of transcription
74
____ syndrome is a type of dwarfism, due to a defective ___ receptor. What are the symptoms?
Laron
GH (deletions in exons 3, 5, 6)
severely impaired growth, normal/high levels of GH
75
3 types of 'second messengers' generated by G-protein activation:
cAMP
DAG (diacylglycerol)
IP3
76
What is the significance of second messengers in GPCRs?
amplify and convey signals
77
What is the most numerous type of receptor?
GPCRs (>140 members)
78
True/False: GPCRs are not exclusive to the endocrine system
True: can be found in non-endocrine signalling as well
79
What are some non-endocrine signal pathways that also use GPCRs? (4)
glutamate (NT)
thrombin
odorants
photoreceptors
80
Examples of GPCR endocrine receptors: (8)
TRH, GnRH, TSH, LH, FSH, ACTH, GHRH, oxytocin
81
Can GPCRs bind steroid molecules?
No; GPCR is cell-surface receptor (steroids act as intracellular signals)
82
What is an easily identifiable feature of GPCRs?
serpentine shape, crosses membrane 7 times (forms pore)
83
The GPCR structure consists of 7 ______ that form a ____
alpha-helices
| pore
84
How do G-proteins function?
GTP bound = ON
GDP bound = OFF
ON => activate adenylate cyclase or PLC
85
True/False: Ras is a type of G-protein
False; also activated by GDP replaced with GTP, but serves as 'relay protein' in other pathways
86
The types of G-protein (alpha subunits) and their roles: (4)
Gs - activate adenylate cyclase
Gi - inhibit adenylate cyclase
Gq - activate PLC
Go - activate ion channels
87
What are the catalytic subunits and second messengers associated with G-proteins?
adenylate cyclase -> cAMP
| PLC -> Ca, DAG
88
Activated PLC will (increase/decrease) DAG and ___ levels
increase
| Calcium
89
What is the general structure of G proteins?
trimeric structure:
alpha subunit
beta + gamma subunit (heterodimer)
90
How are the alpha, beta, and gamma subunits in a G protein related?
beta and gamma form heterodimer
alpha is the activator, can be displaced from beta/gamma and travel through membrane
91
What causes displacement of the G alpha subunit?
GDP replaced with GTP
92
What factors affect what G-protein type will be activated by a certain hormone? (3)
stage in development
concentration of hormone
tissue type
(alter proximity and # of G proteins in membrane)
93
True/False: a hormone can trigger different types of G receptors
True
94
What is McCune Albright syndrome?
G-signal pathway (Gs alpha) permanently active; gonads produce sex hormones without hormone stimulation (no LH or FSH)
symptoms: skin pigmentation, precocial puberty
95
Adenylate cyclases have ___ isoforms. What is the general structure?
>10
membrane bound, 2 sets of 6 membrane-spanning domains + cytoplasmic domains
96
What second messenger is generated by adenylate cyclase?
cAMP (generated from ATP)
97
What immediate downstream action does cAMP cause in the GPCR pathway?
activate PKA
98
True/False: cAMP is required to be bound on the kinase portion of the inactive tetramer in order to free/activate it
False; binds onto regulating subunit -> causes to detach
99
How many cAMP are needed to activate a pair of PKA?
4
100
How does cAMP activate PKA?
cAMP bind to inactive kinase tetramer -> causes removal of the regulating subunit complex -> kinase is freed, become active
101
what is the action of PKA in the GPCR pathway?
phosphorylate transcription factor CREB (on Ser and Thr)
102
What is CREB, and what is its role?
cAMP response element binding protein
binds to DNA to affect gene expression (bind to CRE enhancer sequence to switch on genes)
103
True/False: activation of CREB alone is not enough to trigger a response
True; need other regulatory proteins for transcription
104
How is the GPCR cAMP pathway response terminated?
phosphodiesterases hydrolyse cAMP -> 5'AMP (PKA bound up again, inactive)
105
PLC has ___ major isoforms
3
106
What is the action of PLC?
convert PIP2 (membrane phospholipid) -> DAG, IP3 (second messengers)
107
What are the actions of DAG and IP3?
DAG - activate PKC
| IP3: release Ca from ER
108
What is the effect of triggering Ca release from the ER?
increases Ca -> activates enzymes (kinases) -> phosphorylation cascades
109
How does a cell change its responsiveness to a hormone?
of receptors (synth more, bring more to surface, endocytose, etc)
110
___ % occupancy of a cell's receptor will stimulate a maximal response.
3%
111
Why is it important to maintain a large number of 'empty' receptors on the cell?
act as 'buffer' for additional signalling/stimulation -> up/down regulation
(if all receptors filled -> cell no longer responsive until it can make new ones)
112
Why might excessive amounts of pharmacological hormones be detrimental?
saturation of cell receptors (cell cannot respond to further signals)
113
What happens to the receptor/signal complex after cell signalling?
1. uncoupled
| 2. endocytosis -> hormone removed and receptor recycled, or digested and synth new receptor
114
___ and ____ hormones are lipid soluble, so they target ___ receptors due to their ability to _____.
thyroid; steroid
intracellular
cross the cell/nuclear membrane
115
Do lipophilic hormones generate second messengers? How does this affect their function?
No (act as transcription factors themselves directly)
SLOW response, need to diffuse in, no signal amplification, cannot reuse
116
What features of intracellular receptor hormones make them slower than cell-surface receptor hormones?
1. must synthesize as needed (can't store)
2. can't reuse
3. no second messengers (no amplification, must diffuse in)
4. affects protein transcription/translation -> slower effects
117
A steroid hormone entering a cell will only trigger an effect if: _____
the receptor is present inside
118
there are ___ members in the steroid/thyroid receptor family
>150
119
What is an orphan receptor?
receptor without identified ligand
120
structure and domains of intracellular receptors:
single peptide structure
AF2 (hormone-specific binding domain, C terminus)
DNA binding domain
AF1 (transcription activating domain; hypervariable)
121
Which of the intracellular receptor domains display the least, and most variability?
least variation (highly conserved): DNA binding domain
highly variable: AF1
122
intracellular receptor classes
Class 1: cytsolic - binds hormone, then travel to DNA sequence
Class 2: Nuclear: already bound to DNA, waiting for hormone
123
True/False: domains of intracellular receptors are interchangeable
True
124
DNA binding of steroid hormone receptors is mediated by _____, which are normally covered with _____.
2 zinc fingers (loops with Zn)
| heat shock proteins (inhibitor)
125
What causes activation of a steroid hormone receptor?
binding of hormone -> conformation change -> inhibitor removed, DNA binding zinc fingers exposed
126
Class ____ receptors are ___ hormones, and form complexes with ____ when inactive
Class I
steroid
heat shock proteins (hsp)
127
Class I receptors are partitioned betweeen the ___ and ____
cytoplasm
| nucleus
128
What happens after a Class I steroid hormone is activated?
2 activated receptors -> go inside nucleus -> form HOMODIMER -> bind/regulate DNA transcription
129
the class I hormone receptor will bind to ____ on DNA
HRE (hormone response element)
130
How is the class I hormone receptor homodimer arranged?
the two halves face opposite directions
131
What is the arrangement of a Class II hormone receptor when activated?
form hetero or homodimers, or monomeric; faces same direction
132
What is the action of an activated Class II hormone receptor?
recruit co-activators, TIC (transcriptor initiation complex) => stimulate RNA polymerase to transcript target gene
133
What causes androgen insensitivity syndrome?
defect in androgen receptor (lower #, less binding, or problems with dimerizing)
134
Defects in the Calcitriol receptor leads to:
calcitriol-resistant rickets
135
Androgen receptor defects lead to increased risk of _____
breast or prostate cancer
136
why might target cells need to further modify hormones?
convert to active form (T4 -> T3)
deactivate to prevent cross-reactions (deactive cortisol in kidney to prevent from interfering with aldosterone receptor)
137
What converts T4 to T3?
removal of 5' iodine by tissue specific deiodinase
138
How does the kidney 'protect' cells from accidental activation of the aldosterone receptor?
converts cortisol to cortisone to prevent from binding to aldosterone receptor
139
Testosterone serves as a prohormone in the ____, where it is converted to _____; and also in the _____, where it is converted to _____.
hypothalamus; estradiol (feedback)
prostate; DHT
140
What converts testosterone to DHT?
5 alpha reductase (prostate)
