receptors introduction

7/31/2019 Receptors Introduction

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AN INTRODUCTION TO

RECEPTORS


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RECEPTORS

DEFINITION CLASSIFICATION MOLECULAR STRUCTURE IN BRIEF SIGNIFICANCE


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CONECPT OF RECEPTOR

Pioneers A.J. CLARK :Receptor theory

J.N LANGLEY :Nicotine, Atropine,Pilocarpine PAUL EHRLICH :Lock - Key RAYMOND AHLQUIST :Adrenoceptors


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TARGETS FOR DRUG ACTION

PROTEIN TARGETS RECEPTORS ION CHANNELS ENZYMES CARRIER MOLECULES (TRANSPORTERS).NON-PROTEIN TARGETS-Binding, neutralising, osmosis etc.


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RECEPTORS


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ION CHANNELS


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ENZYMES


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CARRIER MOLECULES (TRANSPORTERS).


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ACTIONS OF DRUGS NOT MEDIATED BY ANY OF THESE

Therapeutic neutralization of gastric acid by a base

(antacid ). Drugs: M annitol -increasing the osmolarity of various

body fluids and causing changes in the distribution of water to promote diuresis, catharsis, expansion of

circulating volume in the vascular compartment, orreduction of cerebral edema

Cholesterol-binding agents, ( cholestyramine resin ) todecrease dietary cholesterol absorption.


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RECEPTORS The term receptor: any cellular macromolecule to which a

drug binds to initiate its effects. Molecular structure (?) on the surface of or within the cell to

which the ligand bind A molecule which binds (attaches) to a receptor is called a

LIGAND ; - a peptide, or other small molecule, such as aneuorotransmitter, hormone, chemical/ drug or a toxin.

A class of cellular macromolecules (cellular proteins) that areconcerned specifically and directly with chemical signalingbetween and within cells.

Combination of a hormone, neurotransmitter, or intracellularmessenger with its receptor(s) results in a change in cellularactivity.

A receptor functions: recognize the particular moleculesthat activate ( act as receptors for endogenous regulatoryligands )+ Message propagation (alter cell function)


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RECEPTOR Macromolecules that bind mediator

substances and transduce this binding into aneffect, i.e., a change in cell function.

The component of a cell or organism that

interacts with a drug and initiates the chainof biochemical events leading to the drug'sobserved effects.

Isolation and characterization -the molecularbasis of drug action.


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Transmembrane Receptor


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RECEPTORS Ligand binding and message propagation (i.e., signalling) Functional domains within the receptor: a ligand-binding domain

and an effector domain. The regulatory actions of a receptor : Directly on its cellular

target(s), effect or protein(s), or may be conveyed by intermediarycellular signaling molecules : Transducers .

The receptor, its cellular target, and any intermediary molecules :Receptor effector system or signal-transduction pathway

An enzyme or transport protein that creates,moves, or degrades asmall metabolite (e.g., a cyclic nucleotide or inositol trisphosphate)or ion (e.g., Ca2+) : Second messenger . (Neuromediator)

Eg; cAMP.IP3, DAG, PDE etc Second messengers : diffuse in the proximity of their binding sites

and convey information to a variety of targets, which can respondsimultaneously to the output of a single receptor binding a singleagonist molecule.


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Receptor transducer effector signal termination complexes established via protein lipid and protein protein interactions.

Receptors and their associated effector and transducer proteins

also act as integrators of information as they coordinatesignals from multiple ligands with each other and with themetabolic activities of the cell.

An important property of physiological receptors : Excellent

targets for drugs- they act catalytically and hence arebiochemical signal amplifiers. The catalytic nature of receptors isobvious when the receptor itself is an enzyme

A single agonist molecule binds to a receptor that is an ionchannel, hundreds of thousands to millions of ions flow throughthe channel every second .

Similarly, a single steroid hormone molecule binds to itsreceptor and initiates the transcription of many copies of specific mRNAs, which , in turn, can give rise to multiple copiesof a single protein.


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D-R Chemical Bonds

DRUG- RECEPTOR COMPLEX Hydrogen

Covalent Ionic Vander Waals

Structure Activity Relationship ( SAR)Lock Key Theory


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Drugs that bind to physiological receptors and mimic theregulatory effects of the endogenous signalingcompounds are termed AGONISTS

(Affinity and efficacy: 1) Agents those bind to receptors without regulatory

effect, but their binding, blocks the binding of theendogenous agonist.:

ANTAGONISTS (Affinity1, efficacy 0) Agents that are only partly as effective as agonists no

matter the dose employed are: PARTIAL AGONISTS ( Affinity 1, Efficacy


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RECEPTOR HETEROGENEITY AND SUBTYPES

Receptors within a given family : Molecular varieties, orsubtypes, with similar architecture; differences in their

sequences, pharmacological properties. Distinct subtypes occur in different regions/organs, and

these differ from the receptors in other organ Eg: Ach-Nicotinic

The sequence variation that accounts for receptor diversityarises at the genomic level, i.e. different genes give rise todistinct receptor subtypes.

A single gene can give rise to more than one receptor isoform .

After translation from genomic DNA, the mRNA contains non-coding regions that are excised splicing before the message istranslated into protein.

Splicing : result in inclusion/deletion of one/more of the mRNAcoding regions, giving rise to long or short forms of the protein.

(eg: GPCR)


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RECEPTOR HETEROGENEITY AND SUBTYPES

Molecular heterogeneity : feature of receptors- functional proteins in general.

New receptor subtypes and isoforms : optionsfor therapy

Pharmacological viewpoint : To understandindividual drugs action, effects; Molecularpharmacology.


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TYPES/FAMILIES OF RECEPTORS

Based on molecular structure and the nature of thelinkage (the transduction mechanism)

Ligand-gated ion channels (Ionotropic)Nicotinic acetylcholine receptor, GABA A receptor

G-protein-coupled receptors (GPCRs)/MetabotropicMuscarinic acetylcholine receptor, adrenoceptors Kinase( Tyrosine)-linked and related receptorsInsulin, growth factors, cytokine receptorsNuclear/ Cytosol receptorssteroids, thyroid hormones, gonadal steroids,vit D


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Oligomeric assemblyof subunitssurrounding centralpore

The rectangularsegments :hydrophobic -helicalregions of protein,(20a.a)membrane-spanning domainsof the receptors

Comprise four or fivesubunits of the type

The whole complexcontain:16-20membrane-spanningsegments surroundinga central ion channel

Structure of the nicotinic acetylcholine receptor


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Structure of the nicotinic acetylcholine receptor(a typical ligand-gated ion channel)

The five receptor subunits ( 2,, , ) : a cluster surrounding acentral transmembrane pore

Contain negatively chargedaminoacids , which makes thepore cation selective.

Two acetylcholine binding sitesin the extracellular portion of the receptor, at the interfacebetween the and the adjoiningsubunits.

On ACh binding: kinked helicesstraighten out or swing out of the way, thus opening thechannel pore.


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Typical ligand-gated ion channel receptor


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Ligand-gated Ion Channel Receptor

The receptor complex consists of five subunits, each

of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh)

molecules to the two -subunits results in opening of the ion channel, with entry of Na+ (and exit of some

K+), membrane depolarization, and triggering of anaction potential

The ganglionic N-cholinoceptors apparently consistonly of and subunits ( 22). :

GABAA subtypeGlutamate and glycine


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GPCR

G C


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GPCR Typically " serpentine," with seven transmembrane spanning

domains, the third one of which is coupled to the G-protein

effector mechanism. The signaling molecule binds to the G-protein coupled

receptor This causes a change in the receptor so it is able to bind to an

inactive G protein. This causes a GTP to replace a GDP which activates a G

protein. Receptor systems coupled via GTP-binding proteins (G-

proteins) to adenylyl cyclase,( converts ATP to a secondmessenger cAMP,) that promotes protein phosphorylation byactivating protein kinase A.

The protein kinase A serves to phosphorylate a set of tissue-

specific substrate enzymes, thereby affecting their activity.


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GPCR


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GPCR


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Amino acid chain thatweaves in and out of themembrane in serpentinefashion

Seven transmembrane helices, with anextracellular N-terminaldomain of varying length,and an intracellular C-terminal domain

Binding of the mediatormolecule or of astructurally relatedagonist molecule - changein the conformation of the receptor protein,enabling the latter tointeract with a G-protein(=guanyl nucleotide-binding protein).


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G-PROTEIN-COUPLED RECEPTORS

The seven -helical membrane-spanning domains probably form acircle around a central pocket that carries the attachment sites for

the mediator substance. Binding of the mediator molecule or of a structurally related agonist

molecule induces a change in the conformation of the receptorprotein, enabling the latter to interact with a G-protein (= guanylnucleotide-binding protein).

G-proteins lie at the inner leaf of the plasmalemma and consist of three subunits designated , , and .

There are various G-proteins that differ mainly with regard to their -unit. Association with the receptor activates the G-protein,

leading in turn to activation of another protein (enzyme, ionchannel).

A large number of mediator substances act via G-protein-coupledreceptors


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Receptors That Function as Transmembrane Enzymes


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Receptors That Function as Transmembrane EnzymesTyrosine kinase linked receptors

Cell-surface receptors, Membrane-spanning macromolecules Bind a large variety of watersoluble ligands, including amines,

amino acids, lipids, peptides, and proteins. The ligand-binding domain is connected to the cytoplasmic

domain by a single transmembrane helix. In receptors with intrinsic enzymatic activity, the cytoplasmic

domain contains a conserved protein tyrosine kinase (PTK)core and additional regulatory sequences that are subjectedto autophosphorylation and phosphorylation by heterologousprotein kinases

Binding of the ligand causes confirmational changes so thatthe kinase domains become activated, ultimately leading tophosphorylation of tissue-specific substrat e proteins.

It initiates a unique cellular response for eachphosphorylated tyrosine.

Tyrosine kinase receptor


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Tyrosine kinase receptor


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Insulin and GH receptor

The insulin receptor protein : a Ligan d-operated enzyme , a catalytic receptor.

When insulin binds to the extracellularattachment site, a tyrosine kinase activity isswitched on at the intracellular portion.

Protein phosphorylation leads to altered cellfunction via the assembly of other signalproteins.


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Most growth factorreceptors incorporate

the ligand-binding andenzymatic (kinase)domains in the samemolecule

Cytokine receptors lackan intracellular kinasedomain but link tocytosolic kinasemolecules


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Intracellular Cytosol/ Nulcear Receptors


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y p

Binding of hormones or drugs to receptorsreleases regulatory proteins that permit of thehormone-receptor complex.

Such complexes interact with response elementson nuclear DNA to modify gene expression.

Eg: drugs interacting with glucocorticoidreceptors lead to gene expression of proteins thatinhibit the production of inflammatorymediators.

Pharmacologic responses elicited via modificationof gene expression are usually slower in onsetbut longer in duration than other drugs.


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Nuclear receptor


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Protein synthesis-regulating receptors

Binding of hormone exposes a normallyhidden domain of the receptor protein,thereby permitting the latter to bind to a

particular nucleotide sequence on a gene andto regulate its transcription.

Transcription is usually initiated or enhanced,

rarely blocked.


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SPARE RECEPTORS


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The production of a maximal tissue response when only a fraction of thetotal number of receptors are occupied

Eg: Acetylcholine analogues in isolated tissues, capable of elicitingmaximal responses at very low occupancies, often less than 1%. The mechanism linking the response to receptor occupancy has a

substantial reserve capacity. Such system-said to possess spare receptors ,or a receptor reserve .

Common with drugs : smooth muscle contraction; less for : RESPONSES-secretion, smooth muscle relaxation or cardiac stimulation: the effect ismore nearly proportional to receptor occupancy.

Do not imply any functional subdivision of the receptor pool, This surplus of receptors over the number actually needed might seem a

wasteful biological arrangement. It means, however, that a given numberof agonist-receptor complexes, corresponding to a given level of biologicalresponse, can be reached with a lower concentration of hormone orneurotransmitter than would be the case if fewer receptors wereprovided..

REGULATION OF RECEPTORS


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REGULATION OF RECEPTORS

Down regulation When tissues are continuously exposed to an

agonist, the number of receptors decreases--lead to a reduction in the number of receptors.( Tachyphylaxis) .

Up regulation Prolonged contact with an antagonist leads to

formation of new receptors-Up regulation.


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receptors introduction

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