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Pharm 2024 > PPT 2 > Flashcards

PPT 2 Flashcards

Unit 1

1
Q

What are the 3 factors in receptor concept

A
  1. Receptors determine relations between dose/concentration of drug and pharmacologic effects (receptor affinity (Kd) determines dose)
  2. Receptors are responsible for selectivity of drug action
  3. Receptors mediate actions of agonists and antagonists
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2
Q

What are orphan receptors?

A

Receptors that have been identified but we don’t know what binds to it (no known endogenous ligand)

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3
Q

What are the 3 components of cell signaling?

A
  1. Signal
  2. Receptor
  3. Effector

If secondary messaging - also has signal transduction proteins and secondary messengers

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4
Q

What are the 2 consequences of hormones regulating gene expression?

A

Lag period - time it takes to make new proteins
Persistence (effects can continue for hours-days)

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5
Q

Where can receptor proteins be located?

A

In the cell or cell membrane

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6
Q

Define coupling

A

the overall transduction process that links drug occupancy of receptors and pharmacologic response

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7
Q

How is the efficiency of coupling determined?

A

Conformational change, downstream cellular response, and dose response (number of receptors bound - linear, or strength of signal transduction cascade - multiplied response)

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8
Q

Describe the phosphorylation cascade

A

Ligand binding → Receptor activation (change of conformation) → First protein (kinase) activation → Subsequent protein (kinase) activation (amplification) → Effector protein activation → Cellular response

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9
Q

What are the 5 mechanisms of transmembrane signaling?

A
  1. Lipid soluble - intracellular
  2. Enzymatic activity allosteric
  3. Catalytic
  4. Ion channels
  5. GPCRs
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10
Q

What binds to the alpha portion of the G protein ?

A

Guanine nucleotide (GTP) - active or GDP (inactive)

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11
Q

What makes G-proteins trimeric?

A

3 different amino acid strands that function together to form G-protein
Alpha - binds to GDP (inactive) or GTP (active)
Beta and gamma - help binding to receptor itself

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12
Q

What receptors are intracellular?

A

Lipid soluble - uncharged
Gasses - easily diffuses through membrane

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13
Q

What is the motif of every GPCR?

A

Have 7 trans-membrane alpha helices

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14
Q

What are the steps to the GPCR cascade?

A
  1. Drug binds to receptor - activates alpha subunit of G protein (conformation change)
  2. G protein releases GDP and binds GTP
  3. G protein activates effector protein
  4. Secondary messenger cascade or ion conductance
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15
Q

What makes a GPCR response fast vs slow?

A

Fast - rapid desensitization, metabotropic ion channels
Slow - secondary messenger (transcription factor activation)

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16
Q

What is the most important part of the G protein?

A

Alpha subunit - activates effector

17
Q

Differentiate between desensitization and resensitization

A
  • When first give agonist, response jumps up, peaks, then declines (muted response with same amount of agonist) - desensitization
  • Stop giving agonist, then wait, then give agonist again → see same response - resensitization
18
Q

Describe the steps to the desensitization process

A
  1. Drug binds to receptor → promotes receptor interaction with G proteins in cytoplasm (closed → open conformation)
  2. Agonist-activated receptors phosphorylated by G protein-coupled receptor kinase (GPK), preventing receptor interaction with G protein → attracts beta-arestin (B-Arr)
  3. B-Arr receptor complex binds to coated pits, promoting receptor internalization
  4. 2 possibilities:
    Possibility 1 - resensitization (Drug falls off receptor→ phosphatase dephosphorylates receptor and receptor recyles back to cell membrane)
    Possibility 2 → degradation (Can’t get drug off of receptor → lysosome merges with drug/receptor complex → enzymes from lysosome degrade receptor)
19
Q

Why would a receptor be degraded instead of resensitized (recycled)?

A

Repeated or prolonged exposure of cells to agonist favors degradation → promoting receptor down-regulation rather than resensitization

20
Q

How does beta-arestin work?

A

Beta-arestin is a protein that binds to -OH groups when receptor in open conformation for long time (prolonged binding - i.e. covalent bonds) and binds to coated pits, preventing G protein from rebinding

21
Q

How does the coated pit engulf the receptor complex?

A

Clathrin coated pit (endocytosis) drags whole receptor with bound drug and beta-arestin into cell

22
Q

Differentiate between kinase and phosphatase

A

Kinase attaches phosphate group to protein
Phosphatase strips away phosphate group from protein

23
Q

How do RTKs work?

A

Receptor tyrosine kinases:
1. Ligands bind to receptors, cause conformation change, and dimerization of 2 receptors
2. RTK activated by dimers and phosphorylates tyrosines on receptor dimer from ATP
3. Docking sites for downstream signaling molecules activated

24
Q

How many ATP are necessary for RTK phosphorylation?

A

6 - or as many as OH groups

25
Q

What are the 2 signal types for ion channels?

A

Ligand and voltage gated

26
Q

How are voltage-gated ion channels activated?

A

Change in voltage activates channel; no drug binding, activated by change in voltage

27
Q

Where are voltage-gated ion channels found?

A

-Found in excitable cells (neurons, muscle, endocrine cells)

28
Q

When are voltage-gated ion channels open vs closed?

A

Closed at resting membrane potential
Open at threshold

29
Q

Describe the different conformations of the voltage-gated ion channels? Which gates are open when?

A

Closed - gate 1 closed, 2 open
Activated - both gates open
Inactivated - gate 2 closes, gate 1 open
Deactivated - both closed

30
Q

Differentiate ionotropic from metabotropic ligand-gated ion channels

A

Ionotropic - Ligand binding site and channel on same protein
Metabotropic - Ligand activates GPCR, second messenger activity opens channel

31
Q

What is the most common second messenger?

A

cAMP (cyclic adenosine monophosphate)

32
Q

Dose response is related to

A

Amount of receptors bound and or the strength of signal transduction cascade

33
Q

2/3 of all non-antibiotic drugs are activated by

A

GPCRs

34
Q

Sodium channels are considered to be

A

fast

35
Q

Calcium ion channels are considered to be

A

slow

36
Q

The example in lecture of a metabotropic ligand gated ion channel is in the ____________ system

A

olfactory

37
Q

Receptors inside the cell can only be easily activated by ________

A

something that is lipid soluble and can freely diffuse through the cell membrane (ex Gasses and steroid hormones)

Pharm 2024 (28 decks)

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