Receptor (biochemistry) 569480 225802803 2008-07-15T13:57:08Z 140.203.12.243 added tags {{Cleanup-jargon|date=May 2008}} {{otheruses3|Receptor}} In [[biochemistry]], a '''receptor''' is a [[protein]] molecule, embedded in either the [[plasma membrane]] or [[cytoplasm]] of a cell, to which a mobile signaling (or "signal") molecule may attach. A molecule which binds to a receptor is called a "[[Ligand (biochemistry)|ligand]]," and may be a peptide (such as a [[neurotransmitter]]), a [[hormone]], a pharmaceutical drug, or a toxin, and when such binding occurs, the receptor ordinarily initiates a cellular response, though some ligands merely block receptors without inducing any response. Ligand-induced changes in receptors result in physiological changes which constitute the biological activity of the ligands. == Overview == The shapes and actions of receptors are studied by [[X-ray crystallography]] and computer modelling, which have advanced the understanding of [[drug action]] at the binding sites of receptors. [[Image:Transmembrane receptor.png|thumb|right|Transmembrane receptor:E=extracellular space; I=intracellular space; P=plasma membrane]] Depending on their functions and [[Ligand (biochemistry)|ligands]], several types of receptors may be identified: * Some receptor proteins are [[peripheral membrane protein]]s. * Many [[hormone receptor|hormone]] and [[neurotransmitter receptor]]s are [[transmembrane receptor|transmembrane proteins]]: transmembrane receptors are embedded in the [[phospholipid bilayer]] of [[cell membrane]]s, that allow the activation of [[signal transduction]] pathways in response to the activation by the binding molecule, or [[Ligand (biochemistry)|ligand]]. ** [[Metabotropic receptor]]s are coupled to [[G protein]]s and affect the cell indirectly through [[enzyme]]s which control [[ion channel]]s. ** [[Ionotropic receptor]]s contain a central pore which functions as a ligand-gated ion channel. * Another major class of receptors are [[intracellular]] proteins such as those for [[steroid]] and [[intracrine]] [[peptide hormone]] receptors. These receptors often can enter the [[cell nucleus]] and modulate [[gene expression]] in response to the activation by the ligand. == 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]]. <center>:<math>\left[\mathrm{Ligand}\right] \cdot \left[\mathrm{Receptor}\right]\;\;\overset{ K_d}{\rightleftharpoons}\;\;\left[\mbox{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<sub>d</sub>. A good fit corresponds with high affinity and low K<sub>d</sub>. The activation of the [[second messenger system|second messenger cascade]], and the final biological response, are achieved only when, after a certain delay, a significant number of receptors are activated. If the receptor exists in two states (see [http://www.bio-balance.com/Receptor2.htm this picture]), then the ligand binding must account for these two receptor states. For a more detailed discussion of two-state binding, which is thought to occur as an activation mechanism in many receptors see [http://www.bio-balance.com/Graphics.htm this link]. ===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="Milligan2003">{{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 |url=}}</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). [[Psychostimulant]]s act as inverse agonists on [[dopamine receptors]]. For the use of [[statistical mechanics]] in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article<ref> Vu-Quoc, L., [http://clesm.mae.ufl.edu/wiki.pub/index.php/Configuration_integral_%28statistical_mechanics%29 Configuration integral (statistical mechanics)], 2008. </ref> on the [[configuration integral]]. ==[[Agonist]]s versus [[Receptor antagonist|antagonist]]s == Not every ligand that binds to a receptor also activates the receptor. The following classes of ligands exist: * ''(Full) agonists'' are able to activate the receptor and result in a maximal biological response. Most natural ligands are full agonists. * ''Partial agonists'' do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists. * ''Antagonists'' bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists. * ''Inverse agonists'' reduce the activity of receptors by inhibiting their constitutive activity. == Peripheral membrane protein receptors == {{seealso|Peripheral membrane protein}} ==Transmembrane receptors== {{main|Transmembrane receptor}} === Metabotropic receptors === {{main|Metabotropic receptor}} ==== G protein-coupled receptors ==== {{main|G protein-coupled receptor}} These receptors are also known as '''seven transmembrane receptors''' or '''7TM''' receptors, because they pass through the membrane seven times. * [[Muscarinic acetylcholine receptor]] ([[Acetylcholine]] and [[Muscarine]]) * [[Adenosine receptor]]s ([[Adenosine]]) * [[Adrenoceptor]]s (also known as [[Adrenergic receptor]]s, for [[adrenaline|''adren''aline]], and other structurally related [[hormone]]s and [[medication|drugs]]) * [[GABA receptor]]s, Type-B ([[Gamma-aminobutyric acid|γ-Aminobutyric acid]] or GABA) * [[Angiotensin receptor]]s ([[Angiotensin]]) * [[Cannabinoid receptor]]s ([[Cannabinoids]]) * [[Cholecystokinin receptor]]s ([[Cholecystokinin]]) * [[Dopamine receptor]]s ([[Dopamine]]) * [[Glucagon receptor]]s ([[Glucagon]]) * [[Metabotropic glutamate receptor]]s ([[Glutamate]]) * [[Histamine receptor]]s ([[Histamine]]) * [[Olfactory receptor]]s (for the [[Olfaction|sense of smell]]) * [[Opioid receptor]]s ([[Opioid]]s) * [[Rhodopsin]] (a [[photoreceptor]]) * [[Secretin receptor]]s ([[Secretin]]) * [[Serotonin receptor]]s, except Type-3 ([[Serotonin]], also known as 5-Hydroxytryptamine or 5-HT) * [[Somatostatin receptor]]s ([[Somatostatin]]) * [[Calcium-sensing receptor]] ([[Calcium]]) * [[Chemokine receptors]] ([[Chemokines]]) * ''many more'' ... {{Expand-section|date=June 2008}} ==== Receptor tyrosine kinases ==== {{main|Receptor tyrosine kinase}} These receptors detect ligands 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 * .... ==== Guanylyl cyclase receptors ==== * GC-A & GC-B: receptors for [[Atrial-natriuretic peptide]] (ANP) and other natriuretic peptides * GC-C: [[Guanylin]] receptor === Ionotropic receptors === Ionotropic receptors are [[heteromeric]] or [[homomeric]] [[oligomers]] <ref name=boron> Medical Physiology, Boron & Boulpaep, ISBN 1-4160-2328-3, Elsevier Saunders 2005. Updated edition. Page 90. </ref>. They are receptors that respond to extracellular ligands and receptors that respond to intracellular ligands. ====Extracellular ligands==== {| class="wikitable" |- | '''Receptor''' || '''Ligand''' || '''Ion current''' |- | [[Nicotinic acetylcholine receptor]] || [[Acetylcholine]], [[Nicotine]] || Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup> <ref name=boron/> |- | [[Glycine receptor]] (GlyR) || [[Glycine]], [[Strychnine]] || Cl<sup>-</sup> > HCO<sup>-</sup><sub>3</sub> <ref name=boron/> |- | [[GABA receptor]]s: GABA-A, GABA-C || [[GABA]] || Cl<sup>-</sup> > HCO<sup>-</sup><sub>3</sub> <ref name=boron/> |- | [[Glutamate receptor]]s: [[NMDA receptor]], [[AMPA receptor]], and [[Kainate receptor]] || [[Glutamate]] || Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup> <ref name=boron/> |- | [[Serotonin receptor|5-HT<sub>3</sub> receptor]] || [[Serotonin]] || Na<sup>+</sup>, K<sup>+</sup> <ref name=boron/> |- | [[P2X receptors]] || [[Adenosine triphosphate|ATP]] || Ca<sup>2+</sup>, Na<sup>+</sup>, Mg<sup>2+</sup> <ref name=boron/> |- |} ====Intracellular ligands==== {| 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#Olfactory_System|olfaction]]) || Na<sup>+</sup>, K<sup>+</sup> <ref name=boron/> |- | [[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] || [[inositol triphosphate|IP<sub>3</sub>]] || Ca<sup>2+</sup> <ref name=boron/> |- | Intracellular [[Adenosine triphosphate|ATP]] receptors || [[Adenosine triphosphate|ATP]] (closes channel)<ref name=boron/> || K<sup>+</sup> <ref name=boron/> |- | [[Ryanodine receptor]] || Ca<sup>2+</sup> || Ca<sup>2+</sup> <ref name=boron/> |} The entire repertoire of human plasma membrane receptors is listed at the Human Plasma Membrane Receptome (http://receptome.stanford.edu). ==Intracellular receptors== {{Main|Intracellular receptor}} <!--additions here need to be mirrored there if possible--> ===Transcription factors=== * [[nuclear receptor]]: ** [[Steroid hormone receptor]] ===Various=== * Ionotropic receptors ([[Inositol triphosphate receptor|IP<sub>3</sub> receptor]] above) * [[Sigma-1 receptor|sigma</sub>1</sub>]] ([[neuroactive steroid|neurosteroids]]) * G protein-coupled receptors <ref>Gobeil F, et al. (2006) G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigm. Can J Physiol Pharmacol. 2006 Mar-Apr;84(3-4):287-97. PMID 16902576 </ref> ==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. ==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 Ligand-bound desensitation of receptors was first characterized by Katz and Thesleff in the [[Nicotinic acetylcholine receptor|nicotine acetylcholine receptor]]<ref name=sun2002>Y. Sun, R. Olson, M. Horning, N. Armstrong, M. Mayer and E. Gouaux. (2002) Mechanism of glutamate receptor desensitization ''Nature'' 417, 245-253</ref><ref>S. Pitchford, J.W. Day, A. Gordon and D. Mochly-Rosen. (1992) Acetylcholine receptor desensitization is Regulate by activation-induced extracellular adenosine accumulation. ''The Journal of Neuroscience'', 1.311): 4540-4544.</ref> Prolonged or repeated exposure to a stimulus often results in decreased responsiveness of that receptor for a stimulus. Receptor desensitization results in altered affinity for the ligand.<ref name =sun2002/> Receptor desensitization can modeled by a two-state model that also predicts that antagonists combined with agonists can prevent receptor desensitization <ref name=lanzara>Lanzara, "Optimal Agonist/Antagonist Combinations Maintain Receptor Response by Preventing Rapid Beta-1 adrenergic Receptor Desensitization" Intl. J. Pharmacol., 1(2): 122-131, 2005.[http://www.bio-balance.com/ijp.pdf </ref> See this link [http://www.bio-balance.com/Graphics.htm] for detailed molecular description Desensitation may be accomplished by *Receptor [[phosphorylation]].<ref name=Boulay1994>G. Boulay, L. Chrbtien, D.E. Richard, AND G. Guillemettes. (1994) 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. ''Endocrinology'' Vol. 135. No. 5 2130-2136</ref> *Uncoupling of receptor effector molecules. *Receptor sequestration (internalization).<ref name=Boulay1994/> ==In 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=Immunology20> Lippincott's Illustrated Reviews: Immunology. Paperback: 384 pages. Publisher: Lippincott Williams & Wilkins; (July 1, 2007). Language: English. ISBN-10: 0781795435. ISBN-13: 978-0781795432. Page 20 </ref> {{Immune receptors}} == See also == * [[Signal transduction]] * [[Neuropsychopharmacology]] * [[Schild regression]] for ligand receptor inhibition * [[Ki Database|K<sub>i</sub> Database]] * [[Wikipedia:MeSH D12.776#MeSH D12.776.543.750 --- receptors.2C cell surface]] ==References== <references/> ==External links== *[http://www.iuphar-db.org IUPHAR GPCR Database and Ion Channels Compendium] *{{MeshName|Cell+surface+receptors}} {{Cell_signaling}} {{G protein-coupled receptors}} {{Receptor tyrosine kinases}} [[Category:Cell biology]] [[Category:Cell signaling]] [[Category:Membrane biology]] [[Category:Receptors]] [[ar:مستقبل (كيمياء حيوية)]] [[cs:Receptor]] [[da:Receptor]] [[de:Rezeptor]] [[es:Receptor celular]] [[fr:Récepteur (biochimie)]] [[it:Recettore]] [[he:קולטן]] [[nl:Receptor]] [[ja:受容体]] [[pl:Receptor]] [[pt:Receptor (bioquímica)]] [[ro:Receptor (biochimie)]] [[ru:Рецептор]] [[sk:Receptor]] [[sl:Receptor (biokemija)]] [[fi:Reseptori (biokemia)]] [[sv:Receptor]] [[th:รีเซพเตอร์]] [[uk:Рецептор]] [[zh:受体]]