RECEPTORS

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a class on receptors

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In the Name of Allah, the Beneficent, the Most Merciful RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GOOD MORNING:

GOOD MORNING RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

RECEPTORS :

RECEPTORS DR.MOHAMMED ABDUL RAOF FIRST YEAR P.G. PHARMACOLOGY D.C.M.S . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

OVERVIEW:

OVERVIEW Definition of Receptor. History on Receptor. Stages of Receptor life-cycle. Functions of Receptor. Importance of Receptor studies. Definition of Agonist, Antagonist & different types. Definition of Affinity & Efficacy. Types of Receptors. Diseases associated due to Receptors. Non-Receptor mediated mechanisms. References. Acknowledgements. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTORS IT IS DEFINED AS A REGULATORY MACROMOLECULE MOSTLY PROTIENS OR BINDING SITES LOCATED ON THE SURFACE OR INSIDE THE EFFECTOR CELL THAT SERVES TO RECOGNIZE THE LIGAND/SIGNAL MOLECULE /DRUG AND INITIATE THE RESPONSE TO IT,BUT ITSELF HAS NO OTHER FUNCTION . RARELY,NUCLIEC ACIDS MAY ALSO SERVE AS RECEPTORS . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTORS LIGAND EXOGENOUS LIGANDS -drugs ENDOGENUS LIGANDS -hormones 0R RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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Flow chart of agonist and receptor interaction RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Drug receptor complex and effect:

Drug receptor complex and effect RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PAUL EHRLICH & JOHN LANGLEY Coined the terms-RECEPTOR, DRUG,EFFECT & DRUG-RECEPTOR COMPLEX .:

PAUL EHRLICH & JOHN LANGLEY Coined the terms-RECEPTOR, DRUG,EFFECT & DRUG-RECEPTOR COMPLEX . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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Earliest receptors to be identified were: MUSCARINIC (BLOCKED BY ATROPINE) NICOTINIC(BLOCKED BY CURARE) RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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Earliest receptors to be identified were: MUSCARINIC (BLOCKED BY ATROPINE) NICOTINIC(BLOCKED BY CURARE) N ow multiple subtypes have been further sub-divided. Stephenson’s modified theory was generally accepted which states- 1.drug response depends on the affinity of a drug for the receptors. 2.maximum dose is achieved even if a fraction of receptors are unoccupied. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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Every receptor exist in two interchangeable states: Ra indicating ACTIVE Ri indicating INACTIVE Receptor discovery often begins by studying the relations between structures and activities of a group of drugs on some conveniently measured response. Cloning of new receptors by SEQUENCE HOMOLOGY has identified a number of subtypes of known receptor classes, such as-adrenoceptors and serotonin receptors RECEPTOR BY DR.MOHAMMED ABDUL RAOF

STAGES OF RECEPTOR LIFE-CYCLE:

STAGES OF RECEPTOR LIFE-CYCLE RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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TO PROPAGATE REGULATORY SIGNALS FROM OUTSIDE TO INSIDE OF THE CELL. TO INTERAGATE VARIOUS EXTRACELLULAR & INTRACELLULAR REGULATORY SIGNALS. TO AMPLIFY THE SIGNAL. TO ADAPT TO SHORT TERM & LONG TERM CHANGES IN REGULATING AND MAINTAINING HOMEOSTASIS. THE RECEPTOR CONCEPT HAS IMPORTANT PRACTICAL CONSEQUENCES IN DEVELOPMENT OF DRUGS AND FOR ARRIVING AT THERAPEUTIC DECISIONS IN CLINICAL PRACTICE. FUNCTIONS OF RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ONE TYPE OF RECEPTOR CAN CAUSE VARIABLE ACTIVITY IN VARIOUS CELL TYPES WITH VARIOUS DRUGS.:

ONE TYPE OF RECEPTOR CAN CAUSE VARIABLE ACTIVITY IN VARIOUS CELL TYPES WITH VARIOUS DRUGS. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

DUAL ROLE OF A RECEPTOR ACTIVITY:

DUAL ROLE OF A RECEPTOR ACTIVITY RECEPTOR BY DR.MOHAMMED ABDUL RAOF

SAME DRUG CAUSE DIFFERENT RESPONSE DEPENDING ON THE RECEPTORS:

SAME DRUG CAUSE DIFFERENT RESPONSE DEPENDING ON THE RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ONE DRUG CAN CREATE MULTIPLE EFFECTS WITH ONE RECEPTOR:

ONE DRUG CAN CREATE MULTIPLE EFFECTS WITH ONE RECEPTOR RECEPTOR BY DR.MOHAMMED ABDUL RAOF

IMPORTANCE OF RECEPTOR STUDIES:

IMPORTANCE OF RECEPTOR STUDIES RECEPTORS LARGELY DETERMINE THE QUANTITATIVE RELATIONS BETWEEN DOSE OR CONCENTRATION OF A DRUG AND ITS PHARMACOLOGIC EFFECTS. RECEPTORS MEDIATE THE ACTIONS OF PHARMACOLOGIC AGONISTS AND ANTAGONISTS. RECEPTORS ARE RESPONSIBLE FOR SELECTIVITY OF DRUG ACTION. THE MOLECULAR SIZE, SHAPE, AND ELECTRICAL CHARGE OF A DRUG DETERMINE WHETHER—AND WITH WHAT AFFINITY—IT WILL BIND TO A PARTICULAR RECEPTOR AMONG THE VAST ARRAY OF CHEMICALLY DIFFERENT BINDING SITES AVAILABLE IN A CELL, TISSUE OR PATIENT. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Targets for drug action:

Targets for drug action A drug is a chemical that affects physiological function in a specific way. EXCEPTIONS:-(on target proteins) - enzymes - carriers - ion channels -receptors Specificy is reciprocal. No drugs are completely specific. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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PAUL EHRLICH said-- “A DRUG WILL NOT WORK UNLESS IT IS BOUND”

Binding of drugs to receptors:

Binding of drugs to receptors Obeys the law of mass action. At equilibrium receptor occupancy is related to drug concentration by the Langmuir’s equation. The higher the affinity of the drug for the receptor, the lower the concentration at which it produces a given level of occupancy . When two or more drugs compete for the same receptors : each has the effect of reducing the apparent affinity for the other. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

RECEPTOR/AGONIST/ANTAGONIST:

RECEPTOR/AGONIST/ANTAGONIST RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Ligand, agonist & antagonist:

Ligand, agonist & antagonist RECEPTOR BY DR.MOHAMMED ABDUL RAOF

AGONIST:

Drugs which alter the physiology of a cell by binding to plasma membrane or intercellular receptors. a number of receptors must be occupied by agonists before a measurable change in cell function occurs. For example- a muscle cell does not depolarize simply because one molecule of acetylcholine binds to a nicotinic receptor and activates an ion channel. AGONIST RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

TYPES OF AGONIST:

TYPES OF AGONIST Partial agonist is a drug which fails to produce maximal effects, even when all the receptors are occupied are occupied by the agonist . Weak agonist must be bound to many more receptors than a strong agonist to produce the same effect. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Regulation of the activity of a receptor with conformation-selective drugs. Receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors. :

Regulation of the activity of a receptor with conformation-selective drugs . Receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

AGONIST AND INVERSE AGONIST:

AGONIST AND INVERSE AGONIST RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Presence of agonist and antagonist can shift the graph:

Presence of agonist and antagonist can shift the graph RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Relations between DRUG CONCENTRATION AND DRUG EFFECT (PANEL A) OR RECEPTOR-BOUND DRUG(PANEL B).The drug concentrations at which effect or receptor occupancy is half-maximal are denoted EC50 and KD respectively.:

Relations between DRUG CONCENTRATION AND DRUG EFFECT (PANEL A) OR RECEPTOR-BOUND DRUG(PANEL B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted EC 50 and K D respectively. EC 50 (EFFECTIVE CONCENTRATION 50%): The concentration of drug which induces at least 50% to which the drug is administration. Then the specified clinical effect in 50% of the subject is seen. Dissociation constant(K D ):The dissociation constant is the measure of a drug’s affinity for a given receptor.it is the concentration of drug required in solution to achieve 50% occupancy of its receptors. Units are expressed in molar concentration. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Drug antagonism Antagonist inhibit or block responses caused by agonist.:

Drug antagonism Antagonist inhibit or block responses caused by agonist. Occurs by various mechanism:-- Chemical antagonism. Pharmacokinetic antagonism. Competitive antagonism. Non competitive antagonism. Physiological antagonism. Irreversible antagonism. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ANTAGONIST:

ANTAGONIST RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

COMPETITIVE ANTAGONIST:

COMPETITIVE ANTAGONIST COMPETES WITH AGONISTS FOR RECEPTORS.DURING THE TIME THAT A RECEPTOR IS OCCUPIED BY AN ANTAGONIST,AGONIST CANNOT BIND TO THE RECEPTOR. THE NUMBER OF RECEPTORS APPEARS UNCHANGED BECAUSE HIGH DOSE OF AGONIST IS REQUIRED,IN THE PRESENCE OF ANTAGONIST, TO ACHIEVE RECEPTOR OCCUPANCY.THE ANTAGONISM CAN BE OVERCOME BY HIGH DOSES OF AGONISTS . ANTAGONIST AFFINITY, MEASURED IN THIS WAY IS WIDELY USED AS A BASIS FOR RECEPTOR CLASSIFICATION. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

COMPETITIVE ANTAGONIST :

COMPETITIVE ANTAGONIST REVERSIBLE COMPETITIVE ANTAGONISM HAVE TWO MAIN CHARACTERISTICS OF ALL COMPETITIVE ANTAGONISM: 1.IN THE PRESENCE OF ANTAGONIST ,THE AGONIST LOG CONCENTRATION EFFECT CURVE IS SHIFTED TO THE RIGHT WITHOUT CHANGE IN SLOPE/ MAXIMUM. THE EXTENT OF THE SHIFT BEING A MEASURE OF THE DOSE RATIO. 2.DOSE RATIO INCREASES LINEARLY WITH THE ANTAGONIST CONCENTRATION, THE SLOPE OF THIS LINE IS A MEASURE OF THE AFFINITY OF THE ANTAGONIST FOR THE RECEPTOR. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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binds to a site other than the agonist-binding domian . Induces a conformational change in the receptor such that the agonist no longer ‘recognizes’ the agonist –binding domian . Even high doses of agonist cannot overcome this antagonism. Thus, it is considered to be insurmountable. The number of agonist-binding sites appears to be reduced . The affinity of agonist for the ‘unantagonized sites’ remain unchanged. NON-COMPETITIVE ANTAGONIST: RECEPTOR BY DR.MOHAMMED ABDUL RAOF

IRREVERSIBLE ANTAGONIST(NON-EQUILIBRIUM COMPETITIVE): :

IRREVERSIBLE ANTAGONIST(NON-EQUILIBRIUM COMPETITIVE): I rreversible antagonists are also insurmountable. These agents compete with agonists for the agonist-binding domian.in contrast to competitive antagonists- T hey combine permanently with the receptor. The rate of antagonism can be slowed by high concentrations of agonist . Once an irreversible antagonist binds to a particular receptor, however, that receptor cannot be reclaimed by an agonist. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Agonists, antagonists and efficacy :

Agonists, antagonists and efficacy Drugs acting on receptors may be agonists or antagonists. AGONIST ANTAGONIST INITIATES THE CHANGES IN CELL FUNCTION BY PRODUCING EFFECTS IN CELL FUNCTION. BINDS TO RECEPTORS WITHOUT INITIATING SUCH CHANGES. POTENCY DEPENDS ON EFFICACY IT’s EFFICACY IS ZERO SHOW SELECTIVITY FOR ACTIVATED STATES SHOWS NO SELECTIVITY RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

AFFINITY :

AFFINITY AFFINITY : is the ability of a drug to bind with the receptor and form a drug-receptor complex.it doesn't guarantee response. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

EFFICACY:

EFFICACY EFFICACY/INTRINSIC ACTIVITY : which means the ability of a drug-receptor to trigger the pharmacological response. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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Four receptor families on basis of molecular structure and the nature of transduction mechanisms: 1.ION-CHANNEL RECEPTORS (IONOTROPIC /LIGAND-BINDING) 2.G-PROTIEN COUPLED RECEPTORS (METABOTROPIC /SERPENTINE) 3.KINASE LINKED RECEPTORS 4.INTRA-CELLULAR RECEPTORS ( CYTOSOLIC /NUCLEAR) RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

AGONIST AT THE BINDING DOMIAN:

AGONIST AT THE BINDING DOMIAN RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ION-CHANNEL RECEPTORS(IONOTROPIC ):

THESE RECEPTORS ARE LOCALISED ON CELL MEMBRANE AND ARE COUPLED DIRECTLY TO AN ION CHANNEL ARE ALSO CALLED AS LIGAND GATED ION CHANNELS/RECEPTOR OPERATED CHANNELS. THE ONSET AND OFFSET OF RESPONSES IN THIS RECEPTORS IS THE FASTEST OF A MILLISECONDS IN A FAST SYNAPTIC TRANSMISSIONS. IT IS A CHANNEL WITH A RECEPTOR SITE THAT AGONIST CAN OPEN THE CHANNEL,THE ANTAGONIST PREVENTS THE AGONIST FROM OPENING THE CHANNEL AND AN INVERSE AGONIST CLOSES THE OPEN CHANNEL. ION-CHANNEL RECEPTORS(IONOTROPIC ) RECEPTOR BY DR.MOHAMMED ABDUL RAOF

LIGAND GATED CHANNEL IN ACTION:

LIGAND GATED CHANNEL IN ACTION RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ION-CHANNEL RECEPTORS:

ION-CHANNEL RECEPTORS GAMMA AMINO BUTYRIC ACID, 5HYDROXYTRYPTAMINE3 , NICOTINIC-CHOLINERGIC, GLYCINE , GLUTAMATE ARE SOME OF THE RECEPTORS. IN THESE RECEPTORS,AGONISTS DIRECTLY OPERATE THE ION CHANNEL WITHOUT THE INTERVENTION BY ANY COUPLING PROTIEN OR SECOND MESSENGER. THE BEST EXEMPLIFIED NICOTNIC-ACETYLCHOLINE RECEPTOR OPERATED CHANNEL CONSISTS OF 5PROTIEN SUBUNITS (2α+1β+1γ+1δ) ALL OF THEM PASS ACROSS THE CELL MEMBRANE AND SURROND A CENTRAL PORE.INORDER TO ACTIVATE THE RECEPTOR AND OPEN THE CHANNEL ONE MOLECULE OF ACHETYLCHOLINE SHOULD BIND TO EACH OF THE ALPHA SUBUNITS.ACTIVE STATE BY OPENING THE PORE,OTHERWISE INACTIVE STATE RECEPTOR BY DR.MOHAMMED ABDUL RAOF

The nicotinic acetylcholine (ACh) receptor, a ligand-gated ion channel. The receptor molecule is depicted as embedded in a rectangular piece of plasma membrane, with extracellular fluid above and cytoplasm below. Composed of five subunits (two α , one β , one δ , and one γ ), the receptor opens a central transmembrane ion channel when ACh binds to sites on the extracellular domain of its subunits. :

The nicotinic acetylcholine (ACh) receptor, a ligand-gated ion channel. The receptor molecule is depicted as embedded in a rectangular piece of plasma membrane, with extracellular fluid above and cytoplasm below. Composed of five subunits ( two α , one β , one δ , and one γ ), the receptor opens a central transmembrane ion channel when ACh binds to sites on the extracellular domain of its subunits. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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AGONIST SHOULD BIND TO EACH OF THE ALPHA SUBUNITS.THE RECEPTOR REACHES AN ACTIVE STATE BY OPENING THE PORE,OTHERWISE REMAINS IN INACTIVE STATETHE BEST EXEMPLIFIED NICOTNIC-ACETYLCHOLINE RECEPTOR OPERATED CHANNEL CONSISTS OF 5PROTIEN SUBUNITS(2 α +1β+1γ+1δ) ALL OF THEM PASS ACROSS THE CELL MEMBRANE AND SURROND A CENTRAL PORE.INORDER TO ACTIVATE THE RECEPTOR AND OPEN THE CHANNEL ONE MOLECULE OF ACHETYLCHOLINE RECEPTOR BY DR.MOHAMMED ABDUL RAOF

G-PROTIEN COUPLED RECEPTORS:

G-PROTIEN COUPLED RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Transmembrane topology of a typical serpentine receptor. The receptor's cytoplasmic terminal tail contains numerous serine and threonine residues whose hydroxyl (-OH) groups can be phosphorylated. This phosphorylation may be associated with diminished receptor-G protein interaction.:

Transmembrane topology of a typical serpentine receptor . The receptor's cytoplasmic terminal tail contains numerous serine and threonine residues whose hydroxyl (-OH) groups can be phosphorylated. This phosphorylation may be associated with diminished receptor-G protein interaction. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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G protein in action RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GPCR ACTION:

GPCR ACTION RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GPCR IN ACTION:

GPCR IN ACTION RECEPTOR BY DR.MOHAMMED ABDUL RAOF

G-PROTIEN COUPLED RECEPTORS(METABOTROPHIC):

G-PROTIEN COUPLED RECEPTORS(METABOTROPHIC) large family of cell-membrane receptors that are also called 7 pass receptors / 7 trans membrane / serpentine receptors. monomeric structure(rare- dimeric ) with seven trans membrane helices. each receptor is present as a molecule of 7 α helical units that have extra cellular attachment for the drug, intracellular for the signal passage and intercellular gtp activated proteins ( G proteins) for response effect. amino terminus is outside the cell,carboxyisinside the cell. onset time of response is also in seconds. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

G-RECEPTOR IN ACTION :

G-RECEPTOR IN ACTION RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GPCR AND ITS EFFECT:

GPCR AND ITS EFFECT RECEPTOR BY DR.MOHAMMED ABDUL RAOF

G-PROTIEN COUPLED RECEPTORS:

G-PROTIEN COUPLED RECEPTORS one receptor can be coupled to plenty of g- proteins. some g-protein activate and others inhibit in signal transduction. examples are – epinephrine, nor- epinephrine purine,gaba,glutamate,opiods,vasopressin , dopamine,5ht,histamine,adenosine , muscarinic-acetylcholine…. three major effector pathways— --Adenyl cyclase --Phospholipase c -- C hannel regulation RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

DOMINOES EFFECT OF ACTIVATED GPCR:

DOMINOES EFFECT OF ACTIVATED GPCR RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GPCR ACTIVATION EFFECTS:

GPCR ACTIVATION EFFECTS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

G-PROTIEN CONTROLLED RECEPTOR FAMILIES:

G-PROTIEN CONTROLLED RECEPTOR FAMILIES A FOURTH GROUP OF RECEPTORS FOR THE PHEROMONES WITH NO PHARMACOLOGICAL EFFECTS. FAMILY RECEPTORS STRUCTURAL FEATURES RHODOPSIN FAMILY LARGEST GROUP OF RECEPTORS FOR MOST AMINE NEUROTRANSMITTERS,PURINES, NEUROPEPTIDES,PROSTANIODS, CANNABINOIDS,…. SHORT EXTRACELLULAR AMINE TAIL,LIGAND BINDS TO TRANSMEMBRANE HELICES OR TO EXTRA-CELLULAR LOOPS. SECRETIN/GLUCAGON RECERPTOR FAMILY RECEPTORS FOR PEPTIDE HORMONES INCLUDING SECRETIN,GLUCAGON,CALCITONIN INTERMEDIATE EXTRA-CELLULAR TAIL,INCOOPERATING LIGAND-BINDING DOMIAN. METABOTROPIC GLUTAMATE RECEPTOR/CALCIUM SENSOR FAMILY SMALL GROUP:GABA RECEPTORS, CALCIUM SENSING RECEPTORS, METABOTROPIC GLUTAMATE RECEPTORS LONG EXTRACELLULAR TAIL, INCOOPERATING LIGAND BINDING DOMIAN RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Receptors coupled to G proteins (GPCRs) make up a family of "seven-transmembrane" (7-TM) or "serpentine" receptors. :

Receptors coupled to G proteins (GPCRs) make up a family of "seven-transmembrane" (7-TM) or "serpentine" receptors . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

DIFFERENT AGONIST ON GPCR:

DIFFERENT AGONIST ON GPCR RECEPTOR BY DR.MOHAMMED ABDUL RAOF

DUAL ACTION OF GPCR RECEPTORS:

DUAL ACTION OF GPCR RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS:

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS ACTIVATION OF THIS PATHWAY RESULTS IN INTRACELLULAR ACCUMULATION OF SECOND MESSENGER c-AMP WHICH FUNCTIONS MAINLY THROUGH c-AMP DEPENDANT PROTIEN KINASE( PKa ). THE Pka PHOSPHORYLATES & ALTERS THE FUNCTION OF MANY ENZYMES,ION CHANNELS,TRANSPORTERS & STRUCTURAL PROTIENS. INCREASED CONTRACTILITY/IMPULSE GENERATION IN HEART. RELAXES THE SMOOTH MUSCLES. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS:

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS GLYCOGENOLYSIS,LYPOLYSIS & INHIBITION OF SECRETIN/MEDIATOR RELEASE. MODULATION OF JUNCTIONAL TRANSMISSION,HORMONE SYNTHESIS. OPENS Ca2+ CHANNEL IN HEART,BRAIN & KIDNEY, CALLED AS CYCLIC NUCLEOTIDE GATED CHANNEL(CNG) ADENYL CYCLASE IS INHIBITED THROUGH INHIBITORY Gi-protien. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

GPCR C-AMP:

GPCR C-AMP RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS:

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ADENYL CYCLASE -- PATHWAY OF G-PROTIEN RECEPTORS The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P'ase), which remove phosphates from substrate proteins. Open arrows denote regulatory effects.:

ADENYL CYCLASE -- PATHWAY OF G-PROTIEN RECEPTORS The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P'ase), which remove phosphates from substrate proteins . Open arrows denote regulatory effects. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS:

ADENYL CYCLASE - PATHWAY OF G-PROTIEN RECEPTORS ↑/CONTRACTION role/ACTIVATION ↓/RELAXATION role/INHIBITION Adrenergic - β Adrenergic- α 2 Histamine-H 2 Muscarinic-M 2 Dopamine-D1 Dopamine -D2 Glucagon 5-HT 1 FSH & LH GABA B ACTH O TSH A-AT Prostaglandin-EP 2 Prostaglandin-EP 3 Prostacyclin-IP Somatostatin Adenosine-A 2 Adenosine-A 1 RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PHOSPHOLIPASE C--PATHWAY OF G-PROTIEN RECEPTORS:

PHOSPHOLIPASE C--PATHWAY OF G-PROTIEN RECEPTORS ACTIVATION OF PHOSPOLIPASE C (PLc) HYDROLYSES THE MEMBRANE PHOSPHOLIPID PHOSPHATIDYL INOSITOL4,5-BIPHOSPATE(PIP 2 ) TO GENERATE SECOND MESSENGER INOSITOL1,4,5-TRIPHOSPHATE(IP 3 ) & DIACYLGLYCEROL(DAG). THE IP3 MOBILIZES CA2+ FROM INTRACELLULAR DEPOTS. DAG ENHANCES PROTIEN KINASE C (PKc) ACTIVATION BY CA2+ AND CALMODULIN(CAM). CAM,PKc AND OTHER EFFECTORS –MEDIATES/MODULATES CONTRACTION,SECRETION,TRANMITTER RELEASE,EICOSANIOD SYNTHESIS,NEURONAL EXCITABILITY,INTRACELLULAR MOVEMENTS, MEMBRANE FUNCTION,METABOLISM,CELL PROLIFERATION… PLc CAN BE INHIBITED BY INHIBITORY Gi PROTIEN. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PHOSPHOLIPASE C--PATHWAY OF G-PROTIEN RECEPTORS The Ca2+-phosphoinositide signalling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulin-binding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol. Asterisk denotes activated state. Open arrows denote regulatory effects.):

PHOSPHOLIPASE C--PATHWAY OF G-PROTIEN RECEPTORS The Ca2+-phosphoinositide signalling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulin-binding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol. Asterisk denotes activated state. Open arrows denote regulatory effects.) RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PHOSPHOLIPASE C - PATHWAY OF G-PROTIEN RECEPTORS:

PHOSPHOLIPASE C - PATHWAY OF G-PROTIEN RECEPTORS RECEPTORS WITH PHOSPOLIPASE IP 3 -DAG PATHWAY: ADRENERGIC- α 1 HISTAMINE-H 1 MUSCARINIC-M 1, M 3 5-HT 2 VASOPRESSIN-OXYTOCIN BRADYKININ-B 2 ANGIOTENSIN-AT 1 PROSTAGLANDIN-FP,EP 1 ,EP 3 . THROMBOXANE-TP LEUKOTRIENE CHOLECYSTOKININ-GASTRIN PAF RECEPTOR BY DR.MOHAMMED ABDUL RAOF

CHANNEL REGULATION- PATHWAY OF G-PROTIEN RECEPTORS:

CHANNEL REGULATION- PATHWAY OF G-PROTIEN RECEPTORS THE ACTIVATED G-PROTIENS CAN ALSO OPEN OR CLOSE IONIC CHANNELS SPECIFIC FOR Ca2+,K+ OR Na+ WITHOUT THE INTERVENTION OF ANY SECOND MESSENGER LIKE Camp or ip3 AND BRING ABOUT HYPERPOLARIZATION/DEPOLARIZATION/CHANGES IN INTRACELLULAR Ca2 + Gs OPENS CALCIUM CHANNELS IN MYOCARDIUM & SKELETAL MUSCLES. Gi & Go OPENS POTASSIUM CHANNELS IN HEART & SMOOTH MUSCLES. PHYSIOLOGICAL RESPONSES LIKE CHANGES IN INOTROPY, CHRONOTROPY,TRANSMITTER RELEASE,NEURONAL ACTIVITY, SMOOTH MUSCLE RELAXATION IS ENABLED. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

CHANNEL REGULATION- PATHWAY OF G-PROTIEN RECEPTORS:

CHANNEL REGULATION- PATHWAY OF G-PROTIEN RECEPTORS Ca2+↑ Ca2+↓ K+↑ ADRENERGIC- β 1 (heart, skeletal muscle) DOPAMINE-D2 ADRENERGIC- α 2 GABA B MUSCARINIC-M 2 OPIOD- κ DOPAMINE-D2 ADENOSINE-A 1 5-HT 1A SOMATOSTATIN GABA B OPIOD-µ, δ ADENOSINE-A 1 THE ACTIVATED G-PROTIENS CAN ALSO OPEN OR CLOSE IONIC CHANNELS SPECIFIC FOR Ca2+,K+ OR Na+ WITHOUT THE INTERVENTION OF ANY SECOND MESSENGER LIKE Camp or ip 3 AND BRING ABOUT HYPERPOLARIZATION/DEPOLARIZATION/CHANGES IN INTRACELLULAR Ca2+ RECEPTOR BY DR.MOHAMMED ABDUL RAOF

TYROSINE RECEPTORS/TRK:

TYROSINE RECEPTORS/T RK TYROSINE RECEPTORS ARE COMPOSED OF A SINGLE HELIX TRANSMEMBRANE WITH AN EXTR-CELLULAR LIGAND-BINDING DOMAIN,A TRANS-MEMBRANE AND AN INTRACELLULAR DOMAIN THAT HAS TYROSINE KINASE ACTIVITY . SIGNAL TRANSDUCTION GENERALLY INVOLVES DIMENSION OF RECEPTORS, FOLLOWED BY AUTOPHOSPHORLYATION OF TYROSINE RESIDUES. THE PHOSHOTYROSINE RESIDUE ACTS AS ACCEPTORS FOR THE SH2 DOMAIN'S OF A VARIETY OF INTERCELLULAR PROTIENS,THEREBY ALLOWING CONTROL OF MANY CELL FUNCTIONS. ENZYME INVOLVED EXAMPLES OF LIGANDS THAT BIND TO TYROSINE KINASE ARE- INSULIN,NERVE GROWTH FACTOR,PLATELET DERIVED GROWTH CYTOKINES & OTHER GROWTH FACTORS. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PowerPoint Presentation:

RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PowerPoint Presentation:

RECEPTOR BY DR.MOHAMMED ABDUL RAOF

TYROSINE RECEPTORS/TRK:

TYROSINE RECEPTORS/TRK A FEW HORMONE RECEPTORS (ATRIAL NATRIURETIC FACTOR) HAVE A SIMILAR STRUCTURE AND LINKED TO GUANYLATE CYCLASE. CYTOKINE RECEPTORS HAVE AN INTRACELLULAR DOMAIN THAT BINDS AND ACTIVATES CYTOSOLIC KINASES WHEN THE RECEPTORS IS OCCUPIED. THEY ARE INVOLVED IN THE CELL GROWTH AND DIFFERENTIATION, THEY ALSO ACT INDIRECTLY BY REGULATING GENE TRANSCRIPTION. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Tyrosine kinase receptor:

Tyrosine kinase receptor RECEPTOR BY DR.MOHAMMED ABDUL RAOF

TYROSINE RECEPTORS:

TYROSINE RECEPTORS RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Kinase linked receptors . :

Kinase linked receptors . two important pathways are: - the RAS() → RAF() → MAP kinase →GENE TRANSCRIPTION pathway which is important for the cell division, growth and differentiation. - the JAK(JANUS-KINASE) → STAT(SIGNAL TRANSDUCERS & ACTIVATORS OF TRANSCRIPTION) →GENE TRANSCRIPTION pathway, which is activated by many cytokines which is important for the synthesis and release of many inflammatory mediators. TWO OTHER LESS IMPOTANT PATHWAYS ARE PLC- γ & P. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK)are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate-transcription. :

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules ( JAK)are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate-transcription . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

NUCLEAR RECEPTOR:

NUCLEAR RECEPTOR LIGANDS INCLUDE STERIOD HORMONES,THYROID HORMONES,VITAMIN D,RETINOIC ACID,LIPID-LOWERING DRUGS. RECEPTORS ARE INTRACELLULAR PROTIENS,SO LIGANDS MUST FIRST ENTER CELLS. RECEPTORS CONSIST OF A CONSERVED DNA- BINDING DOMIAN ATTACHED TO VARIABLE LIGAND-BINDING AND TRANSCRIPTIONAL CONTROL DOMAINS. DNA-BINDING DOMAIN RECOGNISES SPECIFICBASE SEQUENCES,THUS PROMOTING OR REPRESSING PARTICULAR GENES . RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Nuclear receptor:

Nuclear receptor RECEPTOR BY DR.MOHAMMED ABDUL RAOF

NUCLEAR RECEPTOR:

NUCLEAR RECEPTOR RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PowerPoint Presentation:

PATTERN OF GENES ACTIVATION DEPENDS ON BOTH CELL TYPE AND NATURE OF LIGAND,SO EFFECTS ARE HIGHLY DIVERSE. EFFECTS UCED AS A RESULT OF ALTERED PROTIEN SYNTHESIS AND THEREFORE ARE SLOW IN ONSET. ONE TYPE OF NUCLEAR RECEPTOR IS RESPONSIBLE FOR THE INCREASED EXPRESSION OF DRUG-METABOLIZING ENZYMES. NUCLEAR RECEPTOR RECEPTOR BY DR.MOHAMMED ABDUL RAOF

NUCLEAR RECEPTOR IN ACTION:

NUCLEAR RECEPTOR IN ACTION RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Nuclear receptor in action:

Nuclear receptor in action RECEPTOR BY DR.MOHAMMED ABDUL RAOF

DISEASES ASSOCIATED WITH RECEPTOR ABNORMALITIES:

DISEASES ASSOCIATED WITH RECEPTOR ABNORMALITIES ANY ALTERATION IN THE RECEPTORS EITHER IN FUNCTION,DENSITY OR DAMAGE CAN CAUSE MANY CLINICAL ABNORMALITIES/AUTOIMMUNE STATES. TESTICULAR FEMINIZATION SYNDROME (LOSS OF ANDROGEN RECEPTORS) MYASTHENIA GRAVIS (LOSS OF NICOTINIC CHOLINERGIC RECEPTORS) DIABETES MELLITUS (LOSS/DAMAGED INSULIN RECEPTORS) RECEPTOR BY DR.MOHAMMED ABDUL RAOF

NON-RECEPTOR MEDIATED MECHANISMS:

NON-RECEPTOR MEDIATED MECHANISMS SOME DRUGS ACT BY DIFFERENT MECHANISMS WITHOUT THE PARTICIPATION OF RECEPTORS by— -ENZYMES:H+/K+ ATPase inhibited by OMEPRAZOLE. -PHYSICAL & CHEMICAL PROPERTIES: ANTACIDS & EDTA. -ADSORBENT ACTION: PECTIN & KAOLIN. -OSMOSIS:DEXTRAN & MAGNESIUM SULFATE. -ANTI METABOLITES: ANTI PROLIFERATIVE drugs. -PLACEBO PALLIATIVE THERAPY. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

REFERENCES:

REFERENCES Goodman & Gilman’s-the pharmacological basis of therapeutics(12 th edition). Rang & Dale-Textbook of pharmacology(7 th edition ). Principles of Pharmacology(2 nd edition)-Sharma & Sharma. Katzung’s-Basic and Clinical Pharmacology(11 th edition). Bennet & Brown-Clinical pharmacology(9 th edition). Tripathi’s textbook of pharmacology. Netter’s illustrated pharmacology. Internet. RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PowerPoint Presentation:

FOR A PHARMACOLOGIST … RECEPTOR BY DR.MOHAMMED ABDUL RAOF

PowerPoint Presentation:

THANK YOU RECEPTOR BY DR.MOHAMMED ABDUL RAOF

Acknowledgements:

A cknowledgements MY KIDS… ZAMARUD ZAINAB ZAIN RECEPTOR BY DR.MOHAMMED ABDUL RAOF

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