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Flashcards in Exam V Deck (98)
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1

ACh: Muscarinic vs. Nicotinic Receptors

Shows the versatility of signaling molecules
Muscarinic: decreases heart rate and force of contraction as well as increases saliva production
Nicotinic: contraction of skeletal muscles

2

Example of Autocrine Signaling

T cells that produce and react to its own secretions of IL-2; no IL-2 means that the T cell will undergo apoptosis since there is a lack of signal; signal = proliferation of T cells due to infections

3

Paracrine Signaling- specific example

Synaptic signaling

4

Glucocorticoid Receptor (GR)

The receptors in the cell within the nucleus
Glucocorticoid receptor and is usually found within the cytoplasm and the hormone cortisol enters the cell via diffusion because it is hydrophobic and it will find the receptor that is inactive by binding three molecules bound to the receptor (2 are heat shock proteins and the other is immuophilin) and together they produce an inactive receptor
When cortisol comes along these three proteins separate so the receptor can be activated and it will enter the nucleus and bind to DNA and activate the genes

5

Estrogen Receptor

The estrogen receptor, in this case it is found in the nucleus and the estrogen enters the cell and finds the receptor in the inactive form because Hsp90 is bound, but when estrogen binds to the receptor the Hsp goes away; two estrogens is bound to the receptor creating a dimer and the function only occurs in the form of the dimer; the dimer binds to HAT = coactivator; the molecule is now activated so it can now bind the DNA and active the transcription in the downstream direction

6

Thyroid Hormone Receptor (THR)

THR is always bound to proteins and it remain bound to proteins in absence or presence of the thyroid hormone
In response to a ligand, there will be 2 THR and they are bound to the molecule that acts as a corepressor, HDAC, because they are already bound to the DNA so acting as a repressor
Once the thyroid ligand binds the repressor and HDAC will be removed and then replaced with HAT as an activator and binds to the DNA and transcription proceeds and produces the molecules

7

Pleiotropic Growth Factors

Different effects on same target cell type
Same effect on many different cell types
Inhibition or growth may be dependent on the cell environment- availability or lack of nutrients as example

8

GH Positive Feedback

Positive feedback: tells the hypothalamus to release more GHRH to increase GH
If fuels (food and nutrients) are scarce, then GH is not necessary; GH and insulin like growth factor, they both will send negative signals (feedback) that signal to the hypothalamus and inhibits the release of GHRH and therefore inhibit GH release from the pituitary
If you have plenty of food, the signals are positive so you can grow, and vice versa

9

Fibroblast Growth Factor

fibroblasts make bone, collagen, etc. their regulation is important
4 types of receptors for the fibroblastic growth factor; these are connected with Tyr kinase receptor
Tyr kinase is important for phosphorylation to activate cascades inside the cells
This receptor interacts with heparin sulfate found in the extracellular matrix, and the way it binds the FGF/FGFR/HS in 2:2:2 creating dimers
Induction of transphosphorylation via Tyr kinase which leads to activation to effect the nucleus by activating transcription to produce products that change the cell behavior

10

3 Ways of Signal Transduction

1. Directed towards cytoskeletal organization – important for cell during growth because the cytoskeleton is responsible for movement
2. Anti-apoptosis – increase the survival signals
3. Activation of kinase AMPK that ultimately works at gene level where it creates these TF that will activate transcription or stops the genes from being transcribed (most important part of signaling)

11

Basophils (circulation) & Mast Cells (resident)

Granules contain mediators:
Heparin
Histamine
SRS-A (slow-reacting substance of anaphylaxis)
ECF-A (eosinophil chemotactic factor A)
they produce eosinophil chemotactic factor (ECF), which causes eosinophils to enter area of parasite or allergen

when Ab (IgE) is bound to the something ex. Muscle and on the membrane there is a molecule that is called the FC receptor that binds the Ab FC part of it (stem of the “Y”) and once it is bound the cells will be coated with Ab; the cells involved in allergy (type I hypersensity or immediate hypersensitivy) against bee sting for example; sometimes so severe that one bee sting will cause liver death

12

Mediators of Type I hypersensitivity

Preformed: Histamine, Heparin, Eosinophil chemotactic factor of anaphylaxis (ECF-A), Neutrophil chemotactic factor, Serotonin

Newly Synthesized: Prostaglandins, Thromboxanes, Leukotrienes (Slow reacting substance of anaphylaxis (SRS-A))

For vasodilation: histamine binds to H1
For extravasation: histamine binds to H4 to cause eosinophils to go through the blood vessel and fight infections/allergies

13

Mast Cell Degranulation and Histamine Signaling

Histamine release
Histamine binds endothelial and smooth muscles H1 receptors  Induction of vasodilation
Higher histamine conc.  acting on eosinophil H4 receptors  induction of migration/ extravasation into affected area

14

NO mediated vascular relaxation

Some intercellular signaling molecules (ACh, histamine, ATP, etc) that bind to specific receptors on the endothelial cells leading to activation of enzymes that changes that brings down Arg AA to citrulline so NO can be released which will diffuse through the cell and go to the neighboring cells (paracrine signaling) smooth muscle of blood vessel and bind to Hb to activate the gunaylyl cylase to make cGMP from GTP; cGMP will diffuse and activate other kinases leading to relaxation of vascular muscle cell

15

ErbB2,3, & 4 Receptors

Structure is intracellular, extracellular, and intracellular
2 Cys rich (lots of disulfide bridges) domains, transmembrane protein (hydrophobic) and the Tyr kinase within the cell = three domains of each molecules
ErbB2, 3, and 4 work in dimers; when two different ones are together = heterodimers, but if same = homodimer = basic structures
These have connection with molecules inside the cells and communicate with NRG, a neural regulator, and they can be connected to the EGF and to other molecules
For example: heterodimers are involved in neural crest or heart development, so Erb2 and 3 are found in neural crest and involved in developed where Erb2 and 4 are associated with heart function development

16

Neuregulin -1

present: trabeculation and normal heart develop; absent is vice versa
Two layers: endocardium and myocardium and are connected / communicate with each other via NRG1 signal coming from the endocardium to the receptor heterodimers ErbB2 and 4 in the myocardium so the communication to the myocardium is transmitted and the result is the trabeculation occurs, but if the signal is defected (knocked out for example) then trabeculation of the ventricles of the heart will not be normal

17

TGF-Beta

signaling molecules involved in development and differentiation
serine-threonine kinase receptors, so phosphorylation occurs on Thr and Ser AA
There are two types of receptors: TGF beta R1 and R2; these two receptors, none of them can bind TGF beta by itself (all or none binding) both must cooperate to transduce the signal via a complex
Examples of TBF beta: BMP, Nodal and Lefty, heart valve development, NOTCH signaling

18

BMP Signal Transduction Pathway

BMP has a receptor that have two components: dimer of I and II; and from that there will be TGF beta activated kinase (it will phosphorylate) and act on TAK which activates MKK (mitogen kinase kinase) to phosphorylate other kinases, and these will phosphorylate the molecules like JNK (controls cell cycle) and MAPK/p38
Another pathway that goes above a molecule, Smads, that get phosphorylated and they can go into the nucleus and participate in activation of genes there

19

Development of left and right; nodal protein and lefty

Nodal will bind the receptor and will send a signal through Smads and this will activate the transcription in the nucleus; for example, when nodal cannot bind the receptor and the lefty does (in competition with each other) and no signal is tranduced; aka lefty will stop the signaling through this receptor complex, but nodal will transmit the signal
Nodal is on the left and will have the effects on lefty and on itself and pushes lefty1 to middle between the left and right to prevent things from moving to the side they aren’t supposed to be on
TGF beta like molecule = nodal and lefty; nodal and lefty 2 are in competition, so when nodal is on left side, lefty2 cannot do anything on that side

20

Physiologic and Pathological Cardiac Hypertrophy

Physiologic – when child is born, the heart must grow in size in response to positive signals (with nutrients and exercise/movement)
Pathologic response – occurs in response to signals like stress, high BP, etc. so that the muscle must work much harder to push the blood leading to hypertrophy and can happen after MI
Difference between growth: response to positive/healthy signals = adaptive; and the other is sluggish and like getting fat or something like that = maladaptive
Situations are interchangeable; for example, you can exercise with healthy lifestyle to change from pathologic to physiological response

21

4 Phases of the Cell Cycle

G1 or GAP 1 (only growth)
S stage- DNA replication occurs
G2 or GAP 2 (prep for M)
M or mitosis- nuclear (chromosomes separate) and cytoplasmic (cytokinesis) division
G0: no cell division or growth; Response to a lack of growth factors or nutrients; Parenchymal cells of the liver and kidney enter G0 almost permanently; alternative to apoptosis if cell is damaged; nerve cells that are highly differentiated spend most time in G0

22

Cyclins

work with CDKs to form holoenzymes (depend on each other)
allow the cell cycle to proceed via phosphorylation or dephosphorylation of proteins at the checkpoints; kinases can only phosphorylate; only phosphatases can dephosphorylate
regulated by p21, p27, etc.

23

p27

binds to cyclin and CDK blocking entry into S phase
Breast cancer prognosis is determined by p27 levels
Reduced levels of p27 predict a poor outcome for breast cancer patients and vice versa

24

G1 CDK/Cyclin Association

CyclinD-Cdk4 & CyclinD-Cdk6 and CyclinE-Cdk2

25

S CDK/Cyclin Association

CyclinE-Cdk2

26

G2 CDK/Cyclin Association

CyclinA-Cdk2

27

M CDK/Cyclin Association

CyclinB-Cdk1 (called Cdc2)

28

p53

Regulates G1/S and G2/M checkpoints
Blocks cell cycle if DNA is damaged
Severe damage leads to apoptosis (programmed cell death)
p53 levels are increased in damaged cells, allowing time for DNA repair by blocking the cell cycle
p53 mutation is the most frequent mutation leading to cancer
Mutated p53 found in >50% of cancers
*employs Bcl-2 family to induce apoptosis at mitochondrial level (via Bax)

29

Li Fraumeni syndrome:

extreme case of p53 mutation; genetic defect in p53 leads to a high frequency of cancer in affected individuals

30

pRb

The protein can be found in two states:
1. hypophosphorylated where the protein is not phosphorylated much
2. hyperphosphorylated – a lot of phosphorylation
Hypophosphorylation: pRb is bound to E2F and this will keep the E2F from acting as a TF; and cyclins will phosphorylate the Rb, becoming hyperphosphorylated and loses the E2F and can work as a TF; G2 will then occur because the necessary enzymes for it are now able to be synthesized; these kinases work in response to extracellular agents ex. Damage through carcinogenic substance, etc.