Receptor

Course faculty:Professor Dr. Md. Shah Amran.

Faculty of Pharmacy ,University of DhakaGuest faculty of Department of pharmaceutical sciences

North South University

PREPAERD BY

Atiqur Rahman Nyeem -1320819046Md Samrul Islam -1321111046

Nusrat Jahan Khan - 1321022646Fatama Shoulin Taluckder-132111846Faria Iqbal -132

CONTENTS

Introduction - receptor

Drug – receptor interactions

Ligand gated ion channel receptors

G – protein coupled receptors

Enzyme liked receptors

Nuclear receptors

Comparison of receptor types

Conclusion

References

What Is A Receptor?Definition : Receptors are macromolecules , composed of lipoprotein . They are located on the cell membrane or inside the cell ( either in cytoplasm or nucleus). Receptor bind with drug and form drug- receptor complex.

The magnitude of the response is proportional to the number of drug–receptor complexes:

The receptor not only has the ability to recognize a ligand, but can also couple or transduce this binding into a response by causing a conformational change

)(Re/)(Re)( sponseComplexRDRceptorDDrug Kd

o AffinityThe capability of a drug to form the complex (Drug-Receptor Complex) with its receptor.

o Intrinsic activityThe ability of a drug to trigger the pharmacological response after making the drug-receptor complex.

D+R —> DRD: Drug or endogenous ligandR: ReceptorDR: Drug-Receptor Complex

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

Classification of receptor1)Cell-surface receptor : located on the cell membrane e.g.1. ion channel-linked receptors/ ligand gated receptor 2. G-protein-couple receptors, 3. And enzyme – linked receptor ( tyrosine kinase receptor )

2) Intracellular receptor : located on the cytoplasm e.g. steroid receptor

3) Nuclear receptor : located in the nucleus of the cell.e.g. thyroid receptor .

Ligand Gated Ion Channels

Also called ionotropic receptors.

They are responsible for regulation of the flow of ions across cell membrane

Involved mainly in fast synaptic transmission.

Eg: nAchR, GABAA, and glutamate receptors of the NMDA, AMPA and kainate types.

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.

Ligand binding site

Mechanism of action of Ligand Gated Ion Channel receptor

Ion channels - 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.

G-Protein Coupled Receptors

• G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein.

• All G-protein-linked receptors have seven transmembrane domains, each has its own specific extracellular domain

• E.g. adrenoceptors, dopamine, 5-HT, opiate, peptide, purinoceptors, orphans

• signaling molecule bind with extra cellular domain of receptor , conformational change occur.

• GDP in G- protein is replaced by GTP , which activate G-protein .

• G-protein – GTP complex dissociate from the receptor and activate one of this two pathway

1st pathway – adenylyl cyclase pathway (ALC) 2nd pathway - PLC pathway

Two Pathway

Adenylyl Cyclase System

cAmp-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 increasing or

decreasing activity of adenylyl cyclase and cAMP cAMP-activate-Protein kinases-activate/inactivate enzymes by

phosphorylation-cellular events.

Phospholipase C-Inositol System

Phospholipase C: Celaves membrane phospholipids-phosphoinositides PLC beta-cleaves phosphatidylinositol(4,5) bis Phosphae PIP2 into DAG and

IP3 DAG and IP3-Secondary messengers-elicit cellular response

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.

G-Protein SubtypesG-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 – CAMP21

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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ENZYME LINKED RECEPTORS

Ligand binds to the extracellular domain of kinase linked receptor , a signal is transferred through the membrane and activates the enzyme, which sets off a chain of events within the cell that eventually leads to a response.

The most common enzyme-linked receptors are those that have a tyrosine kinase activity as part of their structure.

Example :epidermal growth factor,

platelet-derived growth factor

atrial natriuretic peptide

insulin They have large extracellular and intracellular domains, but the

membrane-spanning region consists of a single alpha-helical region of the peptide strand.

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MECHANISM OF ENZYME LINKED RECEPTOR

NUCLEAR RECEPTORS

Ligand activated transcription factors.

Present in soluble form – either in cytoplasm or nucleus – freely diffusible.

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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Several diseases are result from alteration in receptors and their immediate signaling effectors . This principle mechanism involved are :

Autoantibodies directed against receptor proteins

Mutation of gene encoding receptors and protein involving receptors

Malfunctioning of receptors

Receptor diseases

Parkinson’s disease: Higher than normal density of dopamine receptors is found in the putamen and caudate nucleus

Hyperkplexia: Decreased affinity of glycine for the glycine receptor, due to a mutation in the glycine receptor

Myasthenia gravis : Where circulating antibodies against acetylcholine receptors decrease the number of receptors at the neuromuscular junction

Desensitization of receptors : A gradual decrease in the effect of a drug on continued or repeated administration

2 types:

1) Homologous desensitization : in which agonist desensitize the same receptor they activate.

2) Heterologous desensitize: In which agonist can desensitize other receptors

Hypersensitivity of receptors : This indicates an increase in the activity of receptors.

• This results rom prolonged suppression of receptor stimulation

• E.g. propranolol

Physiological effect of receptors

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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.RECEPTORS @ VPC31