FDN2_SM_ReceptorFamilies&Signaling

Question 1

What kind of antagonist binds reversibly to the agonist-binding site?

Answer 1

Competitive antagonist

Note: when both ligands are present, partial agonists act as competitive inhibitors of the full agonist

Question 2

Where might a noncompetitive antagonist bind?

Answer 2

Irreversibly to an orthosteric site or irreversibly to an allosteric site. This prevents receptor activation.

Question 3

Where does an uncompetitive inhibitor bind?

Answer 3

The agonist-receptor complex

Question 4

How does a competitive inhibitor affect potency and efficacy?

Answer 4

A competitive inhibitor decreases potency (increases EC50), and has no effect on efficacy

Question 5

How does a noncompetitive inhibitor affect potency and efficacy?

Answer 5

A noncompetitive inhibitor lowers efficacy and has no effect on EC50

Question 6

How does an uncompetitive inhibitor affect potency and efficacy?

Answer 6

An uncompetitive inhibitor lowers efficacy, but actually increases potency (decreases EC50)

Question 7

In this image, what evidence supports the conclusion that Zolpidam is a postive allosteric activator?

Answer 7

Zolpidam has no effect on its own, but increases the efficacy of GABA when they are applied together

Question 8

What is the mechanism of action of P4S? How do you know?

Answer 8

Partial agonist: in the presence of GABA and P4S, there is a right shift; potency is decreased and efficacy is unaffected (remember, that partial agonists can act as competitive inhibitors).

P4S alone results in some receptor activity, indicating that it isn’t just a competitive antagonist

Question 9

What is the mechanism of action of Penicillin? How do you know?

Answer 9

Uncompetitive inhibitor. There is little effect at low agonist concentration, the efficacy is lowered, and the potency is increased (EC50 is lowered)

Question 10

Which ligand is a partial inverse agonist? How do you know?

Answer 10

Beta Carboline is a partial inverse agonist. When it is present, the response is lower than the basal activity without the agonist

Question 11

What is the effect of an inverse agonist in constitutively active system?

Answer 11

The inverse agonist reduces contitutive signaling.

Note: in a constitutively active system, an antagonist would have no effect. Antagonists interfere with the “on switch” of an agonist, but there is no “switch” in a constitutive system

Question 12

Which ligands bind to the orthosteric site of a receptor?

Answer 12

Full agonists, partial agonists, inverse agonists, competitive antagonists

Question 13

What is the effect of an inverse agonist in a quiescent system?

Answer 13

The inverse agonist acts as a competitive antagonist

Question 14

Under what conditions does constitutive receptor activity occur?

Answer 14

• Tumor growth
• Research experiments where researchers artificially overexpress receptors

Question 15

In the image, which ligand might be a competitive antagonist?

Which might be a partial agonist?

How do you know?

Answer 15

Ligand A could be a partial agonist, because it is able to cause a response on its own, without the agonist present

Ligand B could be a competitive antagonist. Actually, it coudl be any kind of antagonist, because it doesn’t produce any response in the absence of an agonist

Question 16

What kind of antagonist only binds to the ligand-receptor complex?

Answer 16

Uncompetitive

Question 17

Is biological response in a cell proportional to the number of receptors bound to the agonist? Why or why not?

Answer 17

No! Maximal biologial response even when only a small % of receptors are bound to the full agonist. Most of the receptors are spares!

The maximal response is produced because there are many chemical intermediates that amplify the initial signal within the cell.

Question 18

This image shows the effect on biological response to Drug A when Drug M is also applied in increasing doses. Why doesn’t efficacy fall after the first two increases in Drug M dose?

Answer 18

Initially, spare receptors compensate for the increased concentration of the antagonist. As the dose of Drug M increases, the spare receptors are “used up,” and efficacy begins to fall.

Question 19

This image shows the effect on biological response to Drug A when Drug M is also applied in increasing doses. Is Drug M a competitive antagonist? How do you know?

Answer 19

Drug M is not a competitive antagonist. At increasing doses of Drug M, efficacy falls. Competitive antagonists do not affect efficacy.

Question 20

Describe the constrained model of coopertivity

Answer 20

In the constrained model, all subunits must take the same acive conformation.

• In the “stressed” conformation, all of the subunits are inactive
• In the “unstressed” conformation, all of the subunits are active

Question 21

Describe the sequential model of cooperativity

Answer 21

Subunits can be sequentially activated and exist in different conformations at the same time

For example, a channel opening may increase in size as each subsequent subunit is activated.

Question 22

If all four subunits of hemoglobin must exist in either the T-state (stressed) or R-state (unstressed), what type of coopertivity does it exhibit?

Answer 22

Constrained aka concerted coopertivity

Question 23

If each oxygen molecule binding to hemoglobin further increases the protein’s affinity for oxygen, what type of coopertivity does hemoglobin exhibit?

Answer 23

Sequential coopertivity

Question 24

How do you calcualte the Therapeutic Index of a drug?

Answer 24

Toxic ED₅₀/Beneficial ED₅₀

OR

LD₅₀/Beneficial ED₅₀

(Use the latter if the adverse event measured is death)

Question 25

What does the LD₅₀ Represent?

Answer 25

The LD₅₀ is the median lethal dose; the effective dose at which 50% of subjects have died

Question 26

What does the ED₅₀ represent in a quantal dose-response curve?

Answer 26

In a quantal dose-response curve, the ED₅₀ is the median effective dose at which 50% of subjects have achieved a therapeutic effect

Question 27

What is the difference between toxic ED₅₀ and LD₅₀?

Answer 27

Toxic ED₅₀ is used when the adverse event in question is toxicity, rather than death

LD₅₀ is used when the adverse event in question in death

Question 28

What does an Na/K ATPase do?

Answer 28

The Na/K ATPase hydrolyzes 1 ATP molecule to move…

3 NA+ ions out of the cell

2K+ ions into the cell

Question 29

Which ions have a higher concentration inside of the cell than out?

Answer 29

K+ only

Question 30

Which ions have a higher concentration outside of the cell than in?

Answer 30

Na+, Cl-, Ca2+

Question 31

What is the resting membrane potential of most cells in the body?

Answer 31

About -70 mEV

Question 32

What is the Nernst equation for a cation?

Answer 32

(Note: [ion]_out is in the denominator and [ion]_in is in the numerator for anions)

Question 33

What does the GHK equation caluclate? What is the equation?

Answer 33

The GHK equation calculates the resting membrane potential, taking into account the contribution of Na+, K+, and Cl-

Question 34

Which ions determine the resting membrane potential of a cell?

Answer 34

Na+, K+, Cl-

Question 35

Describe the determinants of resting membrane potential

Answer 35

The Na/K ATPase pump keeps the contentration of Na+ high outside of the cell, and the concentration of K+ high inside of the cell

Na+ and K+ leak channels oppose the action of the ATPase, pulling the membrane potential toward the equilibrium potential for each ion. The membrane is more permeable to K+, so the resting membrane potential (-70mV) is closer to the Nernst potential of K+ (-95mV)

Question 36

Which ions have a negative equilibrium potential?

Answer 36

K+ and Cl-

Question 37

Which ions have a positive equilibrium potential?

Answer 37

Na+, Ca2+

Question 38

What will happen to extracellular Na+ concentration if the membrane becomes more permeable to Na+

Answer 38

Nothing! Intracellular and extracellular bulk ion concentrations remain the same

Question 39

What will happen to membrane potential if the membrane becomes more permeable to Na+

Answer 39

Na+ will flow into the cell, depolarizing the membrane.

This is typically considered excitatory

Question 40

What will happen to membrane potential if the membrane becomes more permeable to Ca+

Answer 40

Ca+ will flow into the cell, depolarizing the membrane

Question 41

What will happen to membrane potential if the membrane becomes more permeable to Cl-

Answer 41

Cl- will flow into the cell, hyperpolarizing the membrane

This is typically considered inhibitory. This is important in skeletal muscle

Question 42

What will happen to membrane potential if the membrane becomes more permeable to K+

Answer 42

K+ will flow out of the cell, hyperpolarizing the membrane

This is typically considered inhibitory

Question 43

What kinds of stimuli, applied at step 2, might prevent a membrane from reaching the threshold potential?

Answer 43

IPSPs (Inhibitory Graded Potentials) due to transient Cl- channel opening, leading to hyperpolarization. May be caused by Glycine or GABA binding to its receptor

Question 44

How is the hyperpolarization that occurs after an aciton potential rectified?

Answer 44

K+ channels close, and Na+/K+ ATPase re-establishes resting membrane potential

Question 45

Describe what is happening at the apex, between stages 3 and 4

Answer 45

Voltage-gated Na+ channels inactivate (flow of ions stops via an inactivation mechanism)

Voltage-gated K+ Channels open. K+ begins to flow out of the cell, causing repolarization

Question 46

Which channels are open at stage 3?

Answer 46

Voltage-gated Na+ channels. Na+ flows, in, causing depolarization.

Question 47

What kinds of stimuli, applied at step 2, might cause a membrane to reach the threshold potential?

Answer 47

EPSPs: Excitatory Graded Potentials due to transient Na+ or Ca2+ channel opening. May be caused by ACh or Glutamate binding to its receptor.

Question 48

How is Cl- potential different in development vs. adult life?

Answer 48

In development, [Cl-] is increased inside of neurons due to transporter action. When GABA binds, to open a channel, Cl- flows out, causing depolarization.

In all other stages of life, Cl- flows in, causing hyperpolarization upon GABA binding

Question 49

Which channels are open in phase 0?

Answer 49

Fast, voltage-gated Na+ channels open, allowing Na+ to rush into the cell

Question 50

Which channels are open in phase 1?

Answer 50

Fast acting K+ channels open to generate I_TO (Trasient outward current). Na+ channels are closed and inactivated

Question 51

Which channels are open in phase 3?

Answer 51

Voltage-gated L-type Ca2+ channels close and become inactivated.

K+ channels remain open. Repolarization is completed by I_Ki, the rectifying current

Question 52

Which channels are open in phase 2?

Answer 52

Voltage-gated L-type Ca2+ channels allow Ca2+ into the cell, slowing the rate of repolarization

K+ channels open, contriubuting to repolarization through I_Kr and I_Ks

Question 53

What is long QT syndrome, and what causes it?

Answer 53

Long QT is when the interval between the beginning of ventricular depolarization and the end of ventricular repolarization is too long.

Theoretically this may be caused by overactive Ca2+ channels or impaired K+ channels. Most often it is caused by impaired K+ channels

Question 54

What is Diazepam (Valium) and how does it work?

Answer 54

Diazepam (as well as all benzodiazepines) is an Allosteric Activator of GABA_A

Increasing GABA_A activity results in increased Cl- flowing into the cell, which enhances inhibition

This helps to reduce anxiety, reduce muscle spasms, and promote sleep

Question 55

How would inhibiting cardiac Ca+ channels affect the cardiac action potential?

Answer 55

Inhibiting cardiac Ca+ channels would prevent Ca2+ from entering the cell. There would be less Ca2+ to oppose the K+ currents, and repolarization would occur more quickly

Question 56

How would inhibiting cardiac K+ channels affect the cardiac action potential?

Answer 56

Inhibiting cardiac K+ channels would lengthen the cardiac action potential, because it woud take longer for K+ to leave the cell and repolarize the membrane

Question 57

What mechanism lengthens cardiac action potentials in comparison to neuronal action potentials?

Answer 57

Cardiac muscle cells conduct Ca2+, which opposes the re-polarizing K+ current.

It takes longer for the membrane to repolarize, thus lengthening the action potential

Question 58

What mechanism causes the absolute refractory period?

Answer 58

Inactivation of Na+ channels

Question 59

What mechanism causes the relative refractory period?

Answer 59

Hyperpolarization of the membrane due to open K+ channels. Due to hyperpolarization, the membrane is less likely to reach the threshold potential.

Question 60

Describe active transport

Answer 60

Substances are transported across the cell membrane against thier concentration gradient in an energy-dependent manner.

Usually mediated by the action of ATPase pumps

(ex: Na/K ATPase)

Question 61

What is the difference between passive transport and facilitated diffusion?

Answer 61

Both processes move substances across the cell membrane down their concentration gradient.

Passive transport invovles diffusion through a membrane protein. It is controlled by the opening and closing of channels (ex: Na+ and K+ leak channels)

Facilitated Diffusion is a type of passive transport that is mediated by carriers and uniporters that move across the membrane, rather than channels

Question 62

Describe the three types of facilitated diffusion and their associated proteins

Answer 62

All three processes involve carrying at least one substrate across the cell membrane, along its concentration gradient

Symporters: A carrier protein that transports two substrates across the cell membrane in the same direction

Antiporters: A carrier protein that transports two substrates across the cell membrane in opposite directions

Uniporter: Carries one substrate across the membrane

Question 63

Which ion channels are most important in setting resting membrane potential?

Answer 63

Na+ and K+ leak channels

Question 64

What is the purpose of a K+ inward-rectifying channel? Why is their existence somewhat of a paradox?

Answer 64

K+ inward-rectifying channels allow K+ to flow across the cell membrane.

The paradox: These channels are designed to be slightly better at letting K+ into the cell than out. However, [K+] is normally much higher inside of the cell than out, so when the channel is open, K+ will flow out of the cell, under normal physiological conditions.

Question 65

How are K_ATP channels regulated?

Answer 65

K_ATP channels are inhibited by ATP

Under high energy conditions, K_ATP is inhibited and K+ is less likely to flow out and hyperpolarize the cell. This increases the probability of an action potential

Under low-energy conditions, K_ATP is active and K+ is more likely to flow out of the cell, hyperpolarizing it. This decreases the probability of an action potential, reducing the work that a Na/A ATPase would have to do to restore membrane potential after the AP.

Question 66

What kind of channel do Sulfonylurea drugs target? Why?

Answer 66

Sulfonylureas inhibit K_ATP channels (a type of inward-rectifying* K+ channel) to stimulate insulin release.

If the channel is inhibited, K+ cannot flow out of the cell. The increased voltage in the cell opens Ca2+ channels, allowing Ca2+ to flow in and trigger insulin release

*Rembember: although inward-rectifiers are better at allowing ions into a cell, K+ will flow out of an open channel due to its concentration gradient

Question 67

Is the opening of K+ channels considered excitatory or inhibitory?

Answer 67

Inhibitory

when the channel is open, K+ will flow out and hyperpolarize the cell. This reduces the probability that it will reach the threshold potential.

Question 68

What is hERG? What does it do?

Answer 68

hERG (human Ether a Go Go) is the protein that creates K+ channels responsible for establishing I_KR in cardiac muscle.

hERG can be thought of like goldilocks (Go Go = Goldilocks): If hERG is overactive, the QT interval is too short, causing arrhythmia. If hERG is impaired, the QT interval is too long, causing arrhythmia.

Question 69

What kind of drugs target hERG? Why?

Answer 69

Class III anti-arrhythmatic drugs target hERG.

If hERG is blocked, IKR is impaired; K+ cannot flows out of the cell less effectively, slowing the rate of repolarization. This can suppress arrhythmia caused by re-entry, if the QT interval is too short

Question 70

Why are drugs with off-target hERG effects blocked by the FDA?

Answer 70

Off-target interactions with hERG can be pro-arrhythmic.

Inhibiting hERG inhibits I_KR and slows repolarization, resulting in arrhythmia.

Question 71

In general, would K+ channel blockers have an inhibitory or excitatory effect?

Answer 71

Excitatory

Blocking K+ channels stops (+) charges from flowing out of the cell. This increases the probability of depolarization and action potential firing

Question 72

In general, would K+ channel activators have an inhibitory or excitatory effect?

Answer 72

Inhibitory

Activating K+ channels alows (+) current to flow out of the cell. This reduces the probability of depolarization and action potential firing

Question 73

In general, would Ca2+ channel blockers have an inhibitory or excitatory effect?

Answer 73

Inhibitory

Blocking Ca2+ channels reduces the calcium influx into the neuon end plate, inhibiting the release of neurotransmitters

Question 74

In general, would Na+ channel blockers have an inhibitory or excitatory effect?

Answer 74

Inhibitory

Blocking Na+ channels reduces the probability of depolarization and action potential firing

Question 75

What condition can be treated by a drug that activates K+ channels in the brain?

Answer 75

Epilepsy

Drugs that activate K+ channels in the brain activate M-current that repolarizes neurons and dampens excitability.

Question 76

What conditions can be treated by neuronal Na+ channel blockers?

Answer 76

Epilepsy, migrane, chronic pain

Blocking Na+ channels inhibits action potential firing; this can decrease convulsions and pain signals

Question 77

What conditions can be treated by drugs that block T-type Ca2+ channels?

Answer 77

Epilespy

By inhibiting Ca2+ channels during an action potential, they inhibit Ca2+ influx into the cell. This inhibits neurotransmitter release and muscle contraction.

Question 78

What conditions can be treated by drugs that block L-type Ca2+ channels?

Answer 78

Angina pectoris, hypertension, arrhythmia, cardiac eschemia

These drugs are important in…

• Shortening the QT interval (If Ca2+ cannot get into the cell, it will re-polarize more quickly)
• Excitation-contraction coupling in smooth muscle

Question 79

What conditions can be treated by cardiac Na+ channel blockers?

Answer 79

Arrythmia

Blocking Na+ channels inhibits action potential firing

Question 80

What conditions can be treated by nerve-cell Na+ channel blockers?

Answer 80

Acute, localized pain (the drug is a local anesthetic)

Blocking Na+ channels inhibits the action potential that carries the pain signal.

These drugs may have use-dependent properties!

Question 81

What conditions can be treated by cardiac K+ channel blockers?

Answer 81

Arrhythmia

Blocking K+ channels slows repolarization, preventing arrhythima caused by re-entry

These drugs act on hERG!

Question 82

What conditions can be treated by nerve-cell Na+ channel blockers?

Answer 82

Acute pain, localized pain (the drug is a local anesthetic)

Blocking Na+ channels inhibits the action potential that carries the pain signal.

These drugs may have use-dependent properties!

Question 83

What is a use-dependent block?

Answer 83

A use-dependent block is more active when its target is firing at a high frequency

For example, high-frequency stimulation of pain nerves enhances exposure of the drug to its binding site within the targeted ion channel

Question 84

If a patient is suffering from a QT interval that is too short, what kind of drug might you prescribe?

Answer 84

K+ channel blocker;

Decreaseing K+ current into the cell slows the rate or repolarization.

(Theoretically, a Ca2+ channel activator would also work but I don’t think any of these currently exist)

Question 85

If a patient is suffering from a QT interval that is too long, what kind of drug might you prescribe?

Answer 85

Ca2+ channel blocker;

Decreaseing Ca2+ current into the cell allows it to repolarize more quickly.

(Theoretically, a cardiac K+ channel activator would also work but I don’t think any of these currently exist)

Question 86

If the upstroke of a cardiac action potential was too strong, what kind of drug would you prescribe?

Answer 86

Na+ channel blocker.

Decreasing Na+ current into the cell will attenuate the upstroke

Question 87

Tetrodoxin is a toxin that is found in pufferfish that blocks Na+ channels. Why might this be dangerous?

Answer 87

Blocking Na+ channels can prevent action potential firing. This can cause paralysis and interfere with heart beat

Question 88

Sea anemones and some scorpions can activate Na+ channels. Why might this be dangerous?

Answer 88

Activating Na+ channels can cause erratic action potential firing. This can lead to convulsions and muscle spasms.

Question 89

What are the 5 excitatory ionotropic (neurotransmitter) receptors?

Answer 89

• Nicotinic: Receptor for Ach
• 5HT-3: Receptor for Serotonin
• NMDA: Receptor for Glutamate
• AMPA: Receptor for Glutamate

P2X: Receptor for ATP

Question 90

What are the 2 inhibitory ionotropic (neurotransmitter) recptors?

Answer 90

• GABA_A: Receptor for GABA
• Glycine: Receptor for Glycine

Question 91

Describe the mechanism of action of excitatory neurotransmitter receptors

Answer 91

Excitatory neurotransmitter receptors incorporate a nonspecific cation channel.

When the ligand binds, the channel opens, and a cation (always Na+) flows into the cell

Question 92

Describe the mechanism of action of inhibitory neurotransmitter receptors

Answer 92

Inhibitory neurotransmitter recetors are selective Cl- chanels

If Cl- flows in, the cell is hyperpolarized and less likely to fire an action potential

Question 93

What ligand-gated receptor family does Acetylcholine bind to?

Answer 93

Nicotinic

Question 94

What receptor family does serotonin bind to?

Answer 94

5HT-3

Question 95

What receptor families does Glutamate bind to?

Answer 95

NMDA and non-NMDA (AMPA and Kainate)

Question 96

What receptor family does ATP bind to when it acts as a neurotransmitter?

Answer 96

P2X

Question 97

What kind of drugs treat nausea and vomiting?

What receptor do they act on? How?

Answer 97

Drugs with a setron suffix (ondansetron, granisetron) treat nausea and vomiting, especially in chemotherapy patients

They are competitive inhibitors of Serotonin5 HT-3 receptors

Question 98

What condition do -setron drugs treat? How?

Answer 98

Drugs with -setron suffixes treat vomiting and nausea by competitively inhibiting serotonin 5HT-3 receptors

Question 99

Which receptors are active in mediating fast, excitatory CNS transmission?

What is their mechanism of action?

Answer 99

Glutamate-AMPA receptors. They are non-selective, ligand-gated Na+ channels.

*They desensitize very rapidly

Question 100

What is the mechanism of action of Memantine?

What condition does it treat?

Answer 100

Memantine is an open-channel blocker (uncompetitive inhibitor) for Glutamate-NMDA receptors

This drug can treat Alzheimer’s by reducing Ca2+ influx to lower Ca2+ excitotoxicity.

Question 101

Describe the mechanism of action fo Glutamate-NMDA receptors.

In what ways can their action be good? Bad?

Answer 101

Glutamate-NMDA receptors are excitatory Glutamate-gated Ca2+ channels. They require 2 waves of depolarization to allow Ca2+ in; the first washes out Mg2+, and the second allows Ca2+ in

They are associated with slower proccesses, such as learning and memory.

Good: Learning and memory

Bad: Excess Ca2+ is associated with excitotoxicity and Alzheimer’s disease

Question 102

What is the mechanism of action fo Benzodiazepines?

What condiitons can they treat?

Answer 102

Benzodiazepines are positive allosteric modulators of GABA_A

They enhance inhibition to reduce anxiety, decrease muscle spasm, and promote sleep

Question 103

What is the mechanism of action of Zolpidem?

Answer 103

Zolpidem (like all benzodiazepines) is a positive allosteric modulator of GABA_A receptors, known as Ambien.

This drug promotes sleep.

Question 104

What is the mechanism of action of Diazepam?

Answer 104

Diazepam (like all benzodiazepines) is a positive allosteric modulator of GABA_A receptors known as Valium.

It is used to reduce anxiety and muscle spasms

Question 105

What is the mechanism of penicillin’s off-target effect on GABA_A receptors?

Answer 105

Penicllin is an open-channel blocker (uncompetitive inhibitor) of GABA_A receptors.

It interferes with inhibition; Cl- influx is reduced, resulting in inappropriate action potentials and seizures.

Question 106

What is the mechanism of action of Strychnine?

Answer 106

Strychnine is a competitive inhibitor of glycine receptors.

This interfers with normal inhibition, resulting in increased spasticity

Question 107

What is the mechanism of action of Tetanus Toxin?

Answer 107

Tetanus Toxin interferes with glycine release; it is a presynapitc inhibitor

Tetanus toxin interferes with normal inhibition, resulting in increased spasticity

Question 108

What is the mechanism of action of hyperekplexia (familial startle disease)?

Answer 108

Hyperekplexia results in a mutation in the alpha-subunit of glycine receptors.

This intereferes with the normal inhibitory action of the receptors, resulting in increased spasticity and an exacerbated startle response.

Question 109

List the 4 receptor families in order from fastest to slowest

Answer 109

1. Ligand-gated ion channels
2. G-Protein Coupled Receptors
3. Receptor Tyrosine Kinases and Related
4. Cytoplasmic and Nuclear Receptors

Question 110

What are the main types of signalling used by GPCRs, from fastest to slowest?

Answer 110

1. Inhibitory signalling mediated by the beta/gama subunits (milliseconds)
2. Smooth muscle contraction mediated by the PLC water-soluble and lipid-soluble pathways (seconds)
3. cAMP/PKA signaling; cardiac muscle contraction and smooth muscle relaxation (minutes)

Question 111

What signaling process do growth factors use?

Answer 111

Growth factors activate a receptor tyrosine kinase that activates the RAS/MAP Kinase pathway that goes on to alter gene transcription to promote growth

• Increased proliferation, adhesion, migration

Note: Receptor dimerizes after ligand binding

The scaffold protein is GRB2

Question 112

What signaling process does insulin use?

Answer 112

Insulin activates a receptor tyrosine kinase that activates the PI3/AKT/mTOR pathway that goes on to alter gene transcription to promote fuel storage

• Increases gulcose uptake
• Increases glycogen synthesis
• Increases fat storage

Note: The insulin receptor is pre-dimerized prior to insulin binding

Question 113

What are the three main types of signaling used by GPCRs, in order from fastest to slowest?

Answer 113

Fastest (milliseconds): Inhibitory action of G_Beta/Gamma subunit activity. Inhibits ion channels

Medium (seconds): Smooth muscle contraction mediated by G_Alpha. Water-soluble and non-water soluble

Slowest (minutes): Downstream phosphorylation mediated by G_Alpha/cAMP pathway. B₁ cardiac muscle contraction and B₂ smooth muscle relaxation

Question 114

What signaling process do cytokines use?

Answer 114

Cytokines activate the JAK/STAT pathway that is similar to the RTK pathway. Dimerizes STATs go on to alter gene transcription to mount a coordinated immune system response

Note: JAK is NOT an RTK; the tyrosine kinase associates with the receptor, but is not part of it

Question 115

What signaling process do gulcocorticoids use?

Answer 115

Glucocorticoids must cross the cell membrane on their own and activate cytoplasmic receptors.

• Upon binding to glucocorticoid, inhibitory HSP90 dissociates from the receptor
• The receptors dimerize and translocate to the nucleus, where they alter gene transcription, often to inhibit inflammatory responses

Question 116

What kind of signaling would a cell use to prevent a coordinated cytokine response?

Answer 116

Glucocorticoid signaling;

Glucocorticoids cross the cell membrane on their own and bind to their cytoplasmic receptors, then go on to alter gene transcription. The changes in transcription can prevent cytokines from aggregating to mount a coordinated immune response

(This is the equivalent of the police shutting down cell phone service to prevent teenagers from getting together and terrorizing people on Michigan ave)

Question 117

Does ion movement through ion channels affect their intracellular or extracellular concentrations?

Answer 117

NO! Bulk concentrations are not impacted by tiny amounts of ion moving across the membrane.

This movement DOES however, affect membrane potential

Question 118

What is the mechanism of action of _____-setron drugs?

What can they treat?

Answer 118

_____-setron drugs are competitive antagonists of serotonin 5HT-3 receptors

They decrease excitiation to treat nausea and vomiting, especially related to chemotherapy drugs

Question 119

What is the mechanism of action of sleep aids such as eszopiclone (lunesta) or zolpidam (ambien)?

Answer 119

These drugs are positive allosteric modulators of GABA_A. They increase the frequency of Cl- channel opening, thus enhancing the inhibitory response

Question 120

Which drug has the off-target effect of uncompetitive inhibition of GABA_A receptors?​ What are the consequences?

Answer 120

Penicillin; Seizures due to impairment of inhibitory GABA_A Cl- channels

Question 121

What is the mechanism of action of ____-sone drugs? What conditions can they treat?

Answer 121

These drugs are usually corticosteroids that act on glucocorticoid receptors to alter gene transcription. They can be used to treat inflammation related to immune responses

Question 122

Describe desensitization of GPCRs

Answer 122

GPCRs are desensitized within minutes of continuous exposure to the lignd.

GRK phosphorylates the GPCR at the c-terminus, preventing the G-protein from binding to the receptor. This recruits Beta-arrestin to bind to the phosphorylated C-terminus. The receptor is internalized.

If the agonist is removed, Beta-arrestin releases the GPCR and re-sensitization occurs

• If the agonist persists, the GPCR is transported to the lysosome and degrated. Re-sensitization cannot occur

Question 123

What is the role of GRK in GPCR desensitization?

Answer 123

GRK phosphorylates the GPCR at the c-terminus. This prevents the G-protein from binding and recruits beta-arrestin

Question 124

What is the role of beta-arrestin in the action of biased ligands?

Answer 124

Based on the different phosphorylation “barcodes” established by GRKs on G-proteins, different Beta-arrestin conformations can produce different responses

This either increase or decrease beta-arrestin mediated degradation of GPCRs

Question 125

What is a biased ligand?

Answer 125

A ligand that preferrentially activates teh GPCR pathway or the Beta-arrestin pathway

Question 126

What is the role of GRK in the action of biased ligands?

Answer 126

Different GRKs create different phosphorylation patterns (barcodes) at the GPCR c-terminus. This results in differential beta-arrestin activity

Question 127

In what drug is Beta-arrestin evil?

Answer 127

Morphine; the action of beta-arrestin results in rapid desensitization

Question 128

Give an example of a drug that promotes beta-arrestin

Answer 128

Beta-blockers and Angiotensin II; beta-arrestin is cytoprotective

Drug: carvedilol

Question 129

A receptor with a “2” subtype is usually involved in…

Answer 129

Inhibitory activity mediated by G_beta/G_gamma

Ex: smooth muscle relaxation

Question 130

A receptor with a “1” or “3” subtype is usually involved in…

Answer 130

Activation of 2nd messengers mediated by G_alpha

ex: IP3/Ca2+ and smooth muscle contraction

Question 131

Describe GPCR-mediated smooth muscle contraction

Answer 131

The main (water soluble pathway)

GPCR-> PLC-> IP3 -> Ca2+ release, resulting in smooth muscle contraction

This is supplemented by the GPCR -> PLC -> DAG -> PKC pathway that enhances contration

Question 132

What process is initiated when G_alpha activates PLC?

Answer 132

Smooth muscle contraction

Mediated by 2nd messenger synthesis

Question 133

List the 4 receptor types from fastest to slowest desensitization

Answer 133

Ligand-gated ion channels

GPCRs

RTKs and related

Cytoplasmic/nuclear receptors

Question 134

What are the three key determinants of drug movement across cell membranes?

Answer 134

1. The type of membrane
2. The active membrane transporters
3. Physio-chemical properties (size, lipid solubility, acidic/basic)

Question 135

How are ABC and SLC transporters different?

Answer 135

ABC transporters are directly energy dependent, SLC are not

ABC transporters are only active in efflux from cells, SLC are active in uptake and efflux

ABC transporters are pumps, SLC are symporters or antiporters

Question 136

What kind of transporters are implicated in drug resistance?

Answer 136

ABC transporters

MDR1 (P-glycoprotein) and MRP1

Question 137

True or false: “SLC transporters do not depend on ATPase pumps”

Answer 137

False; SLC transporters do not hydrolyze ATP directly, but they do take advantage of concentration gradients created by energy-dependent processes such as ATPases

Question 138

What is the ion-trapping theory?

Answer 138

Drugs that are weakly acidic or basic are absorbed in their uncharged form and “trapped” on one side of the membrane if they are charged.

Differences in pH of stomach, intestine, and interstitial fluid can impact whether a drug is absorbed or trapped

Question 139

Suppose Drug X is a weak base with a pKa of 3.5

Is Drug X more likely to be absorbed in the stomach (pH = 1.4) or the intestine (pH 6.5)? Why?

Answer 139

Drug X is more likely to be absorbed in the intestine

In the stomach, the charged BH+ form will dominante, and the drug will be trapped in the stomach
(~100:1 ratio of charged:uncharged)

In the intestine, the uncharged B form will dominate, allowing the drug to be absorbed
(~1:1000 ratio of charged:uncharged)

Question 140

Suppose Drug Y is weakly acidic, with a pKa of 4.5

Is Drug Y more likely to be absorbed in the stomach (pH = 1.4) or the intestine (pH 6.5)? Why?

Answer 140

Drug Y is more likely to be absorbed in the stomach

In the stomach, the uncharged HA form will dominante, and the drug is able to be absorbed
(~1:1000 ratio of charged:uncharged)

In the intestine, the charged A- form will dominate, trapping the drug
(~100:1) ratio of charged:uncharged

Question 141

What kind of transporters are most active in primary active transport?

Answer 141

ABC transporters

Question 142

What kind of transporters are most active in secondary active transport?

Answer 142

SLC transporters

They may also participate in facilitated diffusion

Question 143

Which (specific) transporters are most active in creating the blood-brain barrier?

Answer 143

ABC; P-glycoprotein

These transporters pump drugs out of the endothelial cells back into the interstitum from whence they came

Question 144

Which route of drug administration results in the slowest and most variable distribution?

Answer 144

Oral

Question 145

Which route of drug administration results in 100% bioavailability?

Answer 145

Intravenous

Question 146

What is the term for the “percentage of unchanged drug that reaches systemic circulation?”

Answer 146

Bioavailability

Question 147

What do two drugs that are pharmaceutical equivalents have in common?

Answer 147

Same active ingredients, dosage, concentration, and route of administration

Question 148

Two drugs that have the same active ingredients, dosage, concentration, and route of administration are…

Answer 148

Pharmaceutical equivalents

Question 149

What do two drugs that are bioequivalents have in common?

Answer 149

Same active ingredients and bioavailability

Question 150

Drugs that have the same active ingredients and bioavailability are…

Answer 150

Bioequivalents

Question 151

What is the relationship of a generic drug to its pharmaceutical parent?

Answer 151

A generic drug is a pharmaceutical equivalent (Same active ingredients, dosage, concentration, and route of administration) of its parent, and it must have 80-125% bioequivalence to its parent

Question 152

Suppose your friend buys the store-brand ibuprofen because it’s $2 cheaper than the name brand. You take the prescribed dose, but you swear it’s not working as well. Your friend tells you to stop being a baby, the drugs are exactly the same. Who is right?

Answer 152

You are! (obviously)

Although generic drugs are pharmaceutical equivalents to their parents and must have the same amount of the active ingredient, they may not be bioequivalents. This means that they may not have the same bioavailability; perhaps less of the generic drug actually reaches the bloodstream

Question 153

What factors may impact the oral absorption of drugs?

Answer 153

FIT-BAD

First-pass metabolism

Interfering substances ingested simultaneously

Transporter activity; is something blocking them? Polymorphism?

Blood flow to GI tract

Age

Destruction by gastric pH (may be exacerbated if gastric emptying is slow due to full stomach)

Question 154

What properties make the blood-brain barrier difficult to cross?

Answer 154

Tight junctions

Non-fenestrated, continuous endothelium

P-Glycoprotein pumps drugs out of the endothelium back into the blood stream (transcellular tranport usually isn’t feasible)

Question 155

What is the apparent volume of distribution (V_D)?

Answer 155

V_D = Total amount of drug administerd/plasma concentration

Question 156

Why are drugs administered intrathecally more likely to cross the blood-brain barrier?

Answer 156

The barrier between the brain and the cerebrospinal fluid is easier to cross than the blood brain barrier.

Epithelial cells lining the brain are leaky, and allow paracellular transport from CSF to brain.

Question 157

Describe the blood-CSF barrier

Answer 157

The epithelial cells of the chorid plexus have tight junctions, but fenestrated capilaries.

Lipid-soluble drugs can penetratete the CSF

From the CSF, drugs and other substances can more easily get to the brain

Question 158

What might cause a large difference in effective concentration and total plasma concentration of a drug?

Answer 158

Binding to plasma proteins;

Binding has no effect on the plasma concentration of the drug, but it lowers the effective (free drug) concentration

Question 159

What is albumin?

Answer 159

Albumin is a plasma protein that binds to weak-base drugs.

Question 160

How might hypoalbuminemia affect one’s response to a weakly-basic drug?

Answer 160

Hypoalbuminemia would increase the free drug concentration relative to what doctors might expect; this may lead to drug overdose or toxicity

Question 161

What is first-pass metabolism?

Answer 161

Metabolism by enzymes in intestinal epithelium or liver following absorption after oral administration

This lowers biovailability of the drug

Question 162

How does albumin affect bioavailability of a drug?

Answer 162

Albumin does not affect bioavailability; it can reduce the effective concentration of the drug once in the bloodstream, but it doesn’t prevent unchanged drug from reaching the bloodstream

Question 163

What is bioavailability?

Answer 163

The fraction of the administered drug that reaches the systemic circulation unchanged

Question 164

In what scenarios does Kd = EC50?

Answer 164

Ligand binding to receptor

(Kd is not equal to EC50 in biological response due to spare receptors)

Question 165

What kind of ligand-gated ion channels allow Cl- into the cell when activated?

Answer 165

GABA/GABA_A Receptor

Glycine/Glycine Receptor

This is associated with an inhibitory response

Question 166

What kind of ligand-gated ion channels allow Ca2+ into the cell when activated?

Answer 166

NMDA receptors for Glutamate

This is associated with an excitatory response

Question 167

What kind of ligand-gated ion channels allow (mostly) Na+ into the cell when activated?

Answer 167

Ach/Nicotinic

Serotonin/5HT-3

ATP/P2X

Question 168

What is the effect of an antagonist to the GABA_A Receptor?

Answer 168

Seizures/convulsion

Question 169

Epinephrine is a non-selective adrenergic agonist, however many of the receptors do very different things when activated.

How is it possible for an agent that acts so differently on different receptors result in a coordinated “fight or flight” response?

Answer 169

Receptor localization!

Not all tissues have the same receptors

For example: Beta 1 receptors in the heart, Beta 2 receptors in the airways arteries supplying skeletal muscle, and Alpha 1 receptors in arteries supplying the gut.

When you’re running away from the bear, your cardiac output increases (Beta 1), you get more oxygen into your lungs and skeletal muscles (Beta 2), and you’re not wasting any blood trying to digest food (Alpha 1)

Question 170

Why are SNARE proteins important in the somatic and autonomic nervous systems?

Answer 170

SNARE protiens prime secretory vesicles in the nerve ending that contain ACh.

They have Ca2+ sensors (synaptotagmins) that allow them to respond to the increased intracellular Ca2+ that results from an action potential.

When Ca2+ binds to the synaptotagmin, the ACh-containing vesicle fuses with the plasma membrane and releases ACh into the synpatic cleft

Question 171

What kind of receptors are found at the motor end plate of the somatic nervous system?

Answer 171

Nicotinic cholinergic receptors; these are fast ligand-gated, nonspecific cation channels

(although Na+ si the ion that flows in due to its nernst potential)

Question 172

How is an end-plate potential generated?

Answer 172

1. Action potential propagates down neuron
2. The AP opens Ca2+ channels in the nerve ending
3. Ca2+ enters the cell and binds to synaptotagmins
4. The SNARE-primed vesicle fuses with the plasma membrane
5. The vesicle releases ACh into the synaptic cleft
6. ACh binds to its nicotinic receptors on the motor end plate
7. The non-selective cation channel associated with the receptor opens
8. Na+ flows into the muscle cell and triggers an end-plate potential (EPP)
9. The EPP triggers a muscle action potential that propagates along the muscle fibers
10. The signal is terminated by AChE

Question 173

Name an agent that interferes with the conduction of action potentials into nerve terminals

Answer 173

Tetrodotoxin (TTX) blocks voltage-gated Na+ channels, preventing action potential initiation and propagation

• This acts on nerve and muscle

Question 174

Name 2 agents that prevent Ca2+ influx into the nerve ending

Answer 174

Mg2+ and other polyvalent cations compete with Ca2+

Aminoglycoside antibiotics block voltage-gated Ca2+ channels

Both prevent ACh release

Question 175

Name an agent that interferes with SNARE proteins

Answer 175

Botulinum Toxins; Botox A cleaves SNARE SNAP-25 and prevents the ACh-containing vesicle in the nerve terminal from becoming fusion-competent, thus preventing ACh release

Question 176

Name 3 agents that prevent ACh release from the nerve ending

Answer 176

Polyvalent cations, aminoglycoside antibiotics, botulinum toxins

Question 177

Name 3 pharmachologic agents that act as nicotinic receptor blockers

Answer 177

Tubucurarine (non-depolarizing)

-curonium drugs (non-depolarizing)

Succinylcholine (depolarizing)

Question 178

Name a disease that interferes with nicotinic receptor blockers

Answer 178

Myasthenia Gravis - antibodies destroy the nicotinic receptors

Question 179

Name an agent that reversibly inhibits Acetylcholinesterase

Answer 179

Neostigmine; used to enhance nicotinic receptor signaling

Treats Myasthenia Gravis and speeds recovery from non-depolarizing blockers during surgery

Question 180

All receptors at motor end plates of sympathetic neurons are…

Answer 180

Alpha- or Beta- andrenergic GPCRs that respond to norepinephrine or epinephrine

Question 181

All receptors at motor end plates of the parasympathetic nervous system are…

Answer 181

Muscarinic cholinergic GPCRs

Question 182

The action of which receptors slows heart rate?

Answer 182

Parasympathetic: muscarinic receptors that activate the membrane-delimited G-beta/G-gamma motif

Question 183

How does vagal stimulation affect heart rate?

Describe the pathway

Answer 183

Vagal (parasympathetic) stiumlation results in decreased heart rate

1. ACh binds to its muscarinic receptor
2. G-Beta/G-Gamma subunits activated
3. G-Beta/G-Gamma activates K+ channesl
4. K+ flows in and hyperpolarizes the membrane, thus inhibiting contraction

This happens in milliseconds

Question 184

How does vagal stimulation affect airway?

Describe the pathway

Answer 184

Vagal (parasympathetic) stimulation constricts the airways

1. ACh binds to its muscarinic receptor
2. G-Alpha is activated
3. G-Alpha stimulates Phospholipase C (PLC)
4. PLC induces PIP2 to turn into IP3 (the water-soluble smooth muscle contraction motif)
5. IP3 induces Ca2+ release from the ER
6. Increased smooth muscle contraction = airway constriction

No phosphorylation is required; this happens in seconds

Question 185

What is the effect of sympathetic stimulation on the heart?

Describe the pathway

Answer 185

Sympathetic stimulation increases heart contractions

1. Norepinephrine/epinephrine binds to its Beta-1 receptor in the heart (Beta 1 = #1 in our hearts)
2. G-Alpha is activated
3. G-Alpha activates Adenylyl Cyclase
4. Adenylyl Cyclase produces cAMP
5. cAMP activates Protein Kinase A
6. Lots of downstream phosphorylation
7. Cardiac stiumulation and increased contractile force

This happens in minutes (cAMP/PKA pathway is slowest)

Question 186

What is the effect of sympathetic stimulation on blood vessel radius in the GI system?

Describe the pathway

Answer 186

Sympathetic stimulation of smooth muscle in the arterioles of the GI system is mediated by Alpha-1 receptors, and results in vasoconstriction

1. Norepinephrine/epinephrine binds to its Alpha-1 receptor
2. G-Alpha is activated
3. G-Alpha activates PLC
4. PLC induces PIP2 to turn into IP3
5. IP3 induces Ca2+ release from the ER

6. Smooth muscle contraction = vasoconstriction in the arterioles of the GI system (we don’t need to digest when we’re fighting for our lives)

This happens in seconds

Question 187

What is the effect of sympathetic stimulation on our airways?

Describe the pathway

Answer 187

Sympathetic stimulation in the pulmonary system results in activation of Beta-2 receptors -> dilation of the airway and the arterioles supplying the airway.

1. Epinephrine binds to its receptors on bronchioles and arterioles
2. G-Alpha is activated
3. G-Alpha activates Adenylyl cyclase
4. Adenylyl cyclase increases cAMP
5. cAMP activates PKA
6. PKA phosphorylates many things
7. Smooth muscle relaxation: bronchio- and vaso-dilation in the pulmonary system

(Beta2 = we have 2 lungs)

Question 188

Why does epinephrine affect the heart and lungs differently?

Answer 188

cAMP has different effects on cardiac and smooth muscle

In cardiac muscle, cAMP augments Ca2+ entry and storage in the cell, resulting in more forceful contractions

In smooth muscle, cAMP decreases intracellular calcium

Question 189

What is the effect of a Beta 2 agonist?

Answer 189

Dilation of the airways and arteriole in the pulmonary system

Question 190

What is the effect propanolol on the cardiopulmonary system?

Answer 190

Propanolol = a nonselective beta blocker

Beta 1: Decreased contractility of the heart

Beta 2: Decreased dilation of the bronchiole and arterioles of the pulmonary system (it constricts the airways)

Question 191

What would you prescribe to increase heart rate?

Answer 191

Epinephrine (promotes contractility via Beta-1 agonism)

Atropine (inhibits decreased contractility via muscarinic antagonism)

Question 192

Which of the following is under sympathetic control only?

A. The heart

B. The blood vessels

C. The lungs

Answer 192

B: The blood vessles

This is why sympathetic tone is super important for blood pressure!

Question 193

What is the relationship between total peripheral resistance (TPR) and blood vessel diameter?

Answer 193

TPR is proportional to (1/r⁴)

This means that:

• Small increases in the radius result in a large drop in TPR (decreased BP)
• Small decreases in the radius result in a large increase in TPR (increased BP)

Question 194

What is the relationship between TPR and blood pressure?

Answer 194

BP = CO * TPR

TPR = total peripheral resistance

BP = blood pressure

CO = cardiac output

Question 195

What is the role of the adrenal medula in sympathetic signaling?

Answer 195

The adrenal medula is basically a post-synaptic ganglion.

The presynaptic sympathetic neuron releases ACh to adrenal chromaffin cells.

This triggers systemic release of epinephrine (80%) and norepinephrine (20%)

The result is global amplification of the fight or flight response

Question 196

Order the following from fastest to slowest
A) cAMP/PKA pathway

B) PLC/IP3 pathway

C) Ligand-gated ion channel

D) Muscarinic K+ opening

Answer 196

1. Fastest: C) ligand-gated ion channel
2. D) Muscarinic K+ opening
3. B) PLC/IP3
4. A) cAMP/PKA

Question 197

Which (general) pathway is activated in the “smooth muscle contraction motif?”

Answer 197

PLC/IP3

Question 198

Which (general) pathway is activated in both cardiac stimulation and smooth muscle relaxation via Beta-adrenergic receptors?

Answer 198

cAMP/PKA

Question 199

A drug that is an alpha-1 agonist acts via which mechanism?

Answer 199

Alpha-1 agonists stimulate the PLC/IP3 pathway

Question 200

What is the mechanism of action of Botox A?

Answer 200

Botox A cleaves SNARE SNAP-25, preventing the priming of ACh release machinery. The ACh-containing vesicle cannot fuse with the plasma membrane, and therefore cannot release its contents into the synaptic cleft.

The result is ihibition of muscle contraction

Question 201

What is the result of a competitive inhibitor of ACh at a muscarinic GPCR?

Answer 201

Increased heart rate if interfereing with G-Beta/G-Gamma

Opening of the airways if interfering with G-Alpha/PLC/IP3

Question 202

Which drugs promote airway opening? By which mechaism?

Answer 202

• erols: sympathetic Beta-2 agonists
• tropiums: parasympathetic G-Alpha/PLC/IP3 vasoconstriction antagonists

Question 203

What are 2 receptors that act via a phosphorylation pathway?

Answer 203

Beta-1 and Beta-2: Both activate the G-Alpha/cAMP/PKA pathway

Question 204

What are 2 receptors that act via a G-alpha pathway that does not involve phosphorylation?

Answer 204

Alpha-1 (constricts smooth muscle)

Muscarinic G-alpha (constricts airways)

Question 205

Which autonomic signaling receptors are found in the heart?

Answer 205

Sympathetic: Beta-1 -> increased contraction

Parasympathetic: Muscarinic G-Beta/G-Gamma (membrane delimited) -> Decreased contraction

Question 206

Which autonomic signaling receptors are found in blood vessels?

Answer 206

Sympathetic: Alpha-1 -> constriction (in GI tract, kindeys)

Sympathetic: Beta-2 -> Dilation (Arterioles of the pulmonary system)

No parasympathetic control

Question 207

Which autonomic signaling receptors are found in the pulmonary system?

Answer 207

Sympathetic: Beta-2 -> dilation of bronchioles

Parasympathetic: Muscarinic G-Alpha (PLC/IP3) -> constriction of broncioles

Question 208

Which ligand activates inhibitory ligand-gated receptor channels and GPCRs?

Answer 208

GABA

Question 209

What is the effect of inhibiting the Na/K ATPase?

Answer 209

Depolarization of the cell membrane

The leak force of K+ will be attenuated, resulting in more positive charge on the inside of the membrane

Question 210

What is the difference between L-type and T-type Ca2+ channels?

Answer 210

L-type = Large Long Lasting current; Important for excitation-contration coupling in muscle and heart, cardiac potential plateau, smooth muscle contraction

T-type = Tiny Transient current; low-voltage activated. Involved in pacemaker activity of cardiac and neuronal cells

Question 211

What are some processes that T-type Ca2+ channels are involved in?

Answer 211

Involved in pacemaker activity of cardiac and neuronal cells.

(Tiny Transient Current; Low-voltage activated)

Question 212

What are some processes that L-type Ca2+ channels are involved in?

Answer 212

Excitation-contration coupling in muscle and heart, cardiac potential plateau, smooth muscle contraction

(L-type = Large Long Lasting current; high-voltage activated)