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Foundations II > Exam 3 vocab > Flashcards

Exam 3 vocab Flashcards

1
Q

Receptor theory of drug action

A

Drugs do not create effects on their own. They mimic, enhance, or block a naturally occurring phenomena.
No drug has a single action. They are not perfectly selective and therefore create side effects.
Intensity of response is typically proportional to concentration of free drug: the dose makes it a drug or toxin.
Agents cannot act unless bound.

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2
Q

Cell signaling

A

the process by which cells release, transmit, receive and respond to information

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3
Q

Endocrine signaling

A

distant signaling via the bloodstream (ie hormones, steroids, and insulin)

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4
Q

Paracrine signaling

A

locally acting signals (ie nitric oxide, histamine, or neurotransmitters)

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5
Q

Autocrine signaling

A

small molecules released from cells that are self-activating signals (ie growth factors)

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6
Q

Juxtacrine signaling

A

cell-cell or cell-substrate signaling –> they have to be right next to each other; contact dependent (ie integrin signaling and 2nd messenger)

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7
Q

Ligand

A

small molecule that interacts with/binds a protein

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8
Q

Agonist

A

a ligand that activates a receptor protein

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9
Q

Antagonist

A

a ligand that blocks a receptor with high selectivity

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10
Q

Receptor

A

protein that can interact with a small molecule and transmit a signal by changing shape to activate amplifiers or effectors

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11
Q

Amplifier

A

alters levels of 2nd messenger small molecules

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12
Q

2nd messengers

A

activate effector enzymes (ie Ca++, cAMP, cGMP)

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13
Q

What are common 2nd messengers?

A

cAMP, cGMP, Ca++, IP3

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14
Q

What are common signal switches?

A

Phosphorylation, GTP binding, proteolysis

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15
Q

What are the four classes of receptors and their speed?

A

Ion channel (fastest - msec), Enzyme linked receptor (sec), G-protein coupled receptor (sec), steroid hormone/nuclear receptor (slowest - min or hour)

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16
Q

Ion flux

A

movement of ions across the membrane. Changes the voltage and intracellular concentrations

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17
Q

Types of ion channels

A

Voltage-gated, Ligand gated, 2nd messenger gated

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18
Q

What is the one ion with a higher intracellular concentration?

A

Potassium

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19
Q

selectivity or ion filter

A

A narrow region in the ion channel pore that is charged and determines ion specificity

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20
Q

excitable tissues

A

respond to changes in membrane potential and utilize action potential to propagate electrical signals (ie neurons and muscle cells)

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21
Q

Drugs that target voltage gated ion channels

A

Phenytoin blocks voltage gated sodium channels in CNS
Procainamide blocks voltage gated sodium channels in the heart
Nifedipine blocks calcium channels in the blood vessels

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22
Q

Drugs that target ligand gated ion channels

A

Benzodiazepines enhance the effects of GABA at the GABAA receptor ion channel receptor.
Vecuronium blocks nicotinic acetylcholine receptors
Ondansetron is a 5HT3 receptor ion channel antagonist

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23
Q

Drugs that target 2nd messenger regulated ion channels

A

Sulfonylureas inhibit the KATP channel in pancreatic beta cells to increase insulin release

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24
Q

Four steps/stages of an action potential

A
  1. Initial depolarization
  2. Depolarization opens voltage sensitive Na+ channels
  3. Maximal depolarization closes Na+ channels and opens K+ channels, repolarize
  4. Hyperpolarization and K+ channels close
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25
Q

Characteristics of ligand gated ion channels

A

Multiple subunits form a central pore
Agonist binding opens the pore to ion flow
A further conformational change INACTIVATES the channel
The ion channel is reset to CLOSED state and ready to be activated

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26
Q

2nd messenger regulated ion channel characteristic

A

small molecule ligands on the INSIDE of the cell

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27
Q

G coupled protein receptor characteristics

A

7 transmembrane helices form a barrel
3 intracellular loops and a carboxyl tail
Interact with G proteins on the inside of a cell

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28
Q

Possible G protein ligands class

A

light, Ca++, odorants/pheromones, small molecules, proteins

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29
Q

Common drugs acting through GPCRs (only need to know 2)

A

albuterol, pseudoephedrine, diphenhydramine, epinephrine, atropine, haloperidol, olanzapine, loratadine, fexofenadine, morphine, oxytocin, atenolol, sumatriptan, zolmitriptan

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30
Q

What does RGS stand for and do?

A

regulators of G protein signaling that accelerates GTPase activity and a return to the inactive basal state

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31
Q

How are beta and gamma activated in a GPCR?

A

By dissociation from the alpha subunit

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32
Q

G-alpha stimulatory enzyme effector and 2nd messenger/effect

A

stimulates adenylyl cyclase which increases cAMP levels

33
Q

G-alpha inhibitory enzyme effector and 2nd messenger/effect

A

inhibits adenylyl cyclase which decreases cAMP levels

34
Q

G-alpha q enzyme effector and 2nd messenger/effect

A

phospholipase C-beta and increases IP3 and calcium release

35
Q

G-beta-gamma enzyme effector and 2nd messenger/effect

A

K+ channels which causes cell hyperpolarization

36
Q

What does the cholera toxin effect?

A

It activates G-alpha stimulatory which increases cAMP

37
Q

What does the pertussis toxin effect?

A

It inhibits G-alpha inhibitory which increases cAMP

38
Q

What does adenylyl cyclase do?

A

Converts ATP to cAMP

39
Q

What does cAMP do in the adenylyl cyclase pathway?

A

activates the cAMP regulated protein kinase, which triggers signaling pathways

40
Q

What does phosphodiesterase do in the adenylyl cyclase pathway?

A

Convert cAMP to AMP

41
Q

What is Hh ligand and what is it’s receptor?

A

A ligand required in embryonic embryonic development, but abnormally active in certain cancers.
Hh receptor is Patched (PTCH).

42
Q

What does PTCH do?

A

Inhibits smoothened (SMOH).

43
Q

What happens after Hh binds to its receptor?

A

PTCH allows SMOH to travel to the plasma membrane and interact with a cluster of proteins including GLI

44
Q

What does SMOH do?

A

Activates GLI to translocate to the nucleus and activate gene transcription

45
Q

Describe process of Phospholipase C-beta activation and effect.

A

Alpha Gq subunit and beta/gamma heterodimer subunit both activate phospholipase C-beta.

Phospholipase C-beta interacts with membrane bound PIP2, creating IP3 in cytosol and Diacylglycerol in membrane.

IP3 opens calcium gated channels in ER. Diacylglycerol and calcium activate Protein Kinase C

46
Q

Explain how over stimulation of GPCR’s can reduce signaling.

A

Over stimulation causes increased levels of beta/gamma subunits, which activate GRK (GPCR Kinase). GRK phosphates C-tail of 7TMR 3 times causing Beta-Arr to bind, arresting the signal.

GPCR resets by beading into a vesicle in the cytosol and being broken down or rearranged by lysosomes or endosomes, respectively.

This is called receptor desensitization–drug tolerance (Asthma inhaler example)

47
Q

What signaling pathway defect causes basal cell carcinoma?

A

The hedgehog signaling pathway.

SMOH stays at memberane. Drug targets 7TMR portion of SMOH with antagonist.

48
Q

Name the Receptor Enzymes we have covered.

A 
Guanylyl Cyclase (GC) receptor
Receptor Tyrosine Kinase (RTK)
Cytokine Receptors (CR)
49
Q

What are the similarities and differences of GC receptors?

A

Insoluble receptor has extracellular portion called rGC and is activated by AMP. A homodimer is formed and intracellular guanylyl cyclase catalyzes GTP to cGMP

Soluble receptor doesn’t have extracellular portion. Activation is caused by NO gas released by blood vessel endothelium. Dimer comes together, and guanyly cyclase catalyzes GTP to cGMP.

cGMP relaxes smooth muscle

50
Q

What two drugs did we talk about with GC receptors. What are their similarities and differences?

A

Nitrate and Sildenafil

Nitrates increase cGMP by activating soluble GC receptor.
Sildenafil increases cGMP by inhibiting PDES (Phosphodiesterase) which converts cGMP into GMP (and cAMP into AMP, but that’s not for this pathway).

51
Q

What activates TRKs?

A

Growth factors (GF), causing dimerization.

52
Q

How many transmembrane domains does RTK have? (Example: 7TMR has 7 transmembrane domains)

A

RTKs have one transmembrane domain. When activated, they create homodimers and only appear to have two transmembrane domains.

53
Q

What happens when a RTK creates a dimer?

A

Intrinsic intracellular kinase activity. Each tyrosine kinase phosphorylates the other. This phosphorylates and activates adaptor proteins, SOS and Grb2, and attaches them to the tyrosine complex.

The tyrosine complex then activates RAS, a lone G protein. (GTP turns it on, GTPase activity turns it off). RAS activates MAPK cascade.

MAPK cascade includes Raf–> MEK-PO4–> MAPK-PO4, all three of which are held in place by scaffold protein. This cascade affects transcription.

54
Q

What are Small GTPases?

A

A G-protein with only alpha-subunit (no beta/gamma).

Activated by intracellular GEFs

Intrinsic GTPase activity is accelerated by GAPs

Overactive mutants found in some cancers.

RAS is an example of these proteins.

55
Q

What type of signaling pathway uses insulin as a primary messenger?

A

RTK signaling pathway

56
Q

How is glucose absorbed once insulin binds to RTK?

A

RTK dimer forms and phophorylates itself. Adapter protein IRS1 attaches and is phophorylated as well.

Phosphorylated IRS1 attaches adapter protein PI3K (kinase) which phophorylates PIP2 and creates PIP3.

PIP3 (attached to membrane) is a second messenger that activates a downstream kinase cascade initiated by Akt.

This leads to GLUT4, a glucose transport protein, to translocate to cell membrane.

57
Q

How is Akt important in some cancer development?

A

Akt can inhibit apoptosis. Cells that accumulate a lot of mutations can have increased Akt levels.

58
Q

How are RTKs inhibited?

A

RTKs get internalized similarly to GPCRs. They can be recycled or broken down.

59
Q

What do anti-cancer drugs do to RTKs?

A

Force receptors to internalize.

60
Q

What are mAb drugs?

A

monoclonal antibodies that bind to RTKs without eliciting signaling response. They cause cell to think it’s being over stimulated.

61
Q

What are -nib drugs?

A

Tyrosine Kinase inhibitors that prevent phophorylation of tyrosine, blocking the pathway.

62
Q

How do Cytokine Receptors (CRs) work?

A

Similar to RTK.

Forms dimer when activated, and attracts tyrosine kinase called Janus Kinase (JAK).

It attracts adapter protein called Stat, which gets phosporylated as well.

Phosphorylated Stat proteins form dimers, translocate to nucleus, and becaomes a transcription factor.

Known as JAK-Stat pathway

63
Q

What do cytokines do?

A

Mediate immune responses and inflammation, stimulate hematopoiesis and function in reproduction.

64
Q

What are the hemotopoiesis activators that effect red blood cells and white blood cells?

A

Erythropoietin (Epogen) and GM-CSF (Neupogen), respectively.

65
Q

What is the one juxtacrine signaling receptor that we talked about in class?

A

Death Domain Receptor

66
Q

How do Death Domain Receptors work?

A

FAS is a membrane bound homotrimeric protein that attaches to a membrane bound FAS Ligand (FASL) on another cell.

The cell with FAS bound to membrane undergoes proteolytic cascade when activated by FASL.

FAS activation leads to apoptosis.

67
Q

What are Nuclear Hormone Receptors?

A

Intracellular, soluble, non-membrane-associated proteins that function as ligand-dependent transcription factors.

Functions as dimers in nucleus.

DBD portion of receptor (DNA binding domain) bind directly to DNA in promoter region, sits on major groove of DNA helix.

LBD portion of receptor (Ligand binding domain) bind hormone which regulates transcription (activation or repression).

68
Q

Describe Type 1 Nuclear Receptor Transcription Regulation.

A

Type 1 nuclear receptors exist as monomers in cell bound to Heat Shock Protein (Hsp).

Agonist gets into cell, Hsp dissociates, nuclear receptor dimerizes.

Dimer attaches to Hormone Respones Element (HRE) and attract coactivator complex.

Deactivation occurs by breakdown of HRE, nuclear reseptor, and coactivator complex by proteosomes (no recycling).

69
Q

What is P300/CBP?

A

Part of coactivator complex in type 1 nuclear receptor transcriptional regulation. it is a histone acytltransferase.

70
Q

Describe Type 2 Nuclear Receptor Transcription Regulation.

A

Type 2 nuclear receptors stay in the nucleus as heterodimer.

It is apart of a corepressor complex that actively represses gene transcription in the absence of a ligand.

When ligand binds, corepressor falls off and coactivator attaches.

Deactivation occurs by breakdown of proteins.

71
Q

Favorite steroid hormone receptor, dug, and activity.

A

Progesterone receptor
Mifepristone
Pregnancy termination

72
Q

What are the characteristics of drug and receptor binding? (Candy Ligand Activity)

A
  1. Saturable - drug must act through specific sites which are limited
  2. Reversible - receptors are not enzymes
  3. High Affinity - Specific actions require high affinity interactions
  4. Stereoselectivity - Consequence of high affinity interactions
  5. Cause and Effect - Activation of a signaling pathway
73
Q

What is the Law of Mass Action

A

An equation that quantifies a receptors affinity to a drug and predicts the number of receptors on a cell.

At equilibrium: [drug] + [total # of receptors] () [drug bound to receptor]

74
Q

What is the Y and X axis of a Law of Mass Action graph?

A

Y = (Number of receptors with drug bound)/(total number of receptors on cell) Units are fmol/mg

X = (concentration of drug)/(concentration of drug + affinity constant) Units are nM

75
Q

How can you find the affinity constant?

A

(Release constant)/(binding constant)

or

Kd (affinity constant) = drug concentration when 50% of receptors have drug bound.
50% Bmax

76
Q

What is Bmax?

A

All receptors bound to drug

77
Q

What does a low Kd mean?

A

High affinity

Kd and affinity are inversely proportional

78
Q

What does a Competition Binding Curve show?

A

Interactions of different drugs at the same receptor

Foundations II (3 decks)

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