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Receptor and Signal Transduction
Receptor Concept
Dept. Pharmacology, Tzu Chi Univ. T.H. Chiu
I. References for the lecture
II. Development of receptor theory
III. Contribution from physical and biological chemistry
IV. Occupational theory
V. Subsequent modifications of occupational theory
I. References for the lecture
1. R.R. Ruffolo, Jr. Important concepts of receptor theory.
J. Auton. Pharmacol. 2:277-295, 1982.
2. Chapter 15, Cell Communication, pp. 481-512.
From: Essential Cell Biology, B. Alberts et al., 1998
It provides a general schemes of signal transduction.
A good reading materials for the beginners.
3. Signal Transduction, C-H. Heldin & M. Purton,eds.
Chapman & Hall, 1996. A concise description of major
signal transduction pathways you always want but
afraid to ask.
4. See the handouts for the other references relating to the
receptor concept.
II. Development of receptor theory
A. Receptive substance
Langley, 1878, studied the mutual antagonistic effects
of pilocarpine and atropine on salivary secretion; 1905,
studied the antagonism between nicotine and curare
on muscle contraction, led to the idea that nicotine
and curare acted on the same receptive substance.
B. Receptor
Ehrlich, 1913, experiments with tissue stains, snake
venom, and bacterial toxins (side chain theory to
describe the interaction between antigen and
antibody, and the concept of specific cell surface
receptors as the basis for targeting bioactive agents to
the appropriate responsive cells). Awarded Nobel
Prize in Medicine in 1908 (immunochemistry).
Experimental observations supporting specific cell surface
receptors:
1. Many drug responses are obtained at very low
doses or concentrations.
2. Responses can be blocked by other drugs of specific
chemical structures (stereo-specificity).
3. The selectivity of agonists and antagonists is extremely
dependent on chemical structures, and very small
changes in structures can have profound effects on
pharmacological activities.
C. Occupancy theory:
Number of receptors occupied determines the response
Clark, 1926: quantitative mathematical treatment of drug effect
Ariens, 1954: introduced intrinsic activity as the effect caused by unit
drug-receptor complex
Stephenson, 1956: Introduced efficacy as the capacity of a drug to
initiate a response
Furchgott, 1966: Introduced intrinsic efficacy as a quantal unit for the
capacity of a drug to initiate a stimulus from one receptor
Spare receptors:
Nickerson, 1956
Stephenson, 1956
Furchgott, 1955 (awarded Nobel Prize in Medicine, 1999, for the
research on NO)
Ariens, 1960
D. Rate theory:
Paton, 1961: proposed that the effect was proportional to
the rate of drug-receptor interaction, rather than to the
number of receptors occupied by the drug.
Challenging conceptually, but of limited applicability
based on our current understanding or receptor
systems.
E. Molecular models:
Macromolecular perturbation theory, Belleau, 1964
Mobile receptor hypothesis, Cuatrecasas, 1974, explaining
the interaction between βadrenoceptor and adenylyl
cyclase
Allosteric theory, Monod, Wyman & Changeux, 1965
III. Contributions from physical & biological chemistry:
Pharmacological concepts
Receptive substance:
Langley 1878, 1905
Chemical concepts
Lock & key fit of ES:
Fisher, 1894
Receptor: Ehrlich, 1913
Enzyme kinetics:
Henri, 1902
Michaelis-Menten, 1913
Briggs-Haldane, 1925
Lineweaver-Burke, 1934
Occupancy theory: Clark, 1926
Intrinsic activity; Ariens, 1954
Efficacy; Stephenson, 1956
Spare receptors; Nickerson et al., 1956
Intrinsic efficacy, Furchgott, 1966
Induced-fit theory:
Koshland, 1958
Pharmacological concepts
Chemical concepts
Rate theory: Paton, 1961
Macromolecular perturbation theory:
Belleau, 1964
Allosteric transition model:
Monod, Wyman &
Changeux, 1965
Ligand-induced cooperative
model: Koshland,
Nemethy & Filmer, 1966
Mobile receptor hypothesis:
Cuatrecasas, 1974
IV. Occupancy theory:
Quantitative treatment by Clark
Interaction
between drugs
and receptors
follows Law of
Mass Action.
General assumption:
1. One drug molecule reversibly binds to one receptor
molecule.
2. A response results from steady-state occupation of
receptors.
3. A graded response is obtained.
4. Response is proportional to the number of receptors
occupied.
5. EM is proportional to [RT] occupied.
6. [D] >> [RT]
7. The occupation of one receptor does not alter the property
of other receptors.
V. Modifications of occupancy theory
A. Ariens treatment:
Effect is dictated by 2 independent parameters.
1. Affinity: the ability of a drug to bind
2. Intrinsic activity: the ability of drugs to induce an
effect after binding
agonists: possess both affinity and intrinsic activity (1)
antagonists: possess affinity but not intrinsic
activity (0)
partial agonists (or partial antagonists) with intrinsic
activity between 0 and 1.
3. In some cases only a small percentage of receptors
needs to be occupied to elicit a maximal response.
Assumptions for full agonists are the same as in the
Clark treatment.
α: effect per unit drug-receptor complex
ED50 (from dose-response curve) as a measure of
affinity
Maximal effect as a measure of intrinsic activity
B. Stephenson treatment:
Introduced a parameter called “stimulus”, and the response is
some unknown function (f) of stimulus. Thus, function f
dissociates receptor stimulus and tissue response as directly
proportional quantities.
1. Effect doe not need to be linearly proportional to receptor
occupancy.
2. EM can be achieved with occupation of small percentage of
receptors.
3. Different drugs may induce same effects by occupying different
percentage of receptors.
4. It is possible for 2 full agonists with intrinsic activity of 1 to have
different efficacies.
5. Consequence of spare receptors on the relation between ED50
and KD (KD >> ED50).
ED50 = concentration required for a half-maximal response
KD
= concentration required to occupy 50% of receptors
C. Furchgott treatment:
Introduced intrinsic efficacy, “ε”, which is the capacity of a drug
to initiate a stimulus from one receptor. Thus, intrinsic efficacy
was defined as a strictly drug-related term, whereas Stephenson’s
efficacy was a drug- and tissue-related term.
2 tissue factors: [RT] and f (the nature and efficacy of
the functions converting receptor stimulus into
tissue response)
2 drug factors: KD and ε