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Receptor (biochemistry)From Wikipedia, the free encyclopedia

(Redirected from Receptor protein )For other uses, see Receptor (disambiguation) .

1. Ligands2. Receptors

. !econdary "essengers#hese are e$amples of membrane receptors .

%n biochemistry and pharmacology , a receptor is a protein &molecule that recei'es chemical&signals from outside a cell. When such chemical&signals bind to a receptor, they cause someform of cellular tissue&response, e.g. a change in the electrical&acti'ity of a cell. %n this sense,a receptor is a protein&molecule that recognises and responds to endogenous &chemical signals,e.g. an acetylcholine&receptor recogni es and responds to its endogenous&ligand,acetylcholine. *o+e'er, sometimes in pharmacology, the term is also used to include other

proteins that are drug&targets, such as en ymes, transporters and ion&channels.

Receptor& proteins are embedded in all cells plasmatic&membranes- facing e$tracellular&( cellsurface receptors ), cytoplasmic (cytoplasmic&receptors), or in the nucleus (nuclear receptors ).

molecule that binds to a receptor is called a ligand , and can be a peptide (short&protein) oranother small molecule such as a neurotransmitter , hormone , pharmaceutical&drug, to$in, or

parts of the outside of a 'irus or microbe. #he endogenously designated&molecule for a particular receptor is referred to as its endogenous&ligand. /.g. the endogenous&ligand for thenicotinic&acetylcholine receptor is acetylcholine but the receptor can also be acti'ated bynicotine and blocked by curare.

/ach receptor is linked to a specific cellular&biochemical path+ay. While numerous receptorsare found in most cells, each receptor +ill only bind +ith ligands of a particular structure,much like ho+ locks +ill only accept specifically shaped&keys. When a ligand binds to itscorresponding receptor, it acti'ates or inhibits the receptor s associated&biochemical path+ay.

Contents• 1 !tructure

• 2 0inding and acti'ation

o 2.1 gonists 'ersus antagonists

o 2.2 onstituti'e&acti'ity

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o 2. #heories of drug&receptor interaction

2. .1 ccupation&theory

2. .2 Rate&theory

2. . %nduced&fit theory

2. .3 !pare&receptors

• Receptor&regulation

• 3 Ligands

o 3.1 /$tracellular

o 3.2 %ntracellular

• 4 Role in genetic disorders

• 5 %n the immune system

• 6 !ee also

• 7 References

• 8 /$ternal links

Structure

#ransmembrane receptor9/:e$tracellular space- %:intracellular space- ;:plasma membrane

#he structures of receptors are 'ery di'erse and can broadly be classified into the follo+ingcategories9

• #ype 19 L (ionotropic&receptors)< #hese receptors are typically the targets of fast&neurotransmitters such as acetylcholine (nicotinic) and = 0 - and, acti'ation of thesereceptors results in changes in ion&mo'ement across a membrane. #hey ha'e a hetero&structure. /ach subunit consists of the e$tracellular&ligand&binding domain and atransmembrane&domain +here the transmembrane&domain in turn includes four

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transmembrane&alpha heli$es. #he ligand&binding ca'ities are located at the interface bet+een the subunits.

• #ype 29 = protein&coupled receptors (metabotropic) < #his is the largest family ofreceptors and includes the receptors for se'eral hormones and slo+ transmitters e.g.

dopamine, metabotropic&glutamate. #hey are composed of se'en transmembrane&alpha helices . #he loops connecting the alpha&helices form e$tracellular andintracellular&domains. #he binding&site for larger peptidic&ligands is usually located inthe e$tracellular&domain +hereas the binding&site for smaller non&peptidic ligands isoften located bet+een the se'en alpha&helices and one e$tracellular&loop. >1? #heaforementioned receptors are coupled to different intracellular&effector systems 'ia =&

proteins .>2?

• #ype 9 kinase linked and related receptors (see @ Receptor tyrosine kinase @, and@/n yme&linked receptor @) & #hey are composed of an e$tracellular&domain containingthe ligand&binding site and an intracellular&domain, often +ith en ymatic&function,linked by a single transmembrane&alpha heli$. e.g. the insulin&receptor.

• #ype 39 nuclear receptors < While they are called nuclear&receptors, they are actuallylocated in the cytosol and migrate to the nucleus after binding +ith their ligands. #heyare composed of a &terminal&ligand&binding region, a core&AB &binding domain (A0A) and an B&terminal&domain that contains the AF1 (acti'ation function 1) region.#he core&region has t+o inc&fingers that are responsible for recognising the AB &seCuences specific to this receptor. #he B&terminal interacts +ith other cellular&transcription factors in a ligand&independent manner- and, depending on theseinteractions it can modify the binding acti'ity of the receptor. !teroid and thyroid&hormone receptors are e$amples of such receptors. > ?

"embrane&receptors may be isolated from cell&membranes by comple$&e$traction proceduresusing sol'ents , detergents , and or affinity purification .

#he structures and actions of receptors may be studied by using biophysical&methods such asD&ray crystallography , B"R , circular dichroism , and dual polarisation interferometry .

omputer simulations of the dynamic&beha'ior of receptors ha'e been used to gainunderstanding of their mechanisms of action.

Binding and activation

Ligand&binding is an eCuilibrium process. Ligands bind to receptors and dissociate from themaccording to the la+ of mass action .

(the brackets stand for concentrations

ne measure of ho+ +ell a molecule fits a receptor is its binding&affinity, +hich is in'erselyrelated to the dissociation constant K d . good fit corresponds +ith high affinity and lo+ K d .#he final biological&response (e.g. second messenger cascade , muscle&contraction), is onlyachie'ed after a significant number of receptors are acti'ated.

ffinity is a measure of the tendency of a ligand to bind to its receptor. /fficacy is themeasure of the bound&ligand to acti'ate its receptor.

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Agonists versus antagonists

/fficacy spectrum of receptor ligands.

Bot e'ery ligand that binds to a receptor also acti'ates that receptor. #he follo+ing classes ofligands e$ist9

• (Full) agonists are able to acti'ate the receptor and result in a ma$imal&biologicalresponse. #he natural endogenous &ligand +ith the greatest efficacy for a gi'en

receptor is by definition a full&agonist (1EE efficacy).

• Partial agonists do not acti'ate receptors +ith ma$imal&efficacy, e'en +ith ma$imal binding, causing responses +hich are partial compared to those of full&agonists(efficacy bet+een E and 1EE ).

• Antagonists bind to receptors but do not acti'ate them. #his results in a receptor& blockade, inhibiting the binding of agonists and in'erse&agonists. Receptor&antagonistscan be competiti'e (or re'ersible), and compete +ith the agonist for the receptor, orthey can be irre'ersible&antagonists that form co'alent&bonds +ith the receptor andcompletely block it. #he protein&pump inhibitor omepra ole is an e$ample of anirre'ersible&antagonist. #he effects of irre'ersible antagonism can only be re'ersed bysynthesis of ne+ receptors.

• Inverse-agonists reduce the acti'ity of receptors by inhibiting their constituti'e&acti'ity (negati'e&efficacy).

• Allosteric-modulators 9 #hey do not bind to the agonist&binding site of the receptor butinstead on specific allosteric&binding sites, through +hich they modify the effect of theagonist, e.g. ben odia epines (0GAs) bind to the 0GA&site on the = 0 & receptorand potentiate the effect of endogenous&= 0 .

Bote that the idea of receptor&agonism and antagonism only refers to the interaction bet+eenreceptors and ligands and not to their biological&effects.

Constitutive-activity

receptor +hich is capable of producing a biological&response in the absence of a bound&ligand is said to display @constituti'e&acti'ity@. >3? #he constituti'e&acti'ity of a receptor may

be blocked by an in'erse agonist . #he anti&obesity drugs rimonabant and tarannabant arein'erse&agonists at the cannabinoid& 01 receptor and though they produced significant+eight&loss, both +ere +ithdra+n o+ing to a high incidence of depression and an$iety, +hich

are belie'ed to relate to the inhibition of the constituti'e&acti'ity of the cannabinoid&receptor.

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"utations in receptors that result in increased constituti'e&acti'ity underlie some inherited&diseases, such as precocious&puberty (due to mutations in luteini ing&hormone receptors) andhyperthyroidism (due to mutations in thyroid&stimulating hormone receptors).

Theories of drug-receptor interaction

Occupation-theory

#he central&dogma of receptor&pharmacology is that a drug&effect is directly proportional tothe number of receptors that are occupied. Furthermore, a drug effect ceases as a drug&receptor comple$ dissociates.

riHns I !tephenson introduced the terms @affinity@ I @efficacy@ to describe the action ofligands bound to receptors. >4?>5?

• ffinity 9 #he ability of a drug to combine +ith a receptor to create a drug&receptorcomple$.

• /fficacy 9 #he ability of a drug&receptor comple$ to initiate a response.

Rate-theory

%n contrast to the accepted occupation-theory , rate&theory proposes that the acti'ation ofreceptors is directly proportional to the total number of encounters of a drug +ith its receptors

per unit&time. ;harmacological&acti'ity is directly proportional to the rates of dissociation andassociation, not the number of receptors occupied9 >6?

• gonist9 drug +ith a fast association and a fast dissociation.

• ;artial&agonist9 drug +ith an intermediate&association and an intermediate&dissociation.

• ntagonist9 drug +ith a fast&association I slo+&dissociation

Induced-fit theory

s a drug approaches a receptor, the receptor alters the conformation of its binding&site to

produce drugJreceptor comple$.

Spare-receptors

%n some receptor&systems e.g. acetylcholine at the neuromuscular&Kunction in smooth&muscle,agonists are able to elicit ma$imal&response at 'ery lo+&le'els of receptor&occupancy ( 1 ).#hus that system has spare&receptors or a receptor&reser'e. #his arrangement produces aneconomy of neurotransmitter&production and release .> ?

Receptor-regu ation

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ells can increase ( upregulate ) or decrease ( do+nregulate ) the number of receptors to a gi'enhormone or neurotransmitter to alter their sensiti'ity to different molecule. #his is a locallyacting feedback mechanism.

• hange in the receptor conformation such that binding of the agonist does not acti'ate

the receptor. #his is seen +ith ion channel receptors.

• Mncoupling of the receptor effector molecules is seen +ith =&protein couple receptor.

• Receptor seCuestration (internali ation). >7? e.g. in the case of hormone receptors.

!igands

#he ligands for receptors are as di'erse as their receptors. /$amples include9 >8?

"#trace u ar

Receptor !igand Ion current

Bicotinic acetylcholine receptor cetylcholine , Bicotine Ba N, O N, a 2N>8?

=lycine receptor (=lyR) =lycine , !trychnine l P Q * P >8?

= 0 receptors 9 = 0 & , = 0 & = 0 l P Q * P >8?

=lutamate receptors 9 B"A receptor , "; receptor ,and Oainate receptor =lutamate Ba N, O N, a 2N >8?

4&*# receptor !erotonin Ba N, O N >8?

;2D receptors #; a2N

, BaN

, "g2N

>8?

Intrace u ar

Receptor !igand Ion current

cyclic nucleotide&gated ion channels c="; ('ision ), c "; and c=#; (olfaction ) Ba N, O N >8?

%; receptor %; a 2N >8?

%ntracellular #; receptors #; (closes channel) >8? O N >8?

Ryanodine receptor a2N

a2N

>8?

Ro e in genetic disorders

"any genetic disorders in'ol'e hereditary defects in receptor genes. ften, it is hard todetermine +hether the receptor is nonfunctional or the hormone is produced at decreasedle'el- this gi'es rise to the @pseudo&hypo&@ group of endocrine disorders , +here there appearsto be a decreased hormonal le'el +hile in fact it is the receptor that is not respondingsufficiently to the hormone.

In the immune system

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"ain article9 %mmune receptor

#he main receptors in the immune system are pattern recognition receptors (;RRs), toll&likereceptors (#LRs), killer acti'ated and killer inhibitor receptors (O Rs and O%Rs),complement receptors , Fc receptors , 0 cell receptors and # cell receptors .>1E?

See a so• O i Aatabase

• %on channel linked receptors

• Beuropsychopharmacology

• !child regression for ligand receptor inhibition

• !ignal transduction

• !tem cell marker

• Wikipedia9"e!* A12.665 "e!* A12.665.43 .64E < receptors.2 cell surface