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Spare receptors

PG Seminar

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Spare receptors

  1. 1. SPARE RECEPTORS DR.RENJU.S.RAVI MD
  2. 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. 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. 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. 5. •THEY ARE NOT HIDDEN RECEPTORS. •WHEN THEY ARE OCCUPIED THEY CAN BE COUPLED TO RESPONSE. •WIDELY MISUNDERSTOOD AS NON FUNCTIONAL.
  6. 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. 7. • A CHARACTERISTIC OF MANY RECEPTORS • PARTICULARLY THOSE THAT RESPOND TO HORMONES, NEUROTRANSMITTERS AND PEPTIDES • ABILITY TO AMPLIFY SIGNAL DURATION AND INTENSITY
  8. 8. 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.
  9. 9. 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.
  10. 10. • 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.
  11. 11. • 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).
  12. 12. 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.
  13. 13. LINEAR RESPONSE • The relationship between receptor binding and effect is linear • For every 1 receptor bound, 1 “effect unit” is produced • Ion channels
  14. 14. 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.
  15. 15. •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.
  16. 16. •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.
  17. 17. 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.
  18. 18. 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.
  19. 19. •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.
  20. 20. •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.
  21. 21. •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.
  22. 22. •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.
  23. 23. •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.
  24. 24. 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.
  25. 25. THANK YOU

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