SPARE RECEPTORS

DR.RENJU.S.RAVI MD

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.

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 

• 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.

• THEY ARE NOT HIDDEN RECEPTORS.

•WHEN THEY ARE OCCUPIED THEY CAN BE COUPLED TO RESPONSE.

•WIDELY MISUNDERSTOOD AS NON FUNCTIONAL.

• 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.

• A CHARACTERISTIC OF MANY RECEPTORS

• PARTICULARLY THOSE THAT RESPOND TO HORMONES, NEUROTRANSMITTERS AND PEPTIDES

• ABILITY TO AMPLIFY SIGNAL DURATION AND INTENSITY

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.

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.

• 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.

• 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).

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.

LINEAR RESPONSE

• The relationship between receptor binding and effect is linear

• For every 1 receptor bound, 1 “effect unit” is produced

• Ion channels

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.

• 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.

• 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.

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.

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.

• 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.

• 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.

• 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.

• 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.

• 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.

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.

THANK YOU