Exam III Study Guide Flashcards
Make sure you know the answers to all learning objectives
.
describe how cell-cell communication works for endocrine signaling
give examples
endocrine cells release hormones (aka ligands) into bloodstream which diffuse into tissues and bind to receptors on target cells. It is described as “distant” signaling via the bloodstream
steroid hormones, and insulin work by this signaling
describe how cell-cell communication works for paracrine signaling
give examples
locally acting signals released from signaling cells to bind to receptors on target cells
histamine and neurotransmitters work by this signaling
describe how cell-cell communication works for juxtacrine (contact-dependent) signaling
give examples
ligand effect via direct interaction between cells. referred to as cell to cell signaling or cell to substrate signaling
integrin signaling
describe how cell-cell communication works for autocrine signaling
give examples
when a cell produces a hormone to bind to the target receptor on itself to cause changes in the cell
growth factors
describe how cell-cell communication works for gap junctions and plasmodesmata signaling
give examples
direct cell to cell transfer via a “portal” for molecules to pass through
2nd messengers
what is the receptor theory of drug action?
A. drugs do not create effects
B. agents cannot act unless bound to a receptor
C. no drug has a single action
D. intensity of response is typically proportional to concentration of free drug
cells only respond to chemical signals if there is a selective receptor present. different cells respond differently to the same activator depending on the nature of the cell. For example, describe how acetylcholine effects heart muscle cell vs. salivary gland cell vs. skeletal muscle cell
Acetylcholine when binding to heart muscle cell slows the heart down and decreases force of contraction
when binding to salivary gland cell it causes a different effect and secretes saliva
when binding to skeletal muscle cell it causes it to contract
define a ligand
(usually) small molecule that interacts with/binds to a receptor
define an agonist
a ligand that activates a receptor
define an antagonist
binds to a receptor to block signaling
most receptors are:
a. proteins
b. amino acids
c. secondary messengers
d. enzymes
a
what do receptors do to activate amplifiers or effectors?
change shape
Describe the step process of signal transduction
- ligand (primary messenger) binds to receptor
- signal transduction via second messengers occurs
- Seconds messengers cause cellular responses
- Changes in gene expression occur
define amplifier
what are examples of amplifiers?
alters levels of 2nd messenger small molecules which causes cellular responses
Ca++, cyclic AMP, cyclic GMP, IP3
What do 2nd messengers do?
activate effector enzymes to cause signaling
what do effectors do?
initiate signaling cascades to stimulate cellular responses
T/F the response elicited by a drug is independent of the tendency of a drug to bind to a particular receptor
False, they are closely related
a characteristic of drug and receptor binding is that it is saturable, define what this means
drugs must act through specific sites which are limited
a characteristic of drug and receptor binding is that it is reversible, define what this means
receptors are not enzymes, drugs are unchanged by binding to them which means the reaction can go both ways
the ability of a drug to bind to a receptor is dependent on the receptors ____. where specific actions require _____ ____ interactions
affinity
high affinity
what does it mean to say receptors are stereoselective? Why would they be stereoselective?
The R form of drug may bind whereas the L form may not, or vice versa. This is a consequence of high affinity interactions
what is KD? what is it proportional to?
the smaller this value is, means?
equilibrium dissociation constant
koff/kon
more occupied receptors
At equilibrium, demonstrate the proportional concentrations between drug and receptors
[D] + [Rtot] <=> [DR]
T/F the rate at which a drug binds to the receptor is independent of the rate at which it leaves the receptor
True
Define Bmax
how do you determine Bmax on a graph ?
it is the maximum number of bound receptors that is possible, even with an infinite amount of drug. It is determined by when the line becomes flat regardless of drug concentration
how do you determine 50% Bmax on a graph? what is it equal to?
50% Bmax is half of the Bmax, so if Bmax ends at 200, the 50% Bmax will be 100.
50% Bmax is also equal to the dissociation constant (KD)
How is KD related to covid and cannibus?
we can determine how much CBDA or CBGA binds to the spike protein on the virus by measuring the KD. If KD decreases, we can determine that CBDA is binding to the spike protein and thus preventing it from binding to our cells
T/F if a binding site is a verified receptor, then Bmax=Rtot in the system
True
T/F the Bmax value is a measure of the total number of saturable, specific, binding sites in a system
True
[DR]/[Rtot] = [D]/[D]+KD
.
when [DR]/[Rtot]=1/2 then…
KD=[D]
define what the KD value is
the concentration of drug required for 1/2 of all receptors to be in a bound state
KD is a measure of the ___ of a receptor for a drug
affinity
KD is dependent only upon how well the drug ___ the receptor and the receptors ____ then to continue to bind the drug
fits
tendency
KD value is _____ proportional to affinity
inversely
the higher the affinity of a receptor for a drug, the lower the? thus, only a low concentration of a high affinity drug is needed to?
KD value
occupy 1/2 of the receptors
what are the different methods to determine KD? (multiple answers)
a. Mass light spectrometry
b. Isothermal titration calorimetry
c. fluorescence energy resonance transfer
d. plasma ion radiation dating
e. surface plasmon resonance
f. affinity chromatography
g. radioactive isotope binding
h. equilibrium dialysis with radiolabeling or LC-MS/MS
b,c,e,f,h
How do you determine KD using equilibrium dialysis?
you compare the difference of ligands between two divided liquids which will cross to reach equilibrium. when you add receptors to one side of the solution, you will see that free drug will still be at equilibrium at both sides, but more drug will be on the side with receptors due to receptors binding to drug. Thus drug concentration will be higher with receptors present
Know: same ligand can bind to diff receptors at different parts of the body, different tissues express different affinity for ligand meaning some tissues receptors might bind drug more than others
.
T/F comparisons of KD values in different tissues provide evidence for the existence of similar or different receptors in those tissues
True
T/F binding experiments determine if a drug binding to a receptor creates an effect
False, it cannot determine
on a dose response curve, what does ED50 mean?
effective dose to elicit 50% of a response, (similar to 50% Bmax)
define the occupancy theory
response is directly proportional to the number of drug-receptor complexes formed
… 100% occupancy = 100% response
50% occupancy = 50% response
define intrinsic activity
the capacity of a drug to activate transduction after binding to its receptor
define efficacy of a receptor
capacity of a population of receptors to elicit a maximal response when fully bound by an agonist
define potency
a comparison of the doses of several drugs required to cause a specific effect
potency is inversely proportional to?
for example, if drug A had a higher ED50 than drug B, would it be more ore less potent?
ED50 value
Drug A would be more potent
If drug A has a response that is greater at both high and low concentrations compared to drug B, what does this say about drug A’s efficacy?
Drug A is more efficacious
potency versus efficacy:
response compared to drug concentration?
potency means the drug is eliciting larger effects at a lower drug concentration level
a more efficacious drug means the drug produced an overall higher max response
If you have three drugs (A,B,C) and there ranking looks like this:
KD(A)
if they are the same it means drug is binding to the same receptors and thus the effect from the drug is likely due to these receptors
define a partial agonist
what is the efficacy?
ligand/drug that fails to cause a maximal response even when all receptors are bound
efficacy is less than 1
define a full agonist
what is the efficacy?
ligand/drug causing maximal response
efficacy equals 1
define a neutral antagonist
what is the efficacy?
competes and binds to receptor inhibiting any effect from occurring and blocks agonists
efficacy equals 0
define an inverse agonist
what is the efficacy?
produces an opposite response to agonists (negative response)
efficacy is less than 0
what is the two-state receptor theory:
Ractive and Rinactive are…
M is?
full agonists bind only to _____
partial agonists bind preferentially to _____
full inverse agonists bind preferentially to _____
antagonists have _____ affinities for both Ractive and Rinactive
in equilibrium M= equilibrium constant Ractive Ractive Rinactive equal
describe what summation is
When you have two drugs (A and B) that bind to the same site on a receptor causing the same response to occur more quickly and be higher at lower drug concentrations
*both agonist drugs MIGHT be acting on the same mechanism
describe what synergism is
two drugs A and C are both agonists, their combined effect causes a greater response than just drug A alone. This means these two drugs must bind to different sites on the same receptor or on a different receptor altogether while producing the same response
describe what potentiation is
two drugs A and D are present, but only drug A is an agonist. Drug D is ineffective by itself. However, when both drugs act together the response is greater than just drug A alone. This means they must act by different mechanisms
describe what an allosteric agonist is
they are agonists that bind to a completely different site on the receptor than a full agonist and elicit an effect.
what is the full agonist binding site on a receptor called?
orthosteric
T/F allosteric agonists may have effects on their own similar to a full agonist
True
T/F allosteric agonists may have no effect on their own, but potentiate the activity of a full agonist
True
Define affinity modulation of an allosteric agonist
where a direct effect occurs at the orthosteric receptor site which changes the shape of the receptor and changes the affinity of the receptor to the ligand. It can either increase or decrease affinity
Define efficacy modulation of an allosteric agonist
changes the way the signal effects the response (can make it stronger or weaker)
define allosteric agonism of an allosteric agonist
produces its own response independent from the orthosteric ligand
describe quantal dose response curves:
what does it mean?
give an example
response either occurs, or does not occur “all or none”
example: patients reporting having hiccups, they either are hiccupping or not hiccupping, there is no in between
for quantal dose response curves, the differences in slopes reflect differences in?
population variability in drug response
T/F antagonists may be reversible or irreversible
True
define competitive antagonism:
(effect on full agonist response)
how does this look on a graph?
the antagonist binds reversibly to receptor but produces no effect alone. the competitive antagonist causes more of the full agonist drug to be required to cause it’s effective response.
on a graph, the agonist curve will be identical with or without the antagonist, but with the antagonist the agonist curve will shift to show more drug is required for the identical curve response
define noncompetitive antagonism
how does this look on a graph?
irreversibly/pseudo-irreversibly binds to receptor preventing any drug response no matter how much drug there is
on a graph, adding a non-competitive antagonist binds to an “x” number of receptors, causing the drug agonist effect to decrease. the more non-competitive antagonist present to bind to the receptors the lower the effect will become
describe mixed agonist/antagonist
a drug will have different agonist/antagonist effects at different receptor subtypes
T/F an example of a chemical antagonist is chelation
true
define a physiologic antagonist
a drug that acts at a different receptor site to cause an effect that is opposite of an agonist
difference between a physiologic antagonist and an inverse agonist?
inverse agonist acts at the same receptor to cause opposite effects whereas a physiologic antagonist acts at a different receptor to cause opposite effects
what are spare receptors?
these are receptors in a system that are activated when needed and deactivated when not
when would you see spare receptors?
some full agonists only bind to a fraction of receptors yet elicit a full response. Thus the system has spare receptors not required for full response
T/F you will only see spare receptors in a system with a full agonist
True
what are the steps of using direct binding to determine drug affinity?
- identify drug/compound of interest (drug A)
- identify a second drug/compound known to bind to receptor of interest
- prepare a tissue sample
what is the goal of direct binding to determine drug affinity?
- determine total binding of A at each drug concentration
- determine non-specific binding of A at each drug concentration
- determine specific binding of A at each drug concentration
How do you determine specific binding of A?
total binding of A (at each [D]) - non-specific binding of A (at each [D]) = specific binding of A (at each [D])
When would you use Ki? what does it approximate?
Used to estimate receptor affinity in a tissue sample (not inside body)
it approximates KD
