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Phys Exam two > Signaling Dynamics > Flashcards

Signaling Dynamics Flashcards

1
Q

What is a ratio of signal to effect with no second messengers? What about with second messengers?

A

1: 1
1:&raquo_space;>1

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2
Q

What do second messengers allow?

A

modulation, integration, and amplification of signal

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3
Q

Describe how a signal goes from a few molecules to a huge response

A

Epinephrine is bound to the receptor until K Off is active.
Protein is active as long as GTP is bound to the alpha subunit. PKA phosphorylates multiple proteins and is activates as long as its bound to cAMP. Phosphorylase kinase phosphorylates glycogen phosphorylase, this cleaves off a glucose from the end of glycogen, can take off multiple.
1 unit of epinephrine to 100,000,000 fold of glucose.

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4
Q

What is Emax?

A

an infinite concentration, no units

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5
Q

What is EC50?

A

concentration at 1/2 of Emax

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6
Q

Will a more efficacious drug be a higher or lower line?

What will a efficacious drug do to Emax?

A

higher

increase the Emax

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7
Q 
Which drug is more potent?
EC50 =  100 Emax = 100 
(middle curve)
EC50 = 25 Emax = 100 (highest curve)
EC50 =  400 Emax =100 (lowest curve)
A

The drug with the EC50 of 25, it indicates that it takes less of the drug to get to the EC50 so it is more potent

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8
Q

a more efficacious drug will:

be the higher curve or be the lower curve?

A

The higher curve

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9
Q

What does potency have an effect on and what is the effect?

A

Decrease the EC50

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10
Q

What is an agonist

A

ligand binds to a receptor and initiates a response; can be full or partial

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11
Q

What is an antagonist

A

ligand that binds to a receptor and inhibits the response of the agonist or a compound that inhibits signaling through the receptor; can be competitive or noncompetitive

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12
Q

What does a non-competitive antagonist do?

A

prevents the car from going regardless if it has a key or not; binds an allosteric site away form the agonist binding site and prevents change in function

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13
Q

What are the four different kinds of agonists?

A

agonist (full), partial agonist, super agonist, and inverse agonist

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14
Q

What does a full agonist do?

A

a ligand that binds to the receptor and activates maximal response equal to endogenous ligand

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15
Q

What does a partial agonist do?

A

a ligand that binds to the receptor and activates less than maximal response; less efficacious than other ligands

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16
Q

What does a super agonist do?

A

a ligand that binds to the receptor and causes a response greater than an endogenous full agonist

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17
Q

What does an inverse agonist do?

A

a ligand that binds to the receptor and causes the opposite effect of an agonist; often caused by receptors that have basal signaling activity with no agonist.

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18
Q

What does a competitive antagonist do?

A

a ligand that binds to the receptor binding site and prevents the agonist from binding

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19
Q

Noncompetitive antagonists?

A

ligand that binds to the receptor not at the binding site and inhibits a response to the agonist

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20
Q

Antagonists examples

A

competitive - naloxone (competitive for opioid receptors); non-competitive - ketamine (non-competitive at NMDA receptor); competitive antagonist can be overcome by increasing the concentration of signaling ligand; does not kick out antagonist but competes with antagonist for binding sites; ability to overcome is partially dependent on K-1 of antagonist.

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21
Q

Reversible antagonist

A

measurable Koff > it comes back off

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22
Q

Irreversible antagonist

A

no measurable Koff > does not com eback off; covalently bound to receptor

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23
Q

Residence times:
ACH
Morphine
antibodies

A

ACH - low/sub ms range (Koff - 1000/s)
Morphine - at opioid receptor in low minute range (Koff = -0.01/s)
antibodies - residence times in minutes to months (Koff = 0.001/s)

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24
Q

What does practically irreversible mean?

A

the off rate of the antagonist is so low physiological functions cannot occur

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25
Q

What will an irreversible antagonist look like?

A

non-competitive antagonist regardless of where it binds because the agonist cannot compete for binding sites

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26
Q

A dog with a pheochromocytoma (an adrenal tumor secreting catecholamines) is being prepped for surgery; a significant danger during surgery is hemodynamic instability due to massive release of norepinephrine/epinephrine from the tumor; how would we prevent norepinephrine from causing hemodynamic instability?

A

Want to block the receptor so we want to add a non-competitive antagonist; this will work well bc if we added a competitive antagonist, it could be out-competed.Non-competitive inhibitor should reduce the max epinephrine response no matter what the dose.
Phenoxybenzamine is an irreversible, non-competitive inhibitor of alpha-adrenergic receptors and is often used preoperatively for pheochromocytoma resections.
But low doses of phenoxybenzamine appear to shift the dose-response curve to the right, not depress teh max effect allowing massive doses of epinephrine to overwhelm the blockade

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27
Q

Low (tolerable) doses of phenoxybenzamine appear to shift the dose-response curve to the right, not depress the max effect, allowing massive doses of epinephrine to overwhelm the blockade, why?

A

Non-competitive inhibitor should reduce the max epinephrine response no matter what the dose.
Phenoxybenzamine is an irreversible, non-competitive inhibitor of alpha-adrenergic receptors and is often used preoperatively for pheochromocytoma resections.

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28
Q

What is pharmacodynamics?

A

What the drug does to the body

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29
Q

What is pharmacokinetics?

A

what the body does to the drug.

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30
Q

What does ADME stand for? Which side of pharmaceuticals deals with this?

A

absorption, distribution, metabolism, elimination; pharmacokinetics

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31
Q

What are the steps for pharmacodynamics?

A

binding, activation, and systemic response

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32
Q

What is a binding study?

A

measurements of how much affinity a drug has for a receptor

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33
Q

What is Kd and whats it a ratio of and what are the components of the ratio?

A

drug concentration at which half of the receptors are occupied. Ratio of k off to k on; k off is how fast the drug leaves the receptor and k on is how fast it binds to the receptor

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34
Q

What does a low kd =

Which way will the curve shift?

A

high affinity; to the left

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35
Q

what does a high kd = and which way does the curve shift?

A

low affinity; to the right

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36
Q

What are concentration response studies? What are the dependent on? Are they in vitro or in vivo? What is the drug plotted against?

A

A measure of how much signal a ligand causes; dependent on binding and signaling which causes teh effect; they are done in vitro.; plotted against the cellular effect.

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37
Q

Formula for concentration

Which type of studies is this better for (in vitro or in vivo)?

A

mass/volume; in vitro

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38
Q

What is the formula for dose? Which type of studies is this better for (in vitro or in vivo)?

A

mass/weight or mass/SA; in vivo

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39
Q

What does a dose response study combine and is it done in vitro or in vivo?

A

combines pharmacodynamic and pharmacokinetic effects; in vivo to determine hw strong a response a given drug elicits

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40
Q

What are dose response plotted against? What are they dependent on and how are they described?

A

Plotted against the % population with a therapeutic effect; dependent on binding, signaling, and PK effects; described by ED50

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41
Q

What are dose response studies used to describe?

A

ED50 and potential toxicity of a drug

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42
Q

What is the therapeutic effect of a drug described by and whats it plotted against?

A

TD50; % pop with toxic effects can be plotted against drug dose

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43
Q

What is plotted for LD50 and what does it mean?

A

The % population with lethal effects plotted against drug dose; the dose at which 50% of the population die

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44
Q

What two components are needed to determine an effective dose of a drug?

A

Therapeutic effects and toxic effects

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45
Q

What is the therapeutic index defined as and what does a larger one mean?

A

LD50/ED50; larger means larger dose difference b/w the therapeutic and toxic doses which indicates that it is generally a safer drug

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46
Q

What is a therapeutic index for a safe drug?
Midrange?
Dangerous?

A

> > > 100:1 (amoxicillin, pinicillin)
(70:1 or 100:1) morphine and diazepam
15, 4, 2.5, 2, 1.5:1 - cocaine, amphotericin, 5-fluorouracil, digoxin, and cisplatin

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47
Q

Dose response study term

A

a study to determine the effectiveness of a drug in vivo; described by ED50

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48
Q

ED50 term

A

drug dose at which 50% of population shows a therapeutic effect

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49
Q

ED99

A

drug dose at which 99% of population shows a therapeutic effect

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50
Q

TD50

A

drug dose at which 50% of population shows a toxic effect

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51
Q

LD50

A

drug dose at which 50% of population shows a lethal effect

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52
Q

LD1

A

drug dose at which 1% of population shows a lethal effect

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53
Q

Therapeutic index

A

LD50/ED50 (a comparison of doses)

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54
Q

When ED50 = KD; what is going on with the potency? What about the magnitude? Whats the limiting step? What ratio does this suggest for receptors to signal athways?

A

Potency is equal to the binding affinity; magnitude is directly related to the % receptors bound. Limited step - receptor binding event; 1:1 ratio

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55
Q

When EC50 > Kdwhat is going on with the potency? What about the magnitude? Whats the limiting step? What does this suggest?

A

Potency is greater than the binding affinity; magnitude is greater than receptors bound; signaling even is the limiting step; suggest more receptors than signal pathways, meaning there are spare receptors

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56
Q

What do spare receptors create and how?

A

Redundancy as they have a receptor reserve ready to use if the receptors are deactivated somehow

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57
Q

can signaling pathways with spare receptors signal at full effect?

A

yes; even in the presence of some irreversible inhibitor

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58
Q

Without spare receptors, what will happen to the Emax?

A

it will be lowered

59
Q

What do spare receptors make non-competitive antagonist look like?

A

competitive agonists

60
Q

A dog with pheochormocytomae - adrenal tumor secreting catecholamines is being prepped for surgery; a significant danger during surgery is hemodynamic instability due to massive release of norephinphrine/ epinephrine from tumor; how can we counteract the effects of epinephrine release?

A

an a-adrenergic receptor antagonist is given preoperatively to reduce smooth muscle reaction to released catecholamines

61
Q

What type of antagonist is involved in the clinical correlation for the pheochromocyotma dog? What is an example of this?

A

non-competitive; reduce the max epinephrine response no matter what the dose; phenoxybenzamine is an irreversible, non-competitive inhibitor of a-andreergic receptors and is often used for pheochromocytoma resections

62
Q

Low doses of phenoxybenzamine do not depress max effect, allowing massive doses of epinephrine to overwhelm the blockade, why?

A

There appear to be alpha adrenoceptors in many types of smooth muscle, the irreversible antagonist phenoxybenzamine at low tolerated doses does not completely deplete the receptor reserve; because it is not depleted, massive doses of epinephrine can still cause hypertensive crisis.

63
Q

Why not increase the dose of pheoxybenzamine?

A

Therapeutic index; increasing the dose may cause a greater desired effect but can also cause greater toxic effects as well; turns out that adding enough phenoxybenzamine to completely block the adrenoceptors creates substantial toxicity itself, outweighing the benefit - the therapeutic index is too small

64
Q

What does gap 2 consist of?

A

growing stage; two sets of chromosomes

65
Q

What is the M phase and what occurs?

A

mitosis = nuclear division

66
Q

What is Gap 0 composed of and which two routes could it take?

A

quiescence; not dividing but could divide

67
Q

What is gap 1?

A

growing stage, 1 set of chromosomes

68
Q

What happens in the S phase?

A

synthesis; dna replication

69
Q

What is interphase composed of?

A

G1, S, and G2

70
Q

What happens in prophase

A

chromosomes condense; centrosomes duplicate

71
Q

What occurs in prometaphase?

A

centrosomes on opposite ends of cell; nuclear envleope disassembles

72
Q

What occurs in metaphase?

A

chromosomes on metaphase plate

73
Q

What happens in anaphase?

A

chromosomes pulled apart

74
Q

What occurs in telophase?

A

Chromatides on opposite sides; nuclear envelope reforms.

75
Q

What is cytokinesis?

A

contractile ring splits cell; MT form interphase array

76
Q

What is CDK and what does in do?

A

cyclin dependent kinases integrate multiple signals to determine whether to proceed through a checkpoint

77
Q

What are growth signals?

A

growth signals are important signals for progressing through the G1/S checkpoint and starting the cycle.

78
Q

What are cyclins?

A

Cyclins are time keepers of the cell cycle and insure each step happens in the correct sequence

79
Q

Where is the G2/M checkpoint and whats it check for?

A

between the G2 and M stage; checks for DNA replication and damage, and cell size

80
Q

What does the M checkpoint check for?

A

spindle attachment and chromosome distribution

81
Q

Where is the G1/S checkpoint and what does it check for?

A

growth signals, cell size, and DNA damage.

82
Q

What are the two main types of growth signals?

A

growth factors and steroid hormones

83
Q

What are the 4 growth factors?

A 
EGF = epithelial like growth factor
IGF-1 = insulin-like growth factor
PDGF = platelet derived growth factor
EPO = erythropoietin
84
Q

What are the two main steroid hormones?

A

estrogen - signal for female repro cell growth; testosterone - signal for male repro cell growth

85
Q

What is the growth signal pathway for EGF via Ras

A

Epithelial growth factor binds to the EGF receptor, EGFR is a tyrosine kinase receptor and auto-phosphorylates, p+ EGFR associates with Ras, causing Ras to exchange a GDP for GTP, activating Ras, Ras starts signaling cascade through MAP kinases, MAPK is a transcription factor that when activated travels to the nucleus and causes transcription of Jun, Myc, and Fos which are transcription factors that cause transcription of multiple proteins necessary for the cell cycle including G1 cyclin, G1 cyclin dependent kinase, and E2F

86
Q

What is the growth signal pathway for EGF via P13-kinase

A

EGf binds to EGFR causing dimerization and phosphorylation, activated EGFR recruits P13-kinase to the membrane. P13-kinase catalyzes the phosphorylation of PIP 2 and PIP3; PIP3 causes a phosphorylation cascade that activates AKT which inhibits cell cycle arrest and apoptosis and may promote passage through checkpoints.

87
Q

What is the Wnt growth signal pathway?

A

APC, Axin, and GSK3 form a complex that ubiquitinates Catenin B targeting it for degradation. Wnt binds to the LRP/frizzled receptor and recruits and phosphorylates Disheveled which recruits Axin and GSK3, preventing the assembly of the APC/Axin/GSK3 complex. Non-degraded Catenin B is transported to the nucleus where it activates transcription factors such as LEF/TCF which transcribes a variety of cell-cycle related proteins like Cyclin D

88
Q

What is each step in the cell cycle regulated by?

A

a specific cyclin

89
Q

What do cyclins do?

A

Helps activate CDKs that affect each step.

90
Q

What do activated Cyclin-CDK complexes do? What do they act like?

A

trigger next step of degradation of the current cyclin; act like cell-cycle “clock” and prevent reversal of steps

91
Q

G1/S checkpoint

A

growth factors/environmental signals activate CDK1 which phosphorylates Rb protein which releases E2F (a transcription factor that is transported to the nucleus and transcribes genes necessary for DNA replication). Damage signals can activate proteins like ATM which phosphorylates p53, activating it and this will act as a transcription factor and cause transcription of p21 which inhibits CDK1, preventing phosphorylation of Rb, halting the checkpoint

92
Q

7 y/o greyhound with front limb lameness and swelling near distal end of radius; radiograph - reduced cortical bone near site of swelling as well as periosteal proliferation and palisading cortical bone; histo - malignant mesenchymal cells with osteoid matrix.

A

Osteosarcoma; Retinoblastoma protein is mutated in many tumors including some osteosarcomas; this cannot bind to E2F so E2F is constantly active which keeps making genes.

93
Q

What is apoptosis?

A

programmed cell death

94
Q

How does apoptosis happen?

A

DNA is fragmented, cytoplasm splits apart into blebs, cellular content is not spilled into ECM (no inflammation)

95
Q

When does apoptosis occur?

A

Development - formation of digits
Surveillance - removal of damaged cells
Maintenance - removal of old liver cells
Regulation - removal of excessive CD8 and T-cells

96
Q

What is the difference between apoptosis and necrosis?

A

Apoptosis is controlled cell death, result of specific signals, cell neatly packaged for removal, no inflammation

Necrosis is uncontrolled cell death, result of acute stress, cell rupture and contents spilled into ECM and inflammatory.

97
Q

Neoplasia
Homeostasis
Degeneration

A

neoplasia - mitosis more active, more cells
homeostasis - mitosis and apoptosis are equal
Degeneration - more apoptosis than meiosis

98
Q

Apoptosis triggers what are they and what do they lead to

A

cell fate (embryology), removal of survival factors, dna damage, death signal, and calcium release goes to initiator Caspases which lead to effector caspases

99
Q

Bax acts to open pores in the mitochondrial membrane, what are the steps?

A

Open pores allow release of cytochrome C from mitochondria, cytochrome C combines with Apaf-1 to form an apoptosome. The apoptosome activates procaspase 9 and triggers apoptosis; DNA damage can cause more Bax transcription through p53

100
Q

Bcl-2 acts to CLOSE pores in the mitochondrial membrane, what are the steps?

A

closed pores prevent release of cytochrome C from the mitochondria; Cytochrome C cannot combine with Apaf-1 to form an apoptosome which cannot activate procaspase 9 inhibiting apoptosis. Trophic factors can cause more Bcl-2 transcription.

101
Q

What does increased Bax lead to ?

A

Degeneration; more apoptosis

102
Q

What does increased Bcl-2 lead to?

A

Proliferation; more mitosis.

103
Q

Fas/FasL apoptosis pathway

A

FasL binds to Fas, trimerizes, and recruits Fas-associated death domain and activated FADD activates procaspase 8 triggering apoptosis

104
Q

What is an oncogene

A

mutated/overexpressed genes which can cause cancer

105
Q

What is a protooncogene

A

A normal gene involved in apoptosis or cell cycle which mis-regulation or mutation could turn into an oncogene

106
Q

Tumor-suppressor gene definition

A

genes involved in damage surveillance and negative cell cycle regulation

107
Q

RAS as a protooncogene

A

Mutated RAS cannot hydrolyze GTP and remains active WITHOUT a growth signal; mutated RAS continually signals through the MAPK pathways activating Jun,Myc, and Fos. Constant production of Myc/Jun/Fos pushes the cell repeatedly into the cell cycle

108
Q

AKT as a protooncogene

A

Mutated AKT is constantly active and causes overproduction of Bcl-2 which inhibit the internal apoptosis pathway and reduction of apoptosis leads to over population of cells and tumorigenesis

109
Q

p53 - a tumor suppressor gene pathway

A

Mutated P53. cannot be phosphorylated and activated or response to damage signal from ATM and cannot cause transcription of p21 which means no inhibition of CDK1 which can push the cell through the cell cycle regardless of damage

110
Q

APC a tumor supressor gene

A

mutated APC cannot bind Axin/GSK3 and cannot ubiquitinate Catenin which are high regardless of the growth signals and cause transcription of cyclin D repeatedly pushes the cell cycle

111
Q

What is vRas

A

a mutated Ras introduced by some viruses that is constitutively active

112
Q

Human Papilloma virus

A

carries two viral oncogenes, E6 and E7 which is why it is a significant cause of cervical and other cancers.

113
Q

vRas - a viral oncogene pathways

A

Viral RAS cannot hydrolyze GTP and remains active WITHOUT a growth signal; this continually signals through the MAPK pathways activating MycJun/Fos which pushes cell cycle.

114
Q

HPV as a viral oncogene

A

E6 protein causes ubiquitination of p53 leading to degredation of p53 - cell loses damage control; E7 protein binds Rb protein so that it cannot inhibit E2F which pushes the cell forward into the cell; loss of p53 and always active E2F causes tumorigenesis

115
Q

Can mutated proto-oncogenes be viral oncogenes?

A

yes; ras

116
Q

Can mutated tumor suppressor genes be viral oncogenes?

A

No; cell needs to be off to cause cancer; wont do anything if it is off; we have natural tumor suppressor genes

117
Q

9 y/o GS with weight loss, diarrhea, and anorexia; abdominal x-ray shows mass in colon; biopsy shows neoplastic cells

A

Due to the design and redudancy of cell cycle regulation, caners are very rarely the result of a single mutation; instead, cancers are a result of the build up of multiple mutations and in the cell cycle; many or most colon carcinomas have 3 conserved mutations in APC, Ras, and p53

118
Q

What is ROS? are they toxic or nah? Whats the most basic ROS? What are more reactive forms formed from?

A

Reactive oxygen species; they are highly reactive oxygen containing compounds; most basic is superoxide, which is the single electron reduction of molecular oxygen; more reactive formed from superoxide, including hydrogen peroxide

119
Q

What are the most dangerous ROS

A

free radicals with an unpaired electron. Nitrogen species can ba strong ROS

120
Q

What does an oxidation do?

A

Take electrons away

121
Q

Are Ros strong oxidizers or reducers? What do they take away form other atoms?

A

oxidizers, removing electrons from other atoms

122
Q

What can Ros change?

A

oxigen state

123
Q

Ros that are free radicals can cause what type of reactions? How do they do this?

A

radical chain reactions; Free radical ROS take one electron away from an organic compound, creating another radical and then the cycle can continue

124
Q

What is coenzyme Q/heme complex in and what can occur?

A

During metabolism, complex 1 and 3 can leak a small amount of electrons directly onto oxygen producing superoxide at low levels

125
Q

What happens during ischemia?

A

cytochrome C cannot be oxidized, the H+ gradient reduces toward zero and reduced coenzyme Q and heme complexes build up in the mitochondrial membrane and cause a build up of succinate in the mitochondrial matrix to store the extra electrons

126
Q

What happens during reperfusion?

A

The H+ gradient is quickly reestablished but the surplus of reduced Q/heme/succinate causes a respiratory burst of superoxide, primarily at complex 1

127
Q

which is more damaging, reperfusion or ischemia?

A

reperfusion

128
Q

Owner reports that cat had a fall earlier in the day and was given Tylenol; rapid breathing, nausea, drooling, and lethargy, exam shows cyanosis and edema; whats the diagnosis?

A

Acetaminophen toxicity - primary non-toxic pathway is glucuroinidation and dyroxylation is a minor side product and a strong oxidizer; cats lack the gene for the glucuronidation so all the dose is metabolized to NAPQI; this ROS causes massive oxidative damage and cell death in the liver.

129
Q

What do superoxide dismutase and catalase do inside of the cell?

A

prevent build up of superoxide or hydrogen peroxide.

130
Q

What is thioredoxin?

A

protein antioxidant

131
Q

What is glutathione?

A

peptide antioxidant

132
Q

What are two small molecule antioxidants?

A

Vitamin C and Vitamin E

133
Q

How is vitamin C a small molecule antioxidant?

A

Radical will run into vitamin C and steal a proton and electron, generate a radical on vitamin C which is very stable; clenched the radical chain reaction; once we have two vitamin cs that both have radicals we will cross react and generate one active and then one fully oxidized which we will get rid of

134
Q

How is vitamin E a small molecule antioxidant?

A

Membrane soluble antioxidant; have a radical, comes to membrane, vitamin E quenches radical which is stable; don’t want to run out of Vitamin E so we react it with vitamin C to regenerate vitamin E and Vitamin C gets to be the waste product.

135
Q

What is the treatment for acetaminophen toxicity?

A

NAPQI is detoxified in the body by reacting with GSH and it become more toxic when the stores of reduced GSH run low; increasing stores of GSH is a primary treatment; N-acetylcysteine is used by the body as a precursor for GSH production; so treat cat with significant dose of N-acetylcysteine

136
Q

What do HIF factors do?

A

sense low oxygen in individual cells and promote hypoxia response genes

137
Q

What is ASK1?

A

a MAPKKK that is activated during oxidative stress conditions and promotes hyperoxia response genes.

138
Q

Where are the central receptors for breathing?

A

ventrolateral surface of the medulla

139
Q

Where are the peripheral receptors for breathing?

A

carotid and aortic bodies

140
Q

What do central receptors do? What gas do they sense?

A

help regulate the bodys oxygen content through stimulating respiration; they sense CO2 levels and stimulate respiration in response to increased ph and increased pCO2

141
Q

What are peripheral receptors and what do they do?

A

They help regulate the bodys oxygen content through stimulating respiration; are responsive to p)2 and pCO2 and pH

142
Q

How do peripheral receptors sense and signal oxygen levels in the body?

A

Sense amount of oxygen

143
Q

How do cells respond to low oxygen conditions? What are the factors?

A

hypoxia-inducible factors which respond to hypoxia or low O2

144
Q

What pathways are associated with hyperoxia?

A

ASK1 and MAPK Pathways

Phys Exam two (13 decks)

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