2. SPARE RECEPTORS
•RECEPTORS MAY BE CONSIDERED SPARE WHEN
THE MAXIMAL RESPONSE IS ELICITED BY AN
AGONIST AT A CONCENTRATION THAT DOES
NOT PRODUCE FULL OCCUPANCY OF THE
AVAILABLE RECEPTORS.
3. HISTORY
• NICKERSON (1957) - HISTAMINE ON A GUINEA PIG ILEUM
PREPARATION
• FURCHGOTT (1964) - ADRENALINE INDUCED CONTRACTION OF THE
RABBIT AORTIC STRIPS
• ONLY SMALL PERCENTAGE OF RECEPTORS HAD TO BE OCCUPIED
BY AGONIST TO PRODUCE MAXIMUM CONTRACTION(RESPONSE)
• ‘SPARE’ OR ‘RESERVE’ RECEPTOR
• PROPOSED BY STEPHENSON
4. • NOT ALL OF THE RECEPTORS IN THE TISSUE ARE REQUIRED TO
ACHIEVE A MAXIMAL RESPONSE.
• SPARE RECEPTORS EXIST WHEN MAXIMUM DRUG RESPONSE IS
ACHIEVED PRIOR TO SATURATION OF ALL RECEPTORS.
5. •THEY ARE NOT HIDDEN RECEPTORS.
•WHEN THEY ARE OCCUPIED THEY CAN BE
COUPLED TO RESPONSE.
•WIDELY MISUNDERSTOOD AS NON FUNCTIONAL.
6. •SPARE RECEPTOR MAY BE DEMONSTRATED BY USING
IRREVERSIBLE ANTAGONIST.
•EXPERIMENTALLY, THE SPARE RECEPTOR CONCEPT
CAN BE SHOWN WHEN THE AGONIST CAN STILL
PRODUCE AN UNDIMINISHED MAXIMAL RESPONSE IN
PRESENCE OF AN IRREVERSIBLE ANTAGONIST.
7.
8. • A CHARACTERISTIC OF MANY RECEPTORS
• PARTICULARLY THOSE THAT RESPOND TO
HORMONES, NEUROTRANSMITTERS AND PEPTIDES
• ABILITY TO AMPLIFY SIGNAL DURATION AND
INTENSITY
9. EXAMPLES
• ACETYLCHOLINE BLOCKED BY ADDITION OF TOXIN, THE
AMPLITUDE OF MUSCLE TWITCH IN RESPONSE TO ACH, IS NOT
DEMISED UNTIL 50% OF RECEPTOR BECOME OCCUPIED BY TOXIN.
• MAXIMAL STIMULATION OF STEROIDOGENESIS BY LEYDIG
CELLS OCCURS WHEN ONLY 1% OF LH RECEPTOR ARE OCCUPIED.
10. CONTD…
• MYOCARDIUM CONTAIN LARGE POPULATION OF SPARE
RECEPTORS.
• MAXIMAL IONOTROPIC RESPONSE TO CATECHOLAMINE CAN BE
ELICITED EVEN WHEN ONLY LESS THAN 10% OF RECEPTOR OCCUPIED.
• FULL STEROID INDUCED TRANSCRIPTIONAL RESPONSE MAY ONLY
REQUIRE 10% RECEPTOR.
11. • IF TISSUE WITH 100(100%) TOTAL RECEPTOR HAS 90(90%) SPARE
RECEPTOR.
• REQUIRE ONLY 10(10%) OF RECEPTOR OCCUPANCY TO PRODUCE
MAXIMAL (EMAX) RESPONSE.
• HALF MAXIMAL RESPONSE REQUIRE OCCUPANCY OF ONLY
5(5%) OF TOTAL RECEPTOR.
12.
13.
14. • BECAUSE THE EXISTENCE OF SPARE RECEPTORS IS FAIRLY
COMMON, THE EC50 FOR AN AGONIST IS USUALLY NOT
EQUAL TO ITS KD.
• WHEN THE SIGNALING PATHWAYS INVOLVE AMPLIFICATION
STEPS, THE EC50 FOR AN AGONIST MAY BE MUCH LOWER
THAN THE CONCENTRATION NEEDED TO CAUSE HALF
MAXIMAL RECEPTOR OCCUPATION (KD).
15.
16.
17. RECEPTOR EFFECTOR COUPLING
• WHEN A RECEPTOR IS OCCUPIED BY AN AGONIST, THERE IS
CONFORMATIONAL CHANGE.
• THE TRANSDUCTION PROCESS THAT LINKS DRUG
OCCUPANCY OF RECEPTORS AND PHARMACOLOGIC
RESPONSE IS OFTEN TERMED COUPLING.
• COUPLING EFFICIENCY IS ALSO DETERMINED BY THE
BIOCHEMICAL EVENTS THAT TRANSDUCE RECEPTOR
OCCUPANCY INTO CELLULAR RESPONSE.
18. LINEAR RESPONSE
• The relationship between
receptor binding and
effect is linear
• For every 1 receptor
bound, 1 “effect unit” is
produced
• Ion channels
19. NON-LINEAR RESPONSE
• MORE OFTEN, THE RESPONSE IS NON LINEAR.
• THIS IS OFTEN TRUE FOR RECEPTORS LINKED TO ENZYMATIC SIGNAL
TRANSDUCTION CASCADES.
• IN WHICH THE BIOLOGIC RESPONSE OFTEN INCREASES
DISPROPORTIONATELY TO THE NUMBER OF RECEPTORS OCCUPIED BY
THE DRUG.
20. •THE FAMILY OF G PROTEIN–LINKED RECEPTORS
EXEMPLIFIES MANY OF THE POSSIBLE RESPONSES
INITIATED BY LIGAND BINDING TO A RECEPTOR.
•TWO PHENOMENA ACCOUNT FOR THE
AMPLIFICATION OF THE LIGAND - RECEPTOR
SIGNAL.
21. •FIRST
• A SINGLE LIGAND–RECEPTOR COMPLEX CAN INTERACT
WITH MANY G PROTEINS - MULTIPLYING THE ORIGINAL
SIGNAL TO MANY-FOLD.
•SECOND
• THE ACTIVATED G PROTEINS PERSIST FOR A LONGER
DURATION THAN THE ORIGINAL LIGAND - RECEPTOR
COMPLEX.
22. TEMPORAL SPARENESS
• EXAMPLE
• ALBUTEROL - BINDING EXIST FOR A FEW MILLISECONDS, BUT THE SUBSEQUENT
ACTIVATED G PROTEINS MAY LAST FOR HUNDREDS OF MILLISECONDS.
• FURTHER PROLONGATION AND AMPLIFICATION OF THE INITIAL SIGNAL IS
MEDIATED BY THE INTERACTION BETWEEN G PROTEINS AND THEIR RESPECTIVE
INTRACELLULAR TARGETS.
• ONLY A FRACTION OF THE TOTAL RECEPTORS FOR A SPECIFIC LIGAND MAY
NEED TO BE OCCUPIED TO ELICIT A MAXIMAL RESPONSE.
23. SPARENESS IN NUMBER
•IF THE CONCENTRATION OR AMOUNT OF CELLULAR
COMPONENTS OTHER THAN THE RECEPTORS LIMITS
THE COUPLING OF RECEPTOR OCCUPANCY TO
RESPONSE, THEN A MAXIMAL RESPONSE CAN OCCUR
WITHOUT OCCUPANCY OF ALL RECEPTOR.
24. •IF THERE WERE A 1:1 STOICHIOMETRY BETWEEN GPCR
ACTIVATION AND G-PROTEIN STIMULATION, FOR
EXAMPLE, THE EXISTENCE OF 10,000 RECEPTORS AND
ONLY 1000 G-PROTEINS IN A PARTICULAR CELL WOULD
RESULT IN ONLY 10% OF RECEPTORS NEEDING TO BE
ACTIVATED TO CAUSE A FULL RESPONSE.
•FURTHER RECEPTOR OCCUPANCY WOULD NOT RESULT
IN AN INCREASE IN THE MAGNITUDE OF RESPONSE.
25. •THE SENSITIVITY OF A CELL OR TISSUE TO A
PARTICULAR CONCENTRATION OF AGONIST DEPENDS
NOT ONLY ON THE AFFINITY OF THE RECEPTOR FOR
BINDING THE AGONIST (CHARACTERIZED BY THE KD )
BUT ALSO ON THE DEGREE OF SPARENESS.
•THE TOTAL NUMBER OF RECEPTORS PRESENT
COMPARED WITH THE NUMBER ACTUALLY NEEDED
TO ELICIT A MAXIMAL BIOLOGIC RESPONSE.
26. •SPARE RECEPTORS ARE ALSO RESPONSIBLE FOR TISSUE
SPECIFIC ACTIONS OF AGONISTS.
• BECAUSE THE PRESENCE OF SPARE RECEPTORS INCREASES THE
POTENCY OF AN AGONIST.
• TISSUES WITH A HIGH PROPORTION OF SPARE
RECEPTORS WILL RESPOND TO AGONISTS AT LOWER
CONCENTRATIONS, EVEN IF THEY CONTAIN EXACTLY
THE SAME RECEPTOR SUBTYPES.
27.
28. •THIS MEANS THAT IF AN AGONIST HAS A DIFFERENT
EC50 IN TWO DIFFERENT TISSUES.
•ONE CANNOT CONCLUDE THAT THE RECEPTORS IN ONE
TISSUE ARE DIFFERENT FROM THE RECEPTORS IN THE
OTHER TISSUE, BECAUSE THERE IS NO PREDICTABLE
RELATIONSHIP BETWEEN EC50 AND KD FOR A
PARTICULAR AGONIST/RECEPTOR COMBINATION.
29. •SPARE RECEPTORS ALSO COMPLICATE THE ANALYSIS
OF PARTIAL AGONISTS.
•IF A DRUG IS A PARTIAL AGONIST IN ONE TISSUE, IT
MAY BE A FULL AGONIST IN ANOTHER TISSUE,
WHICH HAS A HIGHER PROPORTION OF SPARE
RECEPTORS.
30. BIOLOGICAL SIGNIFICANCE
•THE SPARE RECEPTOR CONCEPT COULD EXPLAIN WHY
THE SENSITIVITY OF TISSUE DEPEND ON BOTH AFFINITY
OF DRUG & TOTAL NUMBER OF RECEPTOR.
• IT IS POSSIBLE TO CHANGE THE SENSITIVITY OF TISSUE
WITH SPARE RECEPTOR BY ALTERING RECEPTOR
CONCENTRATION .
•AN IMPORTANT BIOLOGICAL CONSEQUENCE OF SPARE
RECEPTOR IS THAT ALLOW LOW AFFINITY AGONISTS TO
PRODUCE FULL RESPONSE AT LOW CONCENTRATION.
