Examine individual changes

'{{Other uses|Receptor (disambiguation)}} [[File:Membrane Receptors.svg|thumb|{{ordered list |[[Ligand (biochemistry)|Ligands]] |'''Receptors''' |[[Secondary messenger|Secondary messengers]]}} These are examples of [[membrane receptors]].]] In [[biochemistry]] and [[pharmacology]], a '''receptor''' is a [[protein]] [[molecule]] that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. In this sense, a receptor is a protein-molecule that recognizes and responds to [[endogeny|endogenous]] chemical signals, e.g. an acetylcholine receptor recognizes 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 all cells' plasma membranes; facing extracellular ([[cell surface receptor]]s), cytoplasmic (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 [[protein]] or [[peptide]] (short protein), or another [[small molecule]] such as a [[neurotransmitter]], [[hormone]], pharmaceutical drug, toxin, or parts of the outside of a virus or microbe. 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]].{{CN|date=September 2016}} 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 receptors results in changes in ion movement across a membrane. They have a heteromeric structure in that each subunit consists of the extracellular ligand-binding domain and a transmembrane domain where the transmembrane domain in turn includes four transmembrane [[alpha helix|alpha helices]]. 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 helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding-site for larger peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop.<ref name="pmid19912230">{{cite journal |vauthors=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> The aforementioned receptors are coupled to different intracellular effector systems via [[G protein|G proteins]].<ref name=" pmid=21873996 ">{{Cite journal | author = Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert|date=August 2011 | title = Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers| journal = Nature Chemical Biology | volume = 7 | issue = 11 | pages =740–747 | doi=10.1038/nchembio.642 | pmid=21873996 | pmc=3177959}}</ref> * Type 3: Kinase-linked and related receptors (see "[[Receptor tyrosine kinase]]", and "[[Enzyme-linked receptor]]") - They are composed of an extracellular domain containing the ligand binding site and an intracellular domain, often with enzymatic-function, linked by a single transmembrane alpha helix. The [[insulin receptor]] is an example. * Type 4: [[Nuclear receptor]]s – While they are called nuclear receptors, they are actually located in the [[cytoplasm]] and migrate to the [[cell nucleus|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 recognizing the DNA sequences specific to this receptor. The N terminus 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 receptors are examples of such receptors.<ref name="Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G 2012">{{cite book |authors=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 mechanisms 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) One measure of how well a molecule fits a receptor is its 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 a ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate its 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 that receptor. The following classes of ligands exist: * ''(Full) [[agonist]]s'' are able to activate the receptor and result in a strong 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 partial responses 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 a 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]] (or extremely high affinity non-covalent bonds) with the receptor and completely block it. The proton 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 regulation|Allosteric modulators]]'': They 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. For example, [[benzodiazepines]] (BZDs) bind to the BZD site on the [[GABAA receptor|GABA_A receptor]] and potentiate the effect of endogenous GABA. Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects. === Constitutive activity === A receptor which is capable of producing a 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 [[taranabant]] are inverse agonists at the cannabinoid [[cannabinoid receptor type I|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 a drug-effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a 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 | doi = 10.1111/j.1476-5381.1956.tb00006.x | pmc = 1510558 }}</ref> * [[Dissociation constant#Protein-ligand binding|Affinity]]: The ability of a drug to combine with a receptor to create a drug-receptor complex. * [[Intrinsic activity|Efficacy]]: The ability of a 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 a drug with its receptors per unit-time. Pharmacological-activity is directly proportional to the rates of dissociation and association, '''not''' the 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: A drug with a fast association and a fast dissociation. * Partial-agonist: A drug with an intermediate-association and an intermediate-dissociation. * Antagonist: A drug with a fast-association & slow-dissociation ==== Induced-fit theory ==== As a drug approaches a 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 that system has spare-receptors or a receptor-reserve. This arrangement produces an economy of neurotransmitter-production and release.<ref name="Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G 2012"/> == Receptor-regulation == Cells can increase ([[upregulate]]) or decrease ([[downregulate]]) the number of receptors to a given [[hormone]] or [[neurotransmitter]] to alter their sensitivity to different 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 |vauthors=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|doi=10.1210/en.135.5.2130}}</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 |author1=Boulpaep, EL |author2=Boron WF |year=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^&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 article|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 |vauthors=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}} {{genarch}} {{DEFAULTSORT:Receptor (Biochemistry)}} [[Category:Cell biology]] [[Category:Cell signaling]] [[Category:Membrane biology]] [[Category:Receptors]]'