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Foundations 1 > 8/16/17 > Flashcards

8/16/17 Flashcards

1
Q

Two types of protein degradation pathways

A

Ubiquitin-proteasome

Lysosomal

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2
Q

Ubiquitin-proteasome pathway

A

Selective process for short lived and damaged/misfolded proteins

ATP to add ubiquitin to Lys and get chain of them, ATP to make proteasome function

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3
Q

Ubiquitination of proteins

A

Use ATP to add ubiquitin to E1

E1 transfers ubiquitin to E2

E2 works with E3 to add ubiquitin to the target

E3 is a ubiquitin ligase, many different kinds since they are selective for each protein

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4
Q

Disorders of ubiquitination

A

Cancer: change in stability of proteins for cell division can create uncontrolled growth

Neurodegenerative: proteins aggregate if decreased degradation

Immune disorders, muscle wasting, diabetes

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5
Q

Types of autophagy

A

Macroautophagy

Microautophagy

Chaperone-mediated autophagy

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6
Q

Macroautophagy

A

Isolation membrane (phagophore) is a double membrane that begins to expand to engulf organelles, ribosomes, and protein aggregates

Autophagosome after isolation membrane fully engulf

Autophagosomefuses with lysosome to degrade cargo and inner membrane of the Autophagosome

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7
Q

Microautophagy

A

Lysosomes invaginate and eat cytosolic components and small organelles

The invagination becomes an autophagic tube

Vesicles bud off the autophagic tube into lysosome lumen

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8
Q

Chaperone-mediated autophagy

A

Highly selective unlike other 2 autophagies

Proteins have KEFRQ amino acid sequence or similar that bind to Hsc70 or Hsc73, targeted to go to lysosomal membrane

Protein binds to LAMP-2 at the membrane, oligimerize into a translocator to allow it to enter for degradation in the lysosome

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9
Q

Autophagy-related genes

A

Stressors that induce expression of genes for autophagy

Nutrient depravation, growth factor withdrawal, infection, hypoxia, DNA damage

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10
Q

mTOR

Mammalian target of rapamycin

A

Master regulator protein that promotes cell growth and proliferation by promoting anabolic processes and by limiting autophagy

mTOR inhibits expression of autophagy-related genes when healthy, upregulate when under cellular stress

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11
Q

Pharmacodynamics vs pharmacokinetics

A

Kinetics: what body does to drug
ADME- adsorption, distribution, metabolism, excretion

Dynamics: what drug does to body

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12
Q

Inert binding site

A

Endogenous molecule that binds to a drug but doesn’t lead to a response

Drugs bind to albumin but no effect

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13
Q

Drug targets beside receptors

A

Enzymes: statins inhibit HMGCoA Reductase, lower intra-hepatic cholesterol synthesis

Transport proteins: digitalis inhibits Na-K ATPase

Structural proteins: colchicine binds tubulin

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14
Q

Agonist

A

Affinity for a receptor AND activates intrinsic activity

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15
Q

Orthosteric binding site

A

The main binding site

Allosteric is off to the side

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16
Q

Inverse agonist vs antagonist

A

Inverse agonists generates a response below baseline

Antagonist: produces no effect, neutral

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17
Q

Competitive antagonist

A

Binds to the same site of the agonist

Can be overcome by high conc. of agonists

Reduce agonist potency

18
Q

Noncompetitive antagonist

A

Bind to a site different than the agonist

Prevent binding of the agonist or prevent agonist from activating the receptor

Reduce agonist potency

19
Q

Drug selectivity

A

Drug has high affinity for a receptor

Produces intended effect with little side effects

20
Q

Therapeutic index and margin of safety

A

TD 50 / ED 50

LD 1 / ED 99

21
Q

Drug Receptor types

A

Ligand-gated ion channels: change in membrane potential or ion concentration

G protein-coupled receptors: intracellular protein phosphorylation

Enzyme-linked receptors: intracellular protein and receptor phosphorylation

Intracellular receptors: intracellular protein phosphorylation and altered gene expression

22
Q

Clinical case of defect in transport of molecules across the plasma membrane

CF

A

8 month old with poor growth and chronic cough

Bloating, diarrhea, and failure to thrive whether breast fed or formula

Developed daily cough and respiratory difficulty

Got asthma at 5 months

Large, greasy, foul-smelling stool and failure to thrive

23
Q

CF Symptoms

A

Salty sweat

Progressive respiratory damage

Chronic digestive problems

Obstruction of airways and bacterial infections from abnormally thick mucous

Pancreatic ducts are blocked, digestive enzymes can’t reach intestines

Die from pulmonary disease

24
Q

CF mutation

A

Most due to single AA mutation, many different mutations known

CFTR gene on q arm of chromosome 7

Protein misfolded in ER so never get to plasma membrane even though partly functional

25
Q

Predicted CF protein structure

A

2 membrane spanning domains that form chloride ion channel

2 nucleotide binding domains that bind and hydrolyze ATP

Regulatory domain, not in other ABC transporters

C terminal anchored to cytoskeleton by PDZ interacting domain

26
Q

Model of CFTR channel gating

A
  1. R domain phosphorylated by PKA
  2. Allows binding of ATP to NBD1
  3. Hydrolysis of ATP by NBD1 opens channel (transiently)
  4. PKA phosphorylates more sites on the R domain
  5. NBD2 binds ATP to stabilize open channel
  6. ATP hydrolysis at NBD2 releases ADP, channel closes
  7. R domain dephosphorylation closes channel

CFTR is cAMP activated and ATP gated ion channel

27
Q

Difference between CFTR and other ABC proteins

A

Has an R domain

Allows flow of ions down their electrochemical gradient, ABCs use ATP to go against gradient

28
Q

Location of CFTR

A

Epithelial cells in the lung, liver, pancreas, digestive tract, respiratory tract, and skin

29
Q

6 types of CFTR mutations

A
  1. Lack CTFR synthesis (premature stop codon)
  2. Defective protein processing (misfolded CTFR)
  3. Defective channel regulation/gating (gating defect)
  4. Defective chloride conductance (restricted Cl- movement through channel)
  5. Reduced amount of CFTR protein (alternative splicing)
  6. Accelerated turnover of surface CFTR

1-3 more severe, 4-6 are milder disease forms

30
Q

Class II mutation of CFTR

A

Immature protein synthesized, most common mutation, F508del occurs on the surface of NBD1

Immature protein cuz partial glycosylation, not released from ER for transport to Golgi

Degraded by ubiquitin-proteasomal pathway

31
Q

Salt reabsorption from sweat ducts for CF

A

Secretory cells operate normally

In the reabsorptive duct epithelial Na+ channels in the apical membrane bring sodium ions in the cells to eventually be transported out of the basolateral membrane to the blood

Na+ enters but Cl- doesn’t since CFTR is the only anionic transporter, disrupts electrochemical gradient, little NaCl reabsorbed

Sweat duct has low permeability for water so only ions move

Sweat chloride conc. is the best physiological marker of CF

32
Q

Why salty sweat in CF

A

Failure of NaCl reabsorption and low water permeability in sweat duct

Normal water permeability in secretory coil

33
Q

CFTR in airway epithelium

A

Normally CFTR open to allow Cl- to flow into lumen of lung (and pancreas)

Cl- in lumen slows Na+ from lumen into the cells due to charge

High NaCl conc. causes osmosis so there is normal airway surface liquid to clear pathogens

In CF Na+ go into the cells since Cl- stuck there, little ASL to help fight pathogens

34
Q

Symptoms of CF in the lungs

A

Severe cough- to remove excess mucus

Breathlessness- shortage of oxygen leads to increased tiredness and lack of energy

Infections- bacteria trapped in mucus

35
Q

Pancreatic juice flow with CFTR

A

CFTR pumps out Cl-, so Na+ and H2O follow

Increased volume of pancreatic juice, HCO3- also comes out to modulate pH

In CF the Cl- stays in pancreatic epithelial cells so Na+ enter, ducts filled with viscous pancreatic juice (mucus)

Sticky mucus blocks duct so digestive enzymes not reach duodenum

36
Q

CF pancreas problems

A

Exocrine pancreatic secretions have lower bicarbonate and volume, blocks ducts and obstructs flow of digestive enzymes

Degradation of acinar cells and pancreatic fibrosis

Pancreatic sufficient (mild) or pancreatic insufficient (severe) disease

Pancreatic insufficiency has maldigestiin of fats/proteins, increased fecal loss, steatorrhea (pale loose smelly shits, associated with poor weight gain)

Leads to chronic pancreatitis, possible pancreatic atrophy of endocrine cells that causes Cystic fibrosis-related diabetes

food is not digested and absorbed so patients don’t put on mass and suffer from malnutrition

Trapped digestive enzymes damage beta cells so get diabetes

37
Q

Genotype and phenotype correlations for CF

A

Good correlation: Class I-III mutations lead to pancreatic insufficiency, IV and V lead to PS

Moderate correlation: sweat chloride conc. and pancreatic status

Weak correlation: lung function

No clinical features unless less than 10% of normal CTFR function

38
Q

CF Treatments

A

Gene therapies are unsuccessful

Pharmacotherapy that rescue CFTR function

Gastrointestinal treatment: vitamin supplements, high caloric intake that is low in fat and high in protein

Lung transplant if real bad

39
Q

Reason for persistence of CTFR gene mutations

A

Heterozygotes express 50% of normal CFTR levels, less fluid loss from cholera

Europeans have the mutations mostly

40
Q

Cholera and CF

A

Toxin enters cell, passes through ER where A1 subunit detach and then resold in cytoplasm, A1 ADP-ribosylates the alpha subunit of a G protein, activated G protein activates adenylyl cyclase to make cAMP

cAMP activates PKA that phosphorylates R domain of CFTR

Cl- flows out too much cuz alpha subunit of G protein can’t turn off the signal due to the ADP-ribosylation

High salt conc. outside creates osmotic pressure

Less CFTR means less water movement out and less diarrhea

Foundations 1 (19 decks)

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