Lecture 4

Question 1

Messenger molecules and receptors

Answer 1

receptor = a site that avidly binds messenger molecules (endogenous or exogenous)
messenger molecules also called ligands, drugs, and mediators
ligand-receptor binding translates into an effect

Question 2

Black box era

Answer 2

information limited by techniques
molecules could be added or injected
responses could be measured
what happened in-between inferred

Question 3

Irving Langmuir - The adsorption isotherm

Answer 3

chemist at General Electric in NYC
designed longer lasting electric bulbs
studied adsorption of molecules on surfaces
molecules bound to free surfaces on films
two important factors
number of molecules
availability of free surfaces for binding
molecules moved towards surface and condensed onto them
once bound to the free surface, they tended to evaporate from the surface
equilibrium = the amount diffusing towards the free surface balanced by those tending to leave the surface

Question 4

Occupancy model

Answer 4

AJ Clark = Quantification enters pharmacology
key assumptions
drugs exert effects by occupying receptors
response proportional to receptor occupation
one drug molecule combines with one receptor
for maximal response, all receptors have to be occupied
drug molecules are in excess of receptor availability

Question 5

Framework for analysis

Answer 5

application of chemical equilibrium concepts (law of mass action)
similar to enzyme-substrate interactions
D + R DR complex —> response

Question 6

Law of mass action

Answer 6

[signalling molecule] + [receptor] [signal-receptor complex] —> response
[receptor] refers to free receptors available for binding so at any time the total pool of receptors will be made up of free and bound receptors
remember key assumption = one signalling molecule binds to one receptor

Question 7

Equilibrium

Answer 7

equilibrium is reached when the rate of formation of new signal-receptor complexes equals the rate at which existing signal-receptor complexes dissociate
kON [S][R] = kOFF [S,R]
rearrange to find the equilibrium dissociation constant (kD)
kD = kOFF/kON = [S][R]/[SR]
kD is the concentration of ligand that, at equilibrium is needed to saturate half of the receptors
kA is the reciprocal of kD and measures the affinity of the receptor for the signaling molecule
kA = 1/kD

Question 8

Kinetics

Answer 8

kD is the ratio of 2 rate constants, the ON and the OFF
usually, the ON rate is relatively similar between molecules (being related to diffusion, unstirred layers etc.)
so OFF rate is the major determinant of affinity
neurotransmitters have very fast off rates, so the kD are high and affinities low
the converse is true for hormone receptors

Question 9

Receptors

Answer 9

receptors: protein molecules on plasma membranes that respond to exogenous or endogenous chemicals
classified based on endogenous ligand
response translated into action
recognition - transduction - response

Question 10

Stickability and doability

Answer 10

molecules
bind to receptors
produce a response
measures of molecule activity
affinity (stickability) = ability to bind to a receptor
efficacy (doability) = ability to produce a response

Question 11

Concentration-response relations

Answer 11

standard approach
plot responses (y-axis) in relation to increasing concentration of the drug (x-axis)
consider two elements
concentration required to produce a given response (measure of affinity)
maximal response elicited (measure of efficacy)

Question 12

Concentration-response curves

Answer 12

max effect vs min effect
EC 50
intensity of effect/response (arbitrary units) vs. concentration/dose (log scale)
drug effect and receptor-bound drug
relative potency and relative efficacy

Question 13

Stochastic nature of process

Answer 13

binding of a molecule to a receptor (protein) is stochastic
essentially random, non-deterministic
at any moment there will be a population of binding sites
which sites are bound will depend on the number of molecules that preferentially bind to that site
if the molecule has diffused away from that site, it becomes available for other similar (agonist) or dissimilar (antagonist) molecules

Question 14

Agonism and antagonism

Answer 14

agonist = a molecule that binds to a receptor and elicits a response
antagonist = binds to a receptor, does not elicit a response and prevents the agonist from functioning

Question 15

Defining receptors

Answer 15

using agonists
logic = receptors recognize subtle variations in parent molecule
using antagonists
logic = variations can be introduced that prevent parent molecule from occupying receptor

Question 16

Physiological antagonism

Answer 16

two receptors, two different agonists
each agonist produces a different response, in opposite directions
because of their opposite effects, the two agonists are antagonistic to each other
eg. histamine and adrenaline on airway smooth muscle
histamine constricts, adrenaline relaxes, but each act on their own receptor

Question 17

Emergence of complexity

Answer 17

partial agonism = even with all receptors occupied, full response not seen
partial agonist vs. full agonist
spare receptors = even with small fraction of receptors occupied, full response seen
indications that the simple waiting chair model needed revision

Question 18

Response - a function of stimulus

Answer 18

stimulus dependent on 
agonist concentration
receptor affinity
intrinsic efficacy
total number of receptors

Question 19

Pharmacological antagonism

Answer 19

single receptor
agonism = occupation of the receptor by an agonist leads to a response
antagonism = occupation by an antagonist interferes with that response
competitive antagonist vs. irreversible antagonist