Examine individual changes

'{{Other uses|Receptor (disambiguation)}} {{Technical|date=May 2008}} In the field of [[biochemistry]], a '''receptor''' is a [[molecule]] most often found on the surface of a [[Cell (biology)|cell]], which receives chemical signals originating externally from the cell. Through binding to a receptor, these signals direct a cell to do something—for example to divide or die, or to allow certain molecules to enter or exit. Receptors are [[protein]] molecules, embedded in either the [[plasma membrane]] ([[cell surface receptor]]s) or the [[cytoplasm]] or [[cell nucleus|nucleus]] ([[nuclear receptor]]s) of a cell, to which one or more specific kinds of [[signal transduction|signaling]] molecules may attach. A molecule which binds (attaches) to a receptor is called a [[ligand (biochemistry)|ligand]], and may be a [[peptide]] (short protein) or other [[small molecule]], such as a [[neurotransmitter]], a [[hormone]], a pharmaceutical drug, or a toxin. Numerous receptor types are found within a typical cell and each type is linked to a specific biochemical pathway. Furthermore each type of receptor recognizes and binds only certain ligand shapes (in analogy to a lock and key where the lock represents the receptor and the key, its ligand). Hence the selective binding of a specific ligand to its receptor activates or inhibits a specific biochemical pathway. Ligand binding stabilizes a certain receptor [[conformational change|conformation]] (the three-dimensional shape of the receptor protein). This is often associated with gain of or loss of protein activity, ordinarily leading to some sort of cellular response. However, some ligands (e.g. [[Receptor antagonist|antagonists]]) merely block receptors without inducing any response. Ligand-induced changes in receptors result in cellular changes which constitute the biological activity of the ligands. == 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: * [[peripheral membrane protein]]s * [[transmembrane protein]]s ** [[G protein-coupled receptor]]s – 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 | year = 2010 | month = March | pmid = 19912230 | pmc = 2839258 | doi = 10.1111/j.1476-5381.2009.00476.x | url = }}</ref> ** [[ligand-gated ion channel]]s – Have a hetero[[pentamer]]ic structure. Each subunit of consist of the extracellular ligand-binding domain and a transmembrane domain where the transmembrane domain in turn includes four transmembrane alpha helixes.<ref name="pmid15023997">{{cite journal | author = Cascio M | title = Structure and function of the glycine receptor and related nicotinicoid receptors | journal = J. Biol. Chem. | volume = 279 | issue = 19 | pages = 19383–6 | year = 2004 | pmid = 15023997 | doi = 10.1074/jbc.R300035200 }}</ref> The ligand binding cavities are located at the interface between the subunits. ** [[receptor tyrosine kinase]] – Functional receptors are homodimers. Each monomer possesses a single transmembrane alpha helix and an extracellular domain containing the ligand binding cavity and an intracellular domain with catalytic activity. * soluble [[globular protein]]s ** [[nuclear receptor]]s – Composed of a [[C-terminus|C-terminal]] [[DNA-binding domain]] (DBD) and a [[N-terminus|N-terminal]] ligand-binding domain (LDB). The LBD is composed of twelve alpha helices and an antiparallel [[beta sheet]]. The ligand binding cavity is buried within the interior of the LBD.<ref name="pmid10406480">{{cite journal | author = Kumar R, Thompson EB | title = The structure of the nuclear hormone receptors | journal = Steroids | volume = 64 | issue = 5 | pages = 310–9 | year = 1999 | month = May | pmid = 10406480 | doi = 10.1016/S0039-128X(99)00014-8| url = }}</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. The receptor-ligand affinity is greater than enzyme-substrate affinity.{{Citation needed|date=May 2009}} Whilst both interactions are specific and reversible, there is no chemical modification of the ligand as seen with the substrate upon binding to its enzyme. === 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 thoroughly, 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 blockage, inhibiting the binding of agonists and inverse agonists. * ''[[Inverse agonist]]s'' reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy). === 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 | year = 2003 | month = December | pmid = 14645655 | doi = 10.1124/mol.64.6.1271 }}</ref> The constitutive activity of receptors may be blocked by [[inverse agonist]] binding. 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. ==== Ariens & Stephenson ==== Ariens & 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 | year = 1954 | month = September | 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 | year = 1956 | month = December | pmid = 13383117 | pmc = 1510558 | doi = | url = }}</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:{{cn|date=December 2012}} * 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. == 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. * Receptor desensitization<ref name="Boulay_1994">{{cite journal | author = Boulay G, Chrétien L, Richard DE, Guillemette G | title = Short-term desensitization of the angiotensin II receptor of bovine adrenal glomerulosa cells corresponds to a shift from a high to a low affinity state | journal = Endocrinology | volume = 135 | issue = 5 | pages = 2130–6 | year = 1994 | month = November | pmid = 7956936 | doi = 10.1210/en.135.5.2130}}</ref> * [[Protein quaternary structure|Uncoupling]] of receptor [[G protein-coupled receptor#G-protein activation/deactivation cycle|effector molecules]]. * Receptor [[Endocytosis|sequestration]] (internalization).<ref name="Boulay_1994"/> == Types == === Transmembrane === {{main|Transmembrane receptor}} Three types of transmembrane receptors can be classified into families based on the way they transmit information into the interior of the cell:<ref name="Secko_2011">{{cite journal | author = Secko D | year = 2011 | month = | title = Cell surface receptors: a biological conduit for information transfer | journal = The Science Creative Quarterly | volume = | series = | issue = 6 | page = | pages = | publisher = | pmid = | pmc = | bibcode = | doi = | accessdate = | url = http://www.scq.ubc.ca/cell-surface-receptors-a-biological-conduit-for-information-transfer/ }}</ref> * G protein-linked * Ion channel-linked * Enzyme-linked Other transmembrane receptors include [[sigma receptor|sigma receptors]]. The entire repertoire of human plasma membrane receptors is listed at the Human Plasma Membrane Receptome.<ref name="pmid12815191">{{cite journal | author = Ben-Shlomo I, Yu Hsu S, Rauch R, Kowalski HW, Hsueh AJ | title = Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction | journal = Sci. STKE | volume = 2003 | issue = 187 | pages = RE9 | year = 2003 | month = June | pmid = 12815191 | doi = 10.1126/stke.2003.187.re9 }}</ref><ref name="urlHPMR - Human Plasma Membrane Receptome">{{cite web | url = http://www.receptome.org/HPMR/ | title = HPMR - Human Plasma Membrane Receptome | author = | authorlink = | coauthors = | date = | format = | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2011-12-27 }}</ref> ==== G protein-linked ==== {{main|G protein-coupled receptor|Metabotropic receptor}} G protein-coupled receptors (GPCRs) are also known as seven transmembrane receptors or 7TM receptors, because they possess seven transmembrane alpha helices.<ref name="pmid16902576">{{cite journal | author = Gobeil F, Fortier A, Zhu T, Bossolasco M, Leduc M, Grandbois M, Heveker N, Bkaily G, Chemtob S, Barbaz D | title = G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm | journal = Can. J. Physiol. Pharmacol. | volume = 84 | issue = 3–4 | pages = 287–97 | year = 2006 | pmid = 16902576 | doi = 10.1139/y05-127 }}</ref> Ligand activated GPCRs in turn activate an associated [[G-protein]] that in turn activates intracellular [[signaling cascade]]s. The GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:<ref name="pmid8170923">{{cite journal | author=Attwood TK, Findlay JB | title=Fingerprinting G-protein-coupled receptors | journal=Protein Eng | year=1994 | volume=7 | issue=2 | pages=195–203 | pmid=8170923 | url=http://peds.oxfordjournals.org/cgi/reprint/7/2/195 | doi=10.1093/protein/7.2.195}}</ref><ref>{{cite journal | author=Kolakowski LF Jr | title=GCRDb: a G-protein-coupled receptor database | journal=Receptors Channels | year=1994 | volume=2 | issue=1 | pages=1–7 | pmid=8081729}}</ref><ref name="pmid15914470">{{cite journal | author = Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ | title = International Union of Pharmacology. XLVI. G protein-coupled receptor list | journal = Pharmacol. Rev. | volume = 57 | issue = 2 | pages = 279–88 | year = 2005 | month = June | pmid = 15914470 | doi = 10.1124/pr.57.2.5 }}</ref><ref name="urlSearch for: gpcr">{{cite web | url = http://www.ebi.ac.uk/interpro/ISearch?query=gpcr | title = Search for: gpcr | author = | date = | work = [[InterPro]] | publisher = European Bioinformatics Institute | accessdate = 2011-12-27 }}</ref> * Class A (or 1) ([[Rhodopsin-like receptors|Rhodopsin-like]]) * Class B (or 2) ([[Secretin receptor family]]) * [[Class C GPCR|Class C]] (or 3) ([[Metabotropic glutamate receptor|Metabotropic glutamate]]/pheromone) * Class D (or 4) ([[Fungal mating pheromone receptors]]) * Class E (or 5) ([[Cyclic AMP receptors]]) * Class F (or 6) ([[Frizzled]]/[[Smoothened]]) ====Ion channel-linked==== {{main|Ligand gated ion channel|Ionotropic receptor}} Ligand gated ion channels also known as ionotropic receptors are [[heteromeric]] or [[homomeric]] [[oligomers]].<ref name="boron">{{cite book | author = Boulpaep, Emile L.; Walter F., PhD. Boron; Boron, Walter F. | title = Medical physiology: a cellular and molecular approach | publisher = Elsevier Saunders | location = St. Louis, Mo | year = 2005 | pages = | isbn = 1-4160-2328-3 | oclc = | doi = | page = 90 }}</ref> Binding of a ligand to the ion channel results in opening of the channel to increase ion flow through the channel or closing to decrease ion flow. ==== Enzyme-linked ==== {{main|Enzyme-linked receptor}} An enzyme-linked receptor also known as a catalytic receptor is a transmembrane receptor, where the binding of an extracellular [[ligand]] triggers [[enzymatic]] activity on the intracellular side.<ref name="Dudek2006">{{cite book|author=Ronald W. Dudek|title=High-yield cell and molecular biology|url=http://books.google.com/books?id=g-d--DOdnQAC&pg=PA19|accessdate=16 December 2010|date=1 November 2006|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6887-0|pages=19–}}</ref><ref name="pmid17279064">{{cite journal | author = Alexander SP, Mathie A, Peters JA | title = Catalytic Receptors | journal = Br. J. Pharmacol. | volume = 150 Suppl 1 | issue = S1| pages = S122–7 | year = 2007 | month = February | pmid = 17279064 | pmc = 2013840 | doi = 10.1038/sj.bjp.0707205 | url = }}</ref> ===== Tyrosine kinases ===== {{main|Receptor tyrosine kinase}} These receptors detect ligands through their extracellular domain and propagate signals via the [[tyrosine kinase]] of their intracellular domains. This family of receptors includes; * [[Erythropoietin receptor]] ([[Erythropoietin]]) * [[Insulin receptor]] ([[Insulin]]) * [[Eph receptor]]s * [[Insulin-like growth factor 1 receptor]] * various other [[growth factor receptor|growth factor]] and [[cytokine receptor]]s ==== Other ==== [[sigma receptor|Sigma receptors]]: * [[Sigma-1 receptor|sigma</sub>1</sub>]] ([[neuroactive steroid|neurosteroids]]) * [[Sigma-2 receptor|sigma</sub>2</sub>]] === Peripheral membrane === {{see also|Peripheral membrane protein}} These receptors are relatively rare compared to the much more common types of receptors that cross the cell membrane. An example of a receptor that is a peripheral membrane protein is the [[GLB1|elastin receptor]]. === Intracellular === {{Main|Intracellular receptor}} <!--additions here need to be mirrored there if possible--> ==== Transcription factors ==== * [[nuclear receptor]]: ** [[Steroid hormone receptor]] == Ligands == The ligands for receptors are as diverse as their receptors. Examples include: === Extracellular === {| class="wikitable" |- | '''Receptor''' || '''Ligand''' || '''Ion current''' |- | [[Nicotinic acetylcholine receptor]] || [[Acetylcholine]], [[Nicotine]] || Na⁺, K⁺, Ca²⁺ <ref name=boron/> |- | [[Glycine receptor]] (GlyR) || [[Glycine]], [[Strychnine]] || Cl^&minus; > HCO^&minus;₃ <ref name=boron/> |- | [[GABA receptor]]s: GABA-A, GABA-C || [[GABA]] || Cl^&minus; > HCO^&minus;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|K_i 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 &ndash; 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]] [[ar:مستقبل (كيمياء حيوية)]] [[ca:Receptor (bioquímica)]] [[cs:Receptor]] [[da:Receptor]] [[de:Rezeptor]] [[es:Receptor celular]] [[eo:Ricevanto (biologio)]] [[fa:گیرنده (بیوشیمی)]] [[fr:Récepteur (biochimie)]] [[id:Reseptor (biokimia)]] [[it:Recettore (biochimica)]] [[he:קולטן]] [[ht:Reseptè]] [[ku:Wergir (jînkîmya)]] [[lt:Receptorius (molekulė)]] [[hu:Receptor (biokémia)]] [[nl:Receptor (biochemie)]] [[ja:受容体]] [[pl:Białka receptorowe]] [[pt:Receptor (bioquímica)]] [[ro:Receptor (biochimie)]] [[ru:Клеточный рецептор]] [[simple:Biochemical receptor]] [[sl:Receptor (biokemija)]] [[sr:Receptor (biohemija)]] [[fi:Reseptori (biokemia)]] [[sv:Receptor]] [[th:หน่วยรับความรู้สึก]] [[tr:Reseptör (biyokimya)]] [[uk:Рецептор (біологія)]] [[vls:Receptor]] [[zh:受体 (生物化学)]]'