CONTENTS
Introduction - receptor
Drug – receptor interactions
Ligand gated ion channel receptors
G – protein coupled receptors
Kinase liked receptors
Nuclear receptors
Comparison of receptor types
Conclusion
References
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.
DRUG RECEPTOR
INTERACTIONS
Effect of drug attributed to two factors
t Affinity : tendency of the drug to bind
to receptor and form D-R complex .
mEfficacy or intrinsic activity : ability of the
drug to trigger pharmacological responses
after forming D-R complex .
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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Enhanced
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Natura
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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CLASSIFICATION -
IUPHAR
Cell surface Intracellular
1. Inotropic. 1. Nuclear
receptors .
3. Metabotropic.
5. Ligand regulated
trans membrane.
Also called ionotropic receptors.
involved mainly in fast
synaptic transmission.
Eg: nAchR, GABAA, and
glutamate
receptors of the NMDA, AMPA
and kainate types.
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
STRUCTURE
ligand binding site in
extracellular domain.
5 subunits 2α, 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.
Ligand
binding
site
Cell Membrane
Ion Chan nel
0
ion channel receptor
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GATING MECHANISM IN
GABA A RECEPTOR
CONTD.
Due to the concentration changes of
different ions the following effects are
seen.
Increase in Na and Ca levels- excitatory
Decrease in Na and Ca levels- inhibitory
Increase in K levels – inhibitory
Decrease in K levels – excitatory
Increase in Cl levels – inhibitory
Decrease in Cl levels- excitatory
IMPORTANCE
Generation , propagation of nerve impulse.
Synaptic transmission of neurons.
Muscle contraction.
Salt balance.
Hormone release.
Muscle relaxants , anti-arrhythmatics
,anesthetics – act by blocking ion channels.
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 .
STRUCTURE
GPCR
3 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.
-ROLE
Membrane 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.
SUBTYPES
G-PROTEIN RECEPTOR FOR SIGNALLING
PATHWAY
GS Beta adrenergic Adenylyl cyclase
amines, glucagon
histamine, serotonin CAMP
•
Excitatory effects
Gi1, Gi2, Alpha2 adrenergic adenylyl cyclase
Gi3 amines, mAchR, CAMP
opioid, Cardiac K+
serotonin channel open-
heart rate
Olfactory epithelium Adenylyl cyclase
Golf –
CAMP
G- RECEPTOR SIGNALLING
PROTEIN FOR PATHWAY
GO NT ,Opioid Not clear
cannabinoid
Gq mAchR, PLC
serotonin IP3 , DAG
5HT1C Cytoplasmic Ca
Gt1 , Gt2 Rhodopsin
and colour cGMP
opsins in phosphodiesteras
retinal rod e- cGMP
and cone cells
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
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.
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.
ION CHANNELS
GPCR- directly control ion channel-without secondary
messenger. Eg. mAchR in heart – activate K+
channel.
SYSTEM
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.
Structure of Kinases linked
receptors
Extracellular domain
Binds to the ligand (growth factor)
Trans membrane domain
Y
Y
Intracellular domain
Y
Endogenous kinases
Y bind
Y
and get phosphorlated
Y
TYPES
receptor tyrosine kinases
Eg. EGF , NGF , insulin receptor
serine/ threonine kinases
Eg. TGF
cytokine receptors
Eg. Cytokines ,
CSF
guanylyl cyclase receptors
Eg. ANP
Gene
transcriptio Kinase cascade
n
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.
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.
AF2
AF1
-Binds with
corepressor
Zn fingers;hor
response
elements
Class I Hybrid Class II
class
Present Mainly Present in nucleus
in endocrine
cytoplasm •
Form •
Form hetero
•
Form homodimers hetero dimers with
•
Mainly endocrine; dimers with RXR
•
Associated with RXR •
Mainly lipids
heat shock •
Associated with
proteins. co-repressor
proteins.
High affinity Low
binding affinity
binding
GR, MR, ER, PR, TR, PPAR, LXR, FXR,
AR VDR, RXR
RAR
CLASS - I
homo
HRE-
hormone
response
elements
CLASS II
COMPARISON OF RECEPTORS
TYPES
INOTROPIC METABOTRO KINASE NUCLEAR
PIC LINKED
NO.OF
FAMILIES 483 217 135 4
8
LOCATIO
N MEMBRAN MEMBRANE MEMBRANE
E INTRACELLULA
R
TIME MILLI SECONDS HOURS HOURS
SCALE SECONDS
COUPLIN S DIRECT GABAA VIA
G G-PROTIEN
EXAMPLE nAchR, ADRENOCEP
TORS, DIR VIA DNA
mAchR ECT
STEROIDS
INSULI
N
CYTOKI
NES GF
CONCLUSION
Extensive 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.
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.
