Lecture 4

Question 1

Second messengers are __________ that relay signals received by cell-surface receptors to effector proteins

Answer 1

small molecules and ions

Question 2

what is cAMP?

Answer 2

cAMP is 2nd messenger - released into cytoplasm due to 1st messenger (hormone) binding; a number of others in eukaryotic cells
2nd messengers can activate many cell activities leading to large-scale, coordinated response

Question 3

Activation of Gs and stimulation of the effector

Answer 3

Adenylyl Cyclase (AC)

Question 4

Binding of cAMP to _________releases the cat regions which can phosphorylate proteins

Answer 4

Regulatory sites

Question 5

Cellular Response for Psubstrate

Can include any of these:

Answer 5

• Enzyme activation
  
  • Protein synthesis
  • Muscle contraction / relaxation
  • Nerve stimulation
  • Hormone secretion

Question 6

know this slide

Answer 6

Question 7

Theophylline

Answer 7

its an inhibitor

*Act as competitive inhibitors of
phosphodiesterases

Question 8

What would you expect the effect of
theophylline on cAMP levels to be?
How about on cAMP kinase?

Answer 8

increasing

Question 9

In Liver

Answer 9

activates Phosphorylase Kinase
inactive Glycogen Synthase

Question 10

Ca++ (Calcium) and Phosphoinositides

Answer 10

Another well-studied 2nd messenger system involves receptor-mediated stimulation of phosphoinositide hydrolysis.

Question 11

(Gq-coupled)

Answer 11

Some of the agonists, hormones and growth factors that trigger this pathway bind to G-protein coupled receptors

Question 12

2nd messenger

Ca++
&
phosphoinositides

Answer 12

Receptor

acetylcholine (muscarinic)

alpha1-adrenergic

platelet activating factor

serotonin (5-HT 1C and 5-HT 2)

Question 13

_____ family that produces two second messengers, diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) by hydrolyzing the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2).

Answer 13

Question 14

IP3 goes to ER where it stimulates

Answer 14

release of calcium

Question 15

Released Ca++ binds to

Answer 15

calmodulin

Question 16

Calmodulin becomes activated and stimulates signaling through

Answer 16

calcium/ calmodulin dependent protein kinases

Question 17

DAG stays in membrane where it

Answer 17

binds and activates protein kinase C (PKC)

Question 18

Activated PKC will do what

Answer 18

will phosphorylate certain substrates involved in cellular response

Question 19

Different cell types may contain one or more __________ Calcium/calmodulin-dependent protein kinases with limited substrate specificity

Answer 19

specialized

(eg. myosin light chain kinase)

Question 20

how many different types of pkc have been characterized?

Answer 20

9

Question 21

Multiple mechanisms exist to terminate signaling by this PLC pathway:

Answer 21

IP3 is rapidly dephosphorylated by phosphatases

DAG is either 
	phosphorylated and converted back to 			phospholipids
or
	deacylated to yield arachidonic acid

Ca++ is actively removed from the cytoplasm by calcium ion 	pumps (into ER)

*These and other nonreceptor elements of the calcium-phosphoinositide signaling pathway are now becoming targets for drug development.

Question 22

cGMP (cyclic guanosine-3’,5’-monophosphate) has established signaling roles

Answer 22

in only a few cell types

Question 23

In intestinal mucosa and vascular smooth muscle, cGMP-based signal transduction is initiated when:

Answer 23

*ligand binds to extracellular domain of receptor
*ligand binding stimulates intracellular guanylyl cyclase activity
*cGMP activates cGMP-dependent protein kinases

Question 24

The lipid-soluble gas nitric oxide (NO) is released by nearby
vascular endothelial cells does what?

Answer 24

activates the enzyme

Question 25

Reversible phosphorylation is involved in almost all

Answer 25

2nd messenger systems

Question 26

Phosphorylation plays a key role in every step of signaling:

Answer 26

-Regulation of receptors (eg. autophosphoryltion; desensitization) -Regulation of kinases and kinase-substrates modulating cellular responses

Question 27

Think of phosphorylation as a molecular ‘memory’

Answer 27

phosphorylation records the memory

Question 28

dephosphorylation does what?

Answer 28

erases the memory, often taking longer than is required for dissociation of ligand

Question 29

cAMP, Ca++ and other 2nd messengers can use the presence or absence of kinases or kinase substrates to produce

Answer 29

different effects in different cell types

Question 30

Acetylcholine

Answer 30

activates nicotinic acetylcholine receptors *Ligand-gated ion channel activates muscarinic acetylcholine receptors *G-protein coupled receptor (Gq)

Question 31

Norepinephrine

Answer 31

GPCR

Question 32

Drug selectivity may apply to structurally identical receptors

Answer 32

expressed in different cells

Question 33

the drug tamoxifen acts as an

Answer 33

*antagonist on estrogen receptors in mammary tissue (useful as treatment in breast cancer) *agonist on estrogen receptors in bone. (may help against osteoporosis) *partial agonist on estrogen receptors in the uterus (stimulates endometrial cell proliferation)

Question 34

Graded Dose-Response Curves

Answer 34

show effects on a continuous scale and the intensity of the effect is proportional to the dose

Question 35

When choosing among drugs and determining appropriate doses of drug, it is important to consider each drug’s what?

Answer 35

potency and maximal efficacy

Question 36

what is potency?

Answer 36

refers to the concentration EC50 or dose ED50 of drug required to produce 50% of that particular drug’s maximal effect. *lower the drug dose the more potent it is

Question 37

what is efficacy?

Answer 37

the measure of an effect produced by a drug *C in the example is the partial agonist

Question 38

T/F: potency does not mean efficacy

Answer 38

true

Question 39

Graded dose-reponse curves are limited in their application to clinical decision making

Answer 39

* impossible to use them if pharmacologic response is an ‘either-or’ event (a quantal event) prevention of: convulsions, arrhythmias, death *clinical relevance of a graded dose-response curve in a single patient may be limited in its application to other patients potential variability among patients in *severity of disease *responsiveness to drug

Question 40

Quantal Dose-Effect Curves These problems may be avoided by

Answer 40

determining the dose of drug required to produce an effect of specific magnitude in large numbers of patients (or animals) and then plotting the cumulative frequency distribution of responders vs. the log dose Patients tend to respond to drugs in a distribution similar to a Gaussian normal curve.

Question 41

Quantal dose-effect curves may also be used to generate information regarding the

Answer 41

margin of safety

Question 42

potentially toxic effects of drugs display a distribution similar

Answer 42

to a Gaussian normal curve in people or animals.

Question 43

In order for a drug to have a high margin of safety in patients or animals

Answer 43

therapeutic effects should be observed at lower doses than toxic effects.

Question 44

know this slide

Answer 44

Question 45

know this slide

Answer 45

Question 46

know this slide

Answer 46

Question 47

T/F: No overlap in the quantal dose-response curve is highly desired

Answer 47

True (to avoid unwanted toxic effects), but not always possible)

Question 48

The therapeutic index is defined as the ratio of

Answer 48

TD50 ------- ED50

Question 49

What can be said of a drug’s safety if this ratio is equal or close to 1?

Answer 49

it is highly toxic

Question 50

T/F: The therapeutic index (TI) of a drug in humans is almost known

Answer 50

False It is never know

Question 51

T/F: Both graded and quantal dose-effect curves provide information concerning the potency and selectivity of drugs.

Answer 51

True

Question 52

The graded dose-response curve indicates

Answer 52

the maximal efficacy of a drug

Question 53

The quantal dose-effect curve indicates

Answer 53

the potential variability of responsiveness among patients.

Question 54

idiosyncratic

Answer 54

an unusual response very rarely observed in most patients (very few patients)

Question 55

hypo-responsive

Answer 55

drug effect is smaller than expected (will need higher dose of the drug)

Question 56

hyper-responsive

Answer 56

drug effect is larger than expected (lower dose)

Question 57

tolerance

Answer 57

responsiveness decreases as a consequence of continued drug administration

Question 58

tachyphylaxis

Answer 58

responsiveness diminishes rapidly after administration of the drug

Question 59

Clinical Selectivity: Beneficial vs. Toxic Effects of Drugs

Answer 59

No drug causes only a single, specific effect. Diversity of receptors Diversity of biochemical processes Diversity of cell types, tissue types, organs Drugs are selective but not specific

Question 60

Beneficial and toxic effects mediated by the ______ receptor-effector mechanism

Answer 60

same

Question 61

prazosin

Answer 61

an alpha1-adrenergic receptor antagonist acts on receptors in vascular smooth muscle to reduce blood pressure as a consequence, patients may suffer postural hypotension when standing (sudden drop in BP when standing

Question 62

Many drugs produce their desired effects and toxic effects by acting at the

Answer 62

same receptor

Question 63

digitalis glycosides (inhibit Na+/K+ ATPase)

Answer 63

increases cardiac contractility BUT also cardiac arrhythmias, g.i. effects, vision

Question 64

methotrexate

Answer 64

inhibition of dihydrofolate reductase death of tumor cells BUT also, death of healthy cells

Question 65

Beneficial and toxic effects mediated by identical receptors but in

Answer 65

different tissues or by different effector pathways

Question 66

drug should ALWAYS be administered at the

Answer 66

lowest dose that produces acceptable benefit

Question 67

adjunctive drugs that act through different receptor mechanisms may allow lowering the dose of the first drug doing what?

Answer 67

decreasing its toxicity