Receptors: Binding to Response

Question 1

Two properties of a receptor

Answer 1

Recognition and Transduction

Question 2

Recognition

Answer 2

binds ligands reversibly with high affinity and specificity

Question 3

Transduction

Answer 3

structural-dependent conversion of this binding into a cellular response, reflected in “activity” or “efficacy”
with in cell mechanism to propagate signal -> response

Question 4

Receptor location

Answer 4

usually located in membrane communicates between outside and inside of cell; allows specific binding that turns into specific response

Question 5

receptor binds

Answer 5

and responds to that binding -> cell response -> organ response -> binding response

Question 6

Receptor vs enzyme

Answer 6

both bind with specificity but enzyme only convert substrate to product, this is not reversible except at binding site; receptors bind reversibility but aren’t converted, receptors leads to response

Question 7

ligand

Answer 7

the thing binding to the receptor

Question 8

3 criteria for receptor binding interaction

Answer 8

1. Specificity
2. Saturability
3. Reversibility

Question 9

Specificity

Answer 9

ligand should be structurally complimentary to receptor, producing a structurally specific and high affinity interaction

Question 10

Saturabilty

Answer 10

finite number of receptors per cell should be present as revealed by saturable binding curve (only certain number of sites for ligand)

Question 11

reversibility

Answer 11

after binding to receptor the ligand must dissociate in an unchanged form; concentration of drug decreases drug can dissociate and receptor can relax until next round

Question 12

slower the rate the ___ the Kd

Answer 12

slower the rate the smaller the Kd and larger the on rate

Question 13

If [L]= 0

Answer 13

not bound increase this to infinity; [RL] = tot # of receptors

Question 14

Kd is when

Answer 14

1/2 of receptors are occupied

Question 15

low Kd

Answer 15

high affinity

Question 16

high Kd

Answer 16

low affinity

Question 17

Saturation Isotherm Direct Plot

Answer 17

Concentration of bound ligand plotted as a function of concentration of free ligand producing rectangular hyperbola; Maximum binding approached asymptomatically as ligand concentration increases and is equal to concentration of receptors [R1]; concentration free ligand at which 50% binding sites occupied equal to Kd

Question 18

Saturation Isotherm: Log Plot

Answer 18

concentration of bound ligand plotted as function of logarithm of free ligand concentration; this gives you a nice curve

Question 19

Inhibition of Binding

Answer 19

competitive inhibition; ligands that bind to receptor at same site will inhibit each other’s binding competitively; if 1 is binding other can’t but this is reversible just increase concentration of one in the presence of other and get to saturation and compete out the other one

Question 20

effect of competitive inhibition

Answer 20

decrease apparent affinity of measured ligand (L1) but have no effect on maximum binding of saturation ([Rt]); in presence of competitive inhibitor (L2) the apparent dissociation constant of the measured ligand (L1) increases (bc high Kd low affinity); magnitude or response directly proportional to amount of ligand bound; assumes Ed50= Kd

Question 21

Kd’

Answer 21

apparent Kd this is what changes not actual Kd when there is presence of competitive inhibitor, this leads to a shift R; the Kd as in the property of the thing itself does not change

Question 22

Binding to Response: Classical Theory

Answer 22

It was thought that response was directly related to agonist occupation of receptor but this is not the case for a lot of systems where things similar in structure to RA not enough to make response bc structural dependence to binding that can lead to conformational change in receptor that leads to response

Question 23

Competitive inhibitor binding

Answer 23

can have competitive inhibitor that binds and doesn’t lead to conformational change but blocks to things that would

Question 24

Classical Theory EC50

Answer 24

EC50 (concentration of agonist that produces 50% of maximum response) is = to KDapp (concentration of agonist at which 50% of receptors are occupied)

Question 25

Classical theory true for

Answer 25

activated receptor (response and binding follow) but if you go downstream of this will cause depolarization and will curve at lower concentration

Question 26

Binding to Response: Modified classical theory

Answer 26

Response can occur at much lower concentrations than binding and apparent affinity for response can be much higher than for binding b/c of amplification fo signal that produces “spare receptors” (ie there are more receptors than we need to produce max response bc if you knock out receptors you still get max response); cell amplifies stimulus so get response in cell that is shifted L so can get max response with less than 100% of receptors occupied

Question 27

EC50 modified classical theory

Answer 27

EC50 < Kd app for binding

Question 28

Partial agonists

Answer 28

an agonist that produces less than a maximal response when occupying all of the receptors

Question 29

agonist vs antagonist

Answer 29

agonist activates receptors antagonists don’t activate receptors

Question 30

full agonist

Answer 30

An agonist that produces a maximal response by occupying all or a fraction of the receptors

Question 31

lower EC50 =

Answer 31

greater potency (lower [ ] where it has its effect = higher potency)

Question 32

higher maximum response

Answer 32

higher efficacy

Question 33

potency

Answer 33

binding interacting > binding affinity = more potent

Question 34

efficacy

Answer 34

reflects conversion to activate state

Question 35

efficacy of antagonist

Answer 35

is 0 because no conversion to active state, BUT this does have potency

Question 36

Competitive antagonists

Answer 36

Ligands that bind to the receptor at same site as agonists but do not cause activation of receptor; effect of competitive antagonist is analogous to that of competitive inhibitor of binding; apparent affinity is decrease (EC50 increases; potency decrease), but no effect on maximum response (efficacy unchanged)

Question 37

EC50

Answer 37

concentration of agonist that produces 50% of maximum response

Question 38

antagonist in modified classical receptor theory

Answer 38

antagonist has efficacy of zero and thus produces no stimulus

Question 39

to compete out antagonists

Answer 39

increase agonist concentration

Question 40

competitive inhibitors are about what happens at

Answer 40

binding site so agonists and competitive antagonists are competitive inhibitors of each other

Question 41

all competitive antagonists =

Answer 41

competitive inhibitors

Question 42

not all competitive inhibitors are

Answer 42

competitive antagonists because agonists are competitive inhibitors of competitive antagonists but agonists lead to a response

Question 43

inhibition at level of

Answer 43

binding

Question 44

antagonist at level of

Answer 44

response

Question 45

Noncompetitive antagonists

Answer 45

ligands that bind to receptor at a different site from agonists and prevent activation are noncompetitive antagonists (this = allosteric antagonist); this doesn’t keep agonist from binding but it does keep responses from happening; this doesn’t affect EC50 but does affect max response

Question 46

Competitive antagonist vs noncompetitive antagonist EC50

Answer 46

competitive antagonist: EC50 increases, potency decreases, no response on maximum response (efficacy unchanged) noncompetitive antagonist (EC50 and potency not affected, but does affect max response)

Question 47

Response to response

Answer 47

desensitization, down regulation, upregulation

Question 48

desensitization

Answer 48

essentially every receptor system response to prolonged activation by “slowly” desensitizing or inactivating; receptor systems the cell will want to protect itself from getting worn out so as ligand binds it excites receptor system and system form cell turns itself off so even though ligand binding to neurotransmitter cell not responding

Question 49

5 mechanisms by which cells “turn-off” their response to signals

Answer 49

Receptor sequestration, Receptor down-regulation, receptor inactivation, inactivation of signaling protein, production of inhibitory protein

Question 50

Receptor sequesteration

Answer 50

remove receptor from cell membrane store it and put it in after drug gone for a while; prolonged response (these are what leads to drug tolerance)

Question 51

receptor down regulation

Answer 51

remove receptor from cell and break it down; prolonged response (these are what leads to drug tolerance)

Question 52

receptor inactivation

Answer 52

desensitization; receptor changes conformation to inactive state

Question 53

production of inhibitory protein

Answer 53

in signal transduction system 2nd molecule made to feed back to receptor and turn it off; can turn receptor back on after ligand removed and can reset it

Question 54

desensitization/ inactivation examples

Answer 54

1. most ligand-gated ion channels close in prolonged presence of an agonist
2. Voltage-gated ion channels close w prolonged depolarizatoin
3. Many G- Protein coupled receptors are phosphorylated to inactive form by protein kinase A and bind arresting after phosphorylation by specific protein kinase

Question 55

Down-regulation

Answer 55

G protein coupled beta-adrenergic receptors are endocytose after phosphorylation by specific protein kinase and binding of protein arrestin

Question 56

B receptors over exposed to agonists

Answer 56

down regulate, if you take agonist away get response back; if keep stimulating will loose b receptors on cell membrane and it will take days to resynth b receptors and get back full response

Question 57

chronic use of antagonists

Answer 57

if cell is under stimulated will upregulate its receptors (increase number of receptors expressed) so if you remove the antagonist expect a rebound effect b/c hypersensitive to increased number of receptors

Question 58

partial agonists cardiac conditions

Answer 58

use instead of antagonists in treating cardiac conditions because avoids up regulation of receptors and hypersensitivity if remove antagonist

Question 59

agonist

Answer 59

ligand that activates the receptor to cause a physiological response

Question 60

spare receptors

Answer 60

refers to an observation of maximal response when only a fraction of total number of receptors are occupied

Question 61

antagonist

Answer 61

ligands that does not activate the receptor and interferes with the response produced by an agonist (can be competitive or non competitive antagonist)

Question 62

inhibitor

Answer 62

A ligand that prevents the binding of another ligand to the receptor

Question 63

ED50 or EC50

Answer 63

Dose or Concentration of an agonist that produces half-maximal Effect or response

Question 64

ID50

Answer 64

Dose of an antagonist that produces a half-maximal Inhibition

Question 65

IC50

Answer 65

The Concentration of antagonist or inhibitor that produces half maximal Inhibition