Valence electron - Revision history

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2014-12-17T20:12:44Z

Reverted edits by 207.235.163.2 (talk) (HG)

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76.218.49.175: /* References */

2014-02-18T23:38:48Z

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en>Materialscientist: Reverted edits by 75.97.193.89 (talk) to last version by Dirac66

2014-01-28T23:09:35Z

Reverted edits by 75.97.193.89 (talk) to last version by Dirac66

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{{Other uses|Receptor (disambiguation)}}
{{Technical|date=May 2008}}
In [[biochemistry]] and [[pharmacology]], a '''receptor''' is a protein [[molecule]] usually found inside or on the surface of a [[Cell (biology)|cell]], that receives chemical signals from outside the cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, e.g. change in the electrical activity of the cell. In this sense, a receptor is a protein molecule that recognises and responds to endogenous chemical signals, e.g. the acetylcholine receptor recognised and responds to its endogenous ligand, acetylcholine. However sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels.

Receptor [[protein]]s are embedded in either the cell's [[plasma membrane]] ([[cell surface receptor]]s), the [[cytoplasm]](cytoplasmic receptors), or in the [[cell nucleus|nucleus]] ([[nuclear receptor]]s). A molecule that binds to a receptor is called a [[ligand (biochemistry)|ligand]], and can be a [[peptide]] (short protein) or another [[small molecule]] such as a [[neurotransmitter]], [[hormone]], pharmaceutical drug, or toxin. The endogenously designated molecule for a particular receptor is referred to as its endogenous ligand. E.g. the endogenous ligand for the nicotinic acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine and blocked by curare.
Each receptor is linked to a specific cellular biochemical pathway. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway.

== Structure ==
[[File:Transmembrane receptor.svg|thumb|right|Transmembrane receptor:E=extracellular space; I=intracellular space; P=plasma membrane]]
The structures of receptors are very diverse and can broadly be classified into the following categories:
* Type 1: L (ionotropic receptors)– These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA and activation of these receptor results in changes in ion movement across the membrane. They have a hetero structure. Each subunit consists of the extracellular ligand-binding domain and a transmembrane domain where the transmembrane domain in turn includes four transmembrane alpha helixes. The ligand binding cavities are located at the interface between the subunits.
* Type 2: [[G protein-coupled receptor]]s (metabotropic) – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic glutamate. They are composed of seven transmembrane [[alpha helix|alpha helices]]. The loops connecting the alpha helices form extracellular and intracellular domains. The binding site for larger peptidic ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptidic ligands is often located between the seven alpha helices and one extracellular loop.<ref name="pmid19912230">{{cite journal | author = Congreve M, Marshall F | title = The impact of GPCR structures on pharmacology and structure-based drug design | journal = Br. J. Pharmacol. | volume = 159 | issue = 5 | pages = 986–96 |date=March 2010 | pmid = 19912230 | pmc = 2839258 | doi = 10.1111/j.1476-5381.2009.00476.x | url = }}</ref> These receptors are coupled to different intracellular effector systems via G-proteins.
* Type 3: kinase linked and related receptors - These receptors are composed of an extracellular domain containing the ligand binding site and an an intracellular domain, often with enzymatic function, linked by a single transmembrane alpha helix. e.g. the insulin receptor.
* Type 4: [[nuclear receptor]]s – While they are called nuclear receptors, these are actually located in the cytosol and migrate to the nucleus after binding with their ligands. They are composed of a [[C-terminus|C-terminal]] ligand binding region, a core [[DNA-binding domain]] (DBD) and an [[N-terminus|N-terminal]] domain that contains the ''AF1''(activation function 1) region. The core region has two zinc fingers that are responsible for recognising the DNA sequences specific to this receptor. The N-terminal interacts with other cellular transcription factors in a ligand independent manner and depending on these interactions it can modify the binding/activity of the receptor. Steroid and thyroid hormone recptors are examples of such receptors. <ref>{{cite book |author= Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G | year=2012 | edition= 7th | title= Rang & Dale's Pharmacology |publisher= Elsevier Churchill Livingstone |isbn= 978-0-7020-3471-8}}</ref>

Membrane receptors may be isolated from cell membranes by complex extraction procedures using [[Liquid-liquid extraction|solvents]], [[detergents]], and/or [[affinity purification]].

The structures and actions of receptors may be studied by using biophysical methods such as [[X-ray_crystallography#Biological_macromolecular_crystallography|X-ray crystallography]], [[Nuclear magnetic resonance spectroscopy of proteins|NMR]], [[circular dichroism]], and [[dual polarisation interferometry]]. [[Computer simulation]]s of the dynamic behavior of receptors have been used to gain understanding of their mechanism of action.

== Binding and activation ==
Ligand binding is an [[chemical equilibrium|equilibrium]] process. Ligands bind to receptors and dissociate from them according to the [[law of mass action]].

:<math>\left[\mathrm{Ligand}\right] \cdot \left[\mathrm{Receptor}\right]\;\;\overset{K_d}{\rightleftharpoons}\;\;\left[\text{Ligand-receptor complex}\right] </math>
: (the brackets stand for concentrations)</center>

One measure of how well a molecule fits a receptor is the binding affinity, which is inversely related to the [[dissociation constant]] ''K''''d''. A good fit corresponds with high affinity and low ''K''''d''. The final biological response (e.g. [[second messenger system|second messenger cascade]], muscle contraction), is only achieved after a significant number of receptors are activated.

Affinity is a measure of the tendency of the ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate the receptor.

=== Agonists versus antagonists ===
[[File:Efficacy spectrum.png|right|thumb|320px|Efficacy spectrum of receptor ligands.]]
Not every ligand that binds to a receptor also activates the receptor. The following classes of ligands exist:

* ''(Full) [[agonist]]s'' are able to activate the receptor and result in a maximal biological response. The natural [[endogenous]] ligand with the greatest [[intrinsic activity|efficacy]] for a given receptor is by definition a full agonist (100% efficacy).
* ''[[Partial agonist]]s'' do not activate receptors with maximal efficacy, even with maximal binding, causing responses which are partial compared to those of full agonists (efficacy between 0 and 100%).
* [[Receptor antagonist|''Antagonists'']] bind to receptors but do not activate them. This results in receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible antagonists that form covalent bonds with the receptor and completely block it. The protein pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors.
* ''[[Inverse agonist]]s'' reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy).
* ''Allosteric modulators'': These do not bind to the agonist binding site of the receptor but instead on specific allosteric binding sites, through which they modify the effect of the agonist, e.g. benzodiazepines (BZDs) bind to the BZD site on the GABA-A receptor and potentiate the effect of endogenous GABA.

Note that idea of receptor agonism and antagonism only refers to interaction between receptors and ligands and not their biological effects.

=== Constitutive activity ===
A receptor which is capable of producing its biological response in the absence of a bound ligand is said to display "constitutive activity".<ref name="Milligan_2003">{{cite journal | author = Milligan G | title = Constitutive activity and inverse agonists of G protein-coupled receptors: a current perspective | journal = Mol. Pharmacol. | volume = 64 | issue = 6 | pages = 1271–6 |date=December 2003 | pmid = 14645655 | doi = 10.1124/mol.64.6.1271 }}</ref> The constitutive activity of a receptor may be blocked by an [[inverse agonist]]. The anti-obesity drugs rimonabant and tarannabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.

Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).

=== Theories of drug receptor interaction ===

==== Occupation theory ====

The central dogma of receptor pharmacology is that drug effect is directly proportional to number of receptors occupied. Furthermore, drug effect ceases as drug-receptor complex dissociates.

[[Everhardus Jacobus Ariëns|Ariëns]] & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors.<ref name="pmid13229418">{{cite journal | author = Ariens EJ | title = Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory | journal = Arch Int Pharmacodyn Ther | volume = 99 | issue = 1 | pages = 32–49 |date=September 1954 | pmid = 13229418 | doi = | url = }}</ref><ref name="pmid13383117">{{cite journal | author = Stephenson RP | title = A modification of receptor theory | journal = Br J Pharmacol Chemother | volume = 11 | issue = 4 | pages = 379–93 |date=December 1956 | pmid = 13383117 | pmc = 1510558 | doi = 10.1111/j.1476-5381.1956.tb00006.x | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1510558/?page=1 }}</ref>

* [[Dissociation_constant#Protein-ligand_binding|Affinity]]: ability of the drug to combine with receptor to create drug-receptor complex
* [[Intrinsic activity|Efficacy]]: ability of the drug-receptor complex to initiate a response

==== Rate theory ====

In contrast to the accepted ''occupation theory'', rate theory proposes that the activation of receptors is directly proportional to the total number of encounters of the drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, '''not''' number of receptors occupied:<ref name="isbn0-12-643732-7">{{cite book | author = Silverman RB | title = The Organic Chemistry of Drug Design and Drug Action | edition = 2nd | publisher = Elsevier Academic Press | location = Amsterdam | year = 2004 | isbn = 0-12-643732-7 | pages = | chapter = 3.2.C Theories for Drug—Receptor Interactions }}</ref>

* Agonist: drug with fast association & fast dissociation
* Partial agonist: drug with intermediate association & intermediate dissociation
* Antagonist: drug with fast association & slow dissociation

==== Induced fit theory ====

As the drug approaches the receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex.

==== Spare receptors ====

In some receptor systems e.g. acetylcholine at the neuromuscular junction in smooth muscle, agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus the system has spare receptors or receptor reserve. This arrangement produces an economy of neurotransmitter production and release. <ref>{{cite book |author= Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G | year=2012 | edition= 7th | title= Rang & Dale's Pharmacology |publisher= Elsevier Churchill Livingstone |isbn= 978-0-7020-3471-8}}</ref>

== Receptor regulation ==
Cells can increase ([[upregulate]]) or decrease ([[downregulate]]) the number of receptors to a given [[hormone]] or [[neurotransmitter]] to alter its sensitivity to this molecule. This is a locally acting [[feedback]] mechanism.

* Change in the receptor conformation such that binding of the agonist does not activate the receptor. This is seen with ion channel receptors.
* [[Protein quaternary structure|Uncoupling]] of the receptor [[G protein-coupled receptor#G-protein activation/deactivation cycle|effector molecules]] is seen with G-protein couple receptor.
* Receptor [[Endocytosis|sequestration]] (internalization).<ref> {{cite journal |author= Boulay G, Chrétien L, Richard DE, Guillemette G |date= November 1994 |title= Short-term desensitization of the angiotensin II receptor of bovinde adrenal glomerulosa cells corresponds to a shift from a high to low affinity state |journal= Endocrinology |volume=135 |issue=5 |pages= 2130-6|accessdate=23 January 2014}}</ref> e.g. in the case of hormone receptors.

== Ligands ==

The ligands for receptors are as diverse as their receptors. Examples include:<ref name="boron">{{cite book |author= Boulpaep, EL; Boron WF |date=2005. |title= Medical physiology: a cellular and molecular approach |location= St. Louis, Mo |publisher= Elsevier Saunders |page=90 |isbn=1-4160-2328-3}} </ref>

=== Extracellular ===
{| class="wikitable"
|-
| '''Receptor''' || '''Ligand''' || '''Ion current'''
|-
| [[Nicotinic acetylcholine receptor]] || [[Acetylcholine]], [[Nicotine]] || Na+, K+, Ca2+<ref name=boron/>

|-
| [[Glycine receptor]] (GlyR) || [[Glycine]], [[Strychnine]] || Cl− > HCO−3 <ref name=boron/>
|-
| [[GABA receptor]]s: GABA-A, GABA-C || [[GABA]] || Cl− > HCO−3 <ref name=boron/>
|-
| [[Glutamate receptor]]s: [[NMDA receptor]], [[AMPA receptor]], and [[Kainate receptor]] || [[Glutamate]] || Na+, K+, Ca2+ <ref name=boron/>
|-
| [[Serotonin receptor|5-HT3 receptor]] || [[Serotonin]] || Na+, K+ <ref name=boron/>
|-
| [[P2X receptors]] || [[Adenosine triphosphate|ATP]] || Ca2+, Na+, Mg2+ <ref name=boron/>
|-
|}

=== Intracellular ===
{| class="wikitable"
|-
| '''Receptor''' || '''Ligand''' || '''Ion current'''
|-
| [[cyclic nucleotide-gated ion channel]]s || [[cyclic guanosine monophosphate|cGMP]] ([[Visual system|vision]]), [[Cyclic adenosine monophosphate|cAMP]] and [[cyclic guanosine triphosphate|cGTP]] ([[Olfaction#Main olfactory system|olfaction]]) || Na+, K+ <ref name=boron/>
|-
| [[Inositol triphosphate receptor|IP3 receptor]] || [[inositol triphosphate|IP3]] || Ca2+ <ref name=boron/>
|-
| Intracellular [[Adenosine triphosphate|ATP]] receptors || [[Adenosine triphosphate|ATP]] (closes channel)<ref name=boron/> || K+ <ref name=boron/>
|-
| [[Ryanodine receptor]] || Ca2+ || Ca2+ <ref name=boron/>
|}

== Role in genetic disorders ==
Many [[genetic disorder]]s involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the [[hormone]] is produced at decreased level; this gives rise to the "pseudo-hypo-" group of [[endocrinology|endocrine disorders]], where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.

== In the immune system ==
{{Main|Immune receptor}}
The main receptors in the [[immune system]] are [[pattern recognition receptors]] (PRRs), [[toll-like receptor]]s (TLRs), [[killer activated receptor|killer activated]] and [[killer inhibitor receptor]]s (KARs and KIRs), [[complement receptor]]s, [[Fc receptors]], [[B cell receptor]]s and [[T cell receptor]]s.<ref name="isbn0-7817-9543-5">{{cite book | author = Waltenbaugh C, Doan T, Melvold R, Viselli S | title = Immunology | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2008 | page = 20 | isbn = 0-7817-9543-5 | oclc = | doi = | accessdate = }}</ref>

== See also ==
* [[Ki Database|Ki Database]]
* [[Ion channel linked receptors]]
* [[Neuropsychopharmacology]]
* [[Schild regression]] for ligand receptor inhibition
* [[Signal transduction]]
* [[Stem cell marker]]
* [[Wikipedia:MeSH D12.776#MeSH D12.776.543.750 – receptors.2C cell surface]]

==References==
{{Reflist|colwidth=35em}}

== External links ==
*[http://www.iuphar-db.org IUPHAR GPCR Database and Ion Channels Compendium]
*[http://receptome.stanford.edu/hpmr/Families/FamNav/famnav.asp?undefined Human plasma membrane receptome]
*{{MeshName|Cell+surface+receptors}}

{{Cell_signaling}}
{{Cell surface receptors}}
{{Immune receptors}}
{{Transcription factors|g2}}

{{DEFAULTSORT:Receptor (Biochemistry)}}
[[Category:Cell biology]]
[[Category:Cell signaling]]
[[Category:Membrane biology]]
[[Category:Receptors]]