drug receptors in pharmacology
TRANSCRIPT
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Presented byP.Bindu,M.Pharmacy 1st year,Department of Pharmacology,Sri padmavathi mahila viswavidyalayam,Tirupati.
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CONTENTSIntroduction - receptorDrug – receptor interactionsLigand gated ion channel receptorsG – protein coupled receptorsKinase liked receptorsNuclear receptorsComparison of receptor typesConclusionReferences
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WHAT IS A RECEPTOR?
Paul Ehrlich
Specialized areas of cell to which drugs get bound.
They are regulatory protein macro molecules .
drug should have –selectivity to a receptor ; receptor should have - ligand specificity to elicit action.
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DRUG RECEPTOR INTERACTIONS
Effect of drug attributed to two factors
1.Affinity : tendency of the drug to bind to receptor and form D-R complex .
2.Efficacy or intrinsic activity : ability of the drug to trigger pharmacological responses after forming D-R complex .
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CONTD…
Based on affinity and intrinsic activity :Full agonist : high affinity high intrinsic activity(=1)
Eg. Methacholine on acetylcholine receptors
Antagonist : only affinity no intrinsic activity (=0)Eg. Atropine on muscarinic receptors
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CONTD..
Partial agonist: full affinity intrinsic activity <1 (0 to 1)
Eg. Naloxene on opioid receptors saralasin on angiotensin receptors
Inverse agonist: full affinity intrinsic activity<0(0 to-1)
Eg. Beta carbolines on BZP receptor.
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RECEPTOR CLASSIFICATION - IUPHAR
1. Inotropic.
2. Metabotropic.
3. Ligand regulated trans membrane.
1. Nuclear receptors .
Cell surface Intracellular
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Also called ionotropic receptors.
involved mainly in fast synaptic transmission.
Eg: nAchR, GABAA, and glutamate receptors of the NMDA, AMPA and kainate types.
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FEATURES – ION CHANNELS
Protein molecules form water filled pores that span the membrane.
Switch between open and closed states.
Rate and Direction of movement depends on electrochemical gradient of the ions
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MOLECULAR STRUCTURE
ligand binding site in extracellular domain.
4 subunits α, β, γ and δ.
α2, β, γ - pentameric str - 2 ligand binding sites
Each subunit spans the membrane 4 times; all subunits form a central pore.
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Ligand binding site
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GATING MECHANISM IN GABAA RECEPTOR
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CONTD.
Due to the concentration changes of different ions the following effects are seen.
Increase in Na and Ca levels- excitatoryDecrease in Na and Ca levels- inhibitory
Increase in K levels – inhibitoryDecrease in K levels – excitatory
Increase in Cl levels – inhibitoryDecrease in Cl levels- excitatory
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ION CHANNELS - IMPORTANCEGeneration , propagation of nerve impulse.
Synaptic transmission of neurons.
Muscle contraction.
Salt balance.
Hormone release.
Muscle relaxants , anti-arrhythmatics ,anesthetics – act by blocking ion channels.
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metabotropic or 7-transmembrane-spanning (heptahelical) receptors.
coupled to intracellular effector systems via a G-protein.
mAChRs, adrenoceptors, dopamine, 5-HT, opiate, peptide, purinoceptors, orphans .
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MOLECULAR STRUCTURE
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FAMILIES OF GPCR3 families:A – rhodopsin family eg. Amine NT, purines , cannabinoids
B - secretin/glucagon receptor family Eg. Peptide hormones.
C - metabotropic glutamate receptor/calcium sensor family.
Eg. GABAB , Glutamate.
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G-PROTEIN -ROLEMembrane resident proteins – recognize activated GPCRs- pass message to effector system.
Occurs in interaction with guanine nucleotides ; freely moving in cytoplasm.
α, β and γ subunits – trimer in resting state.
3 subunits attached to GPCR through fatty acid chain – reaction called prenylation.
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G-PROTEIN SUBTYPES
G-PROTEIN
RECEPTOR FOR SIGNALLING PATHWAY
GS Beta adrenergic amines, glucagon histamine, serotonin
Adenylyl cyclase CAMP•Excitatory effects
Gi1, Gi2, Gi3
Alpha2 adrenergic amines, mAchR, opioid,serotonin
adenylyl cyclase CAMP Cardiac K+ channel open- heart rate
Golf Olfactory epithelium
Adenylyl cyclase – CAMP
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G-PROTEIN
RECEPTOR FOR
SIGNALLING PATHWAY
GO NT ,Opioidcannabinoid
Not clear
Gq mAchR, serotonin 5HT1C
PLC IP3 , DAG Cytoplasmic Ca
Gt1 , Gt2
Rhodopsin and colour opsins in retinal rod and cone cells
cGMP phosphodiesterase- cGMP
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SECONDARY MESSENGER SYSTEMS INVOLVED IN SIGNAL TRANSDUCTION
The adenyly cyclase / cAMP system
The Phospholipase C / inositol phosphate system
The Ion channels
The Rho A /Rho kinase system
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ADENYLYL CYCLASE/ CAMP SYSTEM
c AMP –nucleotide synthesized from ATP - by adenylyl cyclase, metabolized by PDE.
Regulate enzymes of metabolism, growth, contractile proteins of muscle.
NT - acts on GPCR –Gs/Gi activated - produce effects – by inc or dec. activity of adenylyl cylase-and cAMP.
c AMP- activate - Protein kinases-activate/inactivate enzymes by phosphorylation – cellular events.
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PHOSPHOLIPASE C-INOSITOL SYSTEM
Phospholipase C : Cleaves membrane phospholipids - phosphoinositides.
PLC beta – cleaves phosphatidylinositol(4,5)bis Phosphate PIP2 - into DAG and IP3.
DAG and IP3 - Secondary messenegers – elicit cellular responses.
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ION CHANNELS GPCR- directly control ion channel-without
secondary messenger. Eg. mAchR in heart – activate K+ channel.
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RHO A / RHO KINASE SYSTEM
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Involved in growth, proliferation, differentiation or survival-called growth factors.
Mediate actions of protein mediators- GF, cytokines , harmones- insulin and leptin.
Slow – require the expression of new genes.
Single membrane spanning helix - extracellular ligand binding domain - intracellular domain.
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Structure of Kinases linked receptors
Y
Y
Y
Y
Y
Y
Extracellular domainBinds to the ligand (growth factor)
Trans membrane domain
Intracellular domainEndogenous kinases bind and get
phosphorlated
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TYPESreceptor tyrosine kinases Eg. EGF , NGF , insulin receptor
serine/ threonine kinases Eg. TGF cytokine receptors Eg. Cytokines , CSF
guanylyl cyclase receptors Eg. ANP
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Kinase cascade
Gene transcription
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Important pathways activated :
1. The Ras/Raf/mitogen- activated protein (MAP) kinase pathway
- activated by tyrosine kinases. - important in cell division, growth, differentiation.
2. The Jak/Stat pathway - activated by cytokines. -controls synthesis and release of inflammatory mediators.
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Ligand activated transcription factors.
Present in soluble form – either in cytoplasm or nucleus – freely diffusable.
Transduce signals by- modifying gene transcription.
Eg: steroid hormones, glucocorticoids, vit D and A, orphan receptors
Play vital role in endocrine signaling and metabolic regulation.
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Zn fingers;hor response elements
-Binds with corepressor coactivator ptns
AF1
AF2
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Class I Hybrid class
Class II
Present in cytoplasm
Mainly endocrine
Present in nucleus
•Form homodimers•Mainly endocrine; •Associated with heat shock proteins.
•Form hetero dimers with RXR
•Form hetero dimers with RXR•Mainly lipids•Associated with co-repressor proteins.
High affinity binding
Low affinity binding
GR, MR, ER, PR, AR
TR, VDR, RAR
PPAR, LXR, FXR, RXR
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homo
HRE- hormone response elements
CLASS - I
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CLASS II
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COMPARISON OF RECEPTORS TYPES
INOTROPIC
METABOTROPIC
KINASE LINKED
NUCLEAR
NO.OF FAMILIES
483 217 135 48
LOCATION MEMBRANE MEMBRANE MEMBRANE INTRACELLULAR
TIME SCALE
MILLI SECONDS
SECONDS HOURS HOURS
COUPLING DIRECT VIA G-PROTIEN
DIRECT VIA DNA
EXAMPLES
nAchR,GABAA
ADRENOCEPTORS, mAchR
INSULINCYTOKINES
GF
STEROIDS
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CONCLUSIONExtensive research done on Receptor
pharmacology -lead to discovery of new drug targets for treatment of several diseases.
Still requires discovery of new receptor types and the mechanisms of many orphan receptors that can result in effective treatment of many diseases.
Requires development of receptor crystallization etc.
Much to be discovered about the nuclear receptors.
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REFERENCES
Rang , Dale, Ritter ,Flower :Rang and Dale’s pharmacology;6th edition, Churchill Livingstone;2008, 9-52.
Bertram G.Katzung : Basic and clinical pharmacology; 10th edition;2006.
KD Tripati: essentials of medical pharmacology ; 6th edition; 2008, 40-52.
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