View source for Biology:Cell surface receptor

{{Short description|Class of ligand activated receptors localized in surface of plama cell membrane}}
{{main|Biology:Receptor (biochemistry)}}

[[File:PDB 1hzx 7TM Sketch Membrane.png|thumb|300px|The seven-transmembrane α-helix structure of a G-protein-coupled receptor]]
'''Cell surface receptors''' ('''membrane receptors''', '''transmembrane receptors''') are [[Biology:Receptor (biochemistry)|receptors]] that are embedded in the [[Biology:Cell membrane|plasma membrane]] of [[Biology:Cell|cell]]s.<ref name="libretexts">{{cite web |title=9.3: Signaling Molecules and Cellular Receptors - Types of Receptors |url=https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/09%3A_Cell_Communication/9.03%3A_Signaling_Molecules_and_Cellular_Receptors_-_Types_of_Receptors |website=Biology LibreTexts |access-date=24 July 2023 |language=en |date=12 July 2018}}</ref> They act in [[Biology:Cell signaling|cell signaling]] by receiving (binding to) [[Biology:Extracellular matrix|extracellular molecule]]s. They are specialized [[Biology:Integral membrane protein|integral membrane protein]]s that allow communication between the cell and the [[Biology:Extracellular|extracellular space]]. The extracellular molecules may be [[Biology:Hormone|hormone]]s, [[Biology:Neurotransmitter|neurotransmitter]]s, [[Biology:Cytokine|cytokine]]s, [[Biology:Growth factor|growth factor]]s, [[Biology:Cell adhesion molecule|cell adhesion molecule]]s, or [[Earth:Nutrient|nutrient]]s; they react with the receptor to induce changes in the [[Biology:Metabolism|metabolism]] and activity of a cell. In the process of [[Biology:Signal transduction|signal transduction]], [[Biology:Ligand (biochemistry)#Receptor/ligand binding affinity|ligand binding]] affects a [[Biology:Biochemical cascade|cascading chemical change]] through the cell membrane.

== Structure and mechanism ==

Many membrane receptors are [[Biology:Transmembrane protein|transmembrane protein]]s. There are various kinds, including [[Chemistry:Glycoprotein|glycoprotein]]s and [[Biology:Lipoprotein|lipoprotein]]s.<ref>{{cite journal | author =Cuatrecasas P. | s2cid = 44727052 | title = Membrane Receptors | journal = Annual Review of Biochemistry | year=1974 | volume=43 | pages=169–214 | doi = 10.1146/annurev.bi.43.070174.001125 | pmid =4368906 }}</ref> Hundreds of different receptors are known and many more have yet to be studied.<ref name="pmid11830263">{{cite journal |vauthors=Dautzenberg FM, Hauger RL |title=The CRF peptide family and their receptors: yet more partners discovered |journal=Trends Pharmacol. Sci. |volume=23 |issue=2 |pages=71–7 |date=February 2002 |pmid=11830263 |doi= 10.1016/S0165-6147(02)01946-6}}</ref><ref name="pmid19387439">{{cite journal |vauthors=Rivière S, Challet L, Fluegge D, Spehr M, Rodriguez I |title=Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors |journal=Nature |volume=459 |issue=7246 |pages=574–7 |date=May 2009 |pmid=19387439| doi=10.1038/nature08029}}</ref> Transmembrane receptors are typically classified based on their [[Chemistry:Biomolecular structure#Tertiary structure|tertiary]] (three-dimensional) structure. If the three-dimensional structure is unknown, they can be classified based on [[Physics:Membrane topology|membrane topology]]. In the simplest receptors, [[Biology:Protein|polypeptide chains]] cross the [[Biology:Lipid bilayer|lipid bilayer]] once, while others, such as the [[Biology:G protein-coupled receptor|G-protein coupled receptor]]s, cross as many as seven times. Each [[Biology:Cell membrane|cell membrane]] can have several kinds of membrane receptors, with varying surface distributions. A single receptor may also be differently distributed at different membrane positions, depending on the sort of membrane and cellular function. Receptors are often clustered on the membrane surface, rather than evenly distributed.<ref>{{cite journal |author1=Rothberg K.G. |author2=Ying Y.S. |author3=Kamen B.A. |author4=Anderson R.G. | title =Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate  | journal = The Journal of Cell Biology | year=1990 | volume=111 | issue=6 | pages=2931–2938 | doi =10.1083/jcb.111.6.2931 | pmid =2148564 | pmc =2116385}}</ref><ref>{{cite journal |author1=Jacobson C. |author2=Côté P.D. |author3=Rossi S.G. |author4=Rotundo R.L. |author5=Carbonetto S. | title =The Dystroglycan Complex Is Necessary for Stabilization of Acetylcholine Receptor Clusters at Neuromuscular Junctions and Formation of the Synaptic Basement Membrane | journal = The Journal of Cell Biology | year=2001 | volume=152 | pages=435–450 | doi = 10.1083/jcb.152.3.435 | pmid =11157973 | issue =3 | pmc =2195998}}</ref>

=== Mechanism ===
Two models have been proposed to explain transmembrane receptors' mechanism of action.
* ''Dimerization'': The dimerization model suggests that prior to ligand binding, receptors exist in a monomeric form. When agonist binding occurs, the monomers combine to form an active [[Biology:Protein dimer|dimer]].
* ''Rotation'': Ligand binding to the extracellular part of the receptor induces a rotation (conformational change) of part of the receptor's transmembrane helices. The rotation alters which parts of the receptor are exposed on the intracellular side of the membrane, altering how the receptor can interact with other proteins within the cell.<ref>{{Cite journal|title = Activation of transmembrane cell-surface receptors via a common mechanism? The "rotation model"|journal = BioEssays|date = 2015-09-01|issn = 1521-1878|pages = 959–967|volume = 37|issue = 9|doi = 10.1002/bies.201500041|first = Ichiro N.|last = Maruyama|pmid=26241732|pmc=5054922}}</ref>

==Domains==
[[File:transmembrane receptor.svg|thumb|300px|{{color|red|'''E'''}} = [[Biology:Extracellular space|extracellular space]]<br>{{color|green|'''P'''}} = plasma membrane<br>{{color|gold|'''I'''}} = intracellular space]]

Transmembrane receptors in [[Biology:Plasma membrane|plasma membrane]] can usually be divided into three parts.

===Extracellular domains===
The extracellular domain is just externally from the cell or [[Biology:Organelle|organelle]]. If the polypeptide chain crosses the bilayer several times, the external domain comprises loops entwined through the membrane. By definition, a receptor's main function is to recognize and respond to a type of ligand.  For example, a [[Biology:Neurotransmitter|neurotransmitter]], [[Biology:Hormone|hormone]], or atomic ions may each bind to the extracellular domain as a ligand coupled to receptor. [[Biology:Klotho|Klotho]] is an enzyme which effects a receptor to recognize the ligand (FGF23).

===Transmembrane domains===
Two most abundant classes of transmembrane receptors are GPCR and single-pass transmembrane proteins.<ref>[https://membranome.org/protein_classes/1 Superfamilies of single-pass transmembrane receptors] in [[Biology:Membranome database|Membranome database]]</ref><ref>[https://membranome.org/protein_classes/2 Superfamilies of single-pass transmembrane protein ligands and regulators of receptors] in [[Biology:Membranome database|Membranome database]]</ref> In some receptors, such as the [[Biology:Acetylcholine receptor|nicotinic acetylcholine receptor]], the transmembrane domain forms a protein pore through the membrane, or around the [[Biology:Ion channel|ion channel]]. Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then diffuse. In other receptors, the transmembrane domains undergo a conformational change upon binding, which affects intracellular conditions. In some receptors, such as members of the [[Biology:G protein-coupled receptor|7TM superfamily]], the transmembrane domain includes a ligand binding pocket.

===Intracellular domains===
The intracellular (or [[Biology:Cytoplasm|cytoplasm]]ic) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamental paths for this interaction: 
* The intracellular domain communicates via protein-protein interactions against ''effector proteins'', which in turn pass a signal to the destination.
* With [[Biology:Enzyme-linked receptor|enzyme-linked receptor]]s, the intracellular domain has ''[[Biology:Enzyme|enzymatic activity]]''. Often, this is [[Biology:Tyrosine kinase|tyrosine kinase]] activity. The enzymatic activity can also be due to an enzyme associated with the intracellular domain.

== Signal transduction ==
[[File:The External Reactions and the Internal Reactions.jpg|thumb|350px|External reactions and internal reactions for signal transduction (click to enlarge)]]
[[Biology:Signal transduction|Signal transduction]] processes through membrane receptors involve the external reactions, in which the ligand binds to a membrane receptor, and the internal reactions, in which intracellular response is triggered.<ref>{{cite journal | author =Ullricha A., Schlessingerb J. | title = Signal transduction by receptors with tyrosine kinase activity  | journal = Cell | year=1990 | volume=61 | issue=2 | pages=203–212 | doi = 10.1016/0092-8674(90)90801-K | pmid =2158859 | last2 =Schlessinger | first2 =J}}</ref><ref name="KSFM">{{cite book | author = Kenneth B. Storey | title = Functional Metabolism | publisher = Wiley-IEEE | year=1990 | pages=87–94 | isbn=978-0-471-41090-4}}</ref>

Signal transduction through membrane receptors requires four parts:
* Extracellular signaling molecule: an extracellular signaling molecule is produced by one cell and is at least capable of traveling to neighboring cells.
* Receptor protein: cells must have cell surface receptor proteins which bind to the signaling molecule and communicate inward into the cell.
* Intracellular signaling proteins: these pass the signal to the organelles of the cell. Binding of the signal molecule to the receptor protein will activate intracellular signaling proteins that initiate a signaling cascade.
* Target proteins: the conformations or other properties of the target proteins are altered when a signaling pathway is active and changes the behavior of the cell.<ref name="KSFM" />

[[File:Three conformation states of acetylcholine receptor.jpg|thumb|350px|Three conformation states of acetylcholine receptor (click to enlarge)]]

Membrane receptors are mainly divided by structure and function into 3 classes: The ion channel linked receptor; The [[Biology:Enzyme-linked receptor|enzyme-linked receptor]]; and The [[Biology:G protein-coupled receptor|G protein-coupled receptor]].

*'''Ion channel linked receptors''' have ion channels for anions and cations, and constitute a large family of multipass transmembrane proteins. They participate in rapid signaling events usually found in electrically active cells such as [[Biology:Neuron|neuron]]s. They are also called [[Biology:Ligand-gated ion channel|ligand-gated ion channel]]s. Opening and closing of ion channels is controlled by neurotransmitters.
*'''Enzyme-linked receptors''' are either enzymes themselves, or directly activate associated enzymes. These are typically single-pass transmembrane receptors, with the enzymatic component of the receptor kept intracellular. The majority of enzyme-linked receptors are, or associate with, protein kinases.
*'''G protein-coupled receptors''' are integral membrane proteins that possess seven transmembrane helices. These receptors activate a [[Biology:G protein|G protein]] upon [[Biology:Agonist|agonist]] binding, and the G-protein mediates receptor effects on intracellular signaling pathways.

=== Ion channel-linked receptor ===
{{Main|Biology:Ligand-gated ion channel}}

During the signal transduction event in a neuron, the neurotransmitter binds to the receptor and alters the conformation of the protein. This opens the ion channel, allowing extracellular ions into the cell. Ion permeability of the plasma membrane is altered, and this transforms the extracellular chemical signal into an intracellular electric signal which alters the cell excitability.<ref>{{cite book | author = Hille B. | title = Ion channels of excitable membranes | publisher = Sunderland, Mass. | year=2001 | isbn=978-0-87893-321-1}}</ref>

The [[Biology:Acetylcholine receptor|acetylcholine receptor]] is a receptor linked to a cation channel. The protein consists of four subunits: alpha (α), beta (β), gamma (γ), and delta (δ) subunits. There are two α subunits, with one [[Chemistry:Acetylcholine|acetylcholine]] binding site each. This receptor can exist in three conformations. The closed and unoccupied state is the native protein conformation. As two molecules of acetylcholine both bind to the binding sites on α subunits, the conformation of the receptor is altered and the gate is opened, allowing for the entry of many ions and small molecules. However, this open and occupied state only lasts for a minor duration and then the gate is closed, becoming the closed and occupied state. The two molecules of acetylcholine will soon dissociate from the receptor, returning it to the native closed and unoccupied state.<ref>{{cite journal |author1=Miyazawa A. |author2=Fujiyoshi Y. |author3=Unwin N. | title = Structure and gating mechanism of the acetylcholine receptor pore | journal = Nature | year=2003 | volume=423 | pages=949–955 | doi = 10.1038/nature01748 | pmid =12827192 | issue =6943}}</ref><ref>{{cite journal |author1=Akabas M.H. |author2=Stauffer D.A. |author3=Xu M. |author4=Karlin A. | title = Acetylcholine receptor channel structure probed in cysteine-substitution mutants  | journal = Science | year=1992 | volume=258 | issue=5080 | pages=307–310 | doi = 10.1126/science.1384130 | pmid = 1384130}}</ref>

=== Enzyme-linked receptors ===
{{main|Biology:Enzyme-linked receptor}}
[[File:Structure of IGF-1R.jpg|thumb|350px|Sketch of an enzyme-linked receptor structure (structure of IGF-1R) (click to enlarge)]]

As of 2009, there are 6 known types of [[Biology:Enzyme-linked receptor|enzyme-linked receptor]]s: Receptor [[Biology:Tyrosine kinase|tyrosine kinase]]s; Tyrosine kinase associated receptors; Receptor-like [[Biology:Protein tyrosine phosphatase|tyrosine phosphatases]]; Receptor [[Chemistry:Serine|serine]]/[[Chemistry:Threonine|threonine]] [[Biology:Kinase|kinase]]s; Receptor guanylyl cyclases and [[Biology:Histidine kinase|histidine kinase]] associated receptors. Receptor tyrosine kinases have the largest population and widest application. The majority of these molecules are receptors for [[Biology:Growth factor|growth factor]]s such as [[Biology:Epidermal growth factor|epidermal growth factor]] (EGF), [[Biology:Platelet-derived growth factor|platelet-derived growth factor]] (PDGF), [[Biology:Fibroblast growth factor|fibroblast growth factor]] (FGF), [[Biology:Hepatocyte growth factor|hepatocyte growth factor]] (HGF), [[Biology:Nerve growth factor|nerve growth factor]] (NGF) and [[Biology:Hormone|hormone]]s such as [[Biology:Insulin|insulin]].
Most of these receptors will dimerize after binding with their ligands, in order to activate further signal transductions. For example, after the [[Biology:Epidermal growth factor|epidermal growth factor (EGF)]]  receptor binds with its ligand EGF, the two receptors dimerize and then undergo [[Biology:Phosphorylation|phosphorylation]] of the [[Chemistry:Tyrosine|tyrosine]] residues in the enzyme portion of each receptor molecule.  This will activate the tyrosine kinase and catalyze further intracellular reactions.

=== G protein-coupled receptors ===
{{main|Biology:G protein-coupled receptor}}

G protein-coupled receptors comprise a large [[Biology:Protein|protein]] family of transmembrane receptors. They are found only in [[Biology:Eukaryote|eukaryote]]s.<ref name="pmid12869759">{{cite journal |vauthors=King N, Hittinger CT, Carroll SB | title = Evolution of key cell signaling and adhesion protein families predates animal origins | journal = Science | volume = 301 | issue = 5631 | pages = 361–3 | year = 2003 | pmid = 12869759 | doi = 10.1126/science.1083853 }}</ref> The [[Biology:Ligand (biochemistry)|ligands]] which bind and activate these receptors include: photosensitive compounds, [[Chemistry:Odor|odor]]s, [[Biology:Pheromone|pheromone]]s, [[Biology:Hormone|hormone]]s, and [[Biology:Neurotransmitter|neurotransmitter]]s. These vary in size from small molecules to [[Chemistry:Peptide|peptide]]s and large [[Biology:Protein|protein]]s. G protein-coupled receptors are involved in many diseases, and thus are the targets of many modern medicinal drugs.<ref>{{cite journal | first=David | last=Filmore | pages=24–28 | title=It's a GPCR world | journal=Modern Drug Discovery | volume=2004 | year=2004 | issue=November | url=http://pubs.acs.org/subscribe/journals/mdd/v07/i11/html/1104feature_filmore.html}}</ref>

There are two principal signal transduction pathways involving the G-protein coupled receptors: the [[Chemistry:Cyclic adenosine monophosphate|cAMP]] signaling pathway and the [[Chemistry:Phosphatidylinositol|phosphatidylinositol]] signaling pathway.<ref>{{cite journal | author = Gilman A.G. | s2cid = 33992382 | title = G Proteins: Transducers of Receptor-Generated Signals | journal = Annual Review of Biochemistry | year=1987 | volume=56 | pages=615–649 | doi = 10.1146/annurev.bi.56.070187.003151 | pmid = 3113327}}</ref> Both are mediated via [[Biology:G protein|G protein]] activation. The G-protein is a trimeric protein, with three subunits designated as α, β, and γ. In response to receptor activation, the α subunit releases bound [[Chemistry:Guanosine diphosphate|guanosine diphosphate]] (GDP), which is displaced by [[Chemistry:Guanosine triphosphate|guanosine triphosphate]] (GTP), thus activating the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly.

== Membrane receptor-related disease ==
If the membrane receptors are denatured or deficient, the signal transduction can be hindered and cause diseases. Some diseases are caused by disorders of membrane receptor function.  This is due to deficiency or degradation of the receptor via changes in the genes that encode and regulate the receptor protein. The membrane receptor [[Biology:TM4SF5|TM4SF5]] influences the migration of hepatic cells and hepatoma.<ref>{{cite journal |author1=Müller-Pillascha F. |author2=Wallrappa C. |author3=Lachera U. |author4=Friessb H. |author5=Büchlerb M. |author6=Adlera G. |author7=Gress T. M. | title = Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer | journal = Gene | year=1998 | volume=208 | issue=1 | pages=25–30 | doi = 10.1016/S0378-1119(97)00633-1 | pmid =9479038}}</ref> Also, the cortical NMDA receptor influences membrane fluidity, and is altered in Alzheimer's disease.<ref>{{cite journal |author1=Scheuer K. |author2=Marasb A. |author3=Gattazb W.F. |author4=Cairnsc N. |author5=Förstlb H. |author6=Müller W.E. | title = Cortical NMDA Receptor Properties and Membrane Fluidity Are Altered in Alzheimer's Disease | journal = Dementia | year=1996 | volume=7 | issue=4 | pages=210–214 | doi = 10.1159/000106881 | pmid =8835885}}</ref> When the cell is infected by a non-enveloped virus, the virus first binds to specific membrane receptors and then passes itself or a subviral component to the cytoplasmic side of the cellular membrane. In the case of [[Biology:Poliovirus|poliovirus]], it is known in vitro that interactions with receptors cause conformational rearrangements which release a virion protein called VP4.The N terminus of VP4 is myristylated and thus hydrophobic【[[Chemistry:Myristic acid|myristic acid]]=CH<sub>3</sub>(CH<sub>2</sub>)<sub>12</sub>COOH】. It is proposed that the conformational changes induced by receptor binding result in the attachment of myristic acid on VP4 and the formation of a channel for RNA.

==Structure-based drug design==
[[File:Flow charts of two strategies of structure based drug design.jpg|thumb|350px|Flow charts of two strategies of structure-based drug design]]
{{Main|Drug design}}

Through methods such as [[Physics:X-ray crystallography|X-ray crystallography]] and NMR spectroscopy, the information about 3D structures of target molecules has increased dramatically, and so has structural information about the ligands. This drives rapid development of structure-based drug design. Some of these new drugs target membrane receptors. Current approaches to structure-based drug design can be divided into two categories. The first category is about determining ligands for a given receptor. This is usually accomplished through database queries, biophysical simulations, and the construction of chemical libraries. In each case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This approach is usually referred to as ligand-based drug design. The key advantage of searching a database is that it saves time and power to obtain new effective compounds. Another approach of structure-based drug design is about combinatorially mapping ligands, which is referred to as receptor-based drug design. In this case, ligand molecules are engineered within the constraints of a binding pocket by assembling small pieces in a stepwise manner. These pieces can be either atoms or molecules. The key advantage of such a method is that novel structures can be discovered.<ref name="ligbuilder">{{cite journal |author1=Wang R. |author2=Gao Y. |author3=Lai L. | title = LigBuilder: A Multi-Purpose Program for Structure-Based Drug Design | journal = Journal of Molecular Modeling | year=2000 | volume=6 | pages=498–516 | doi = 10.1007/s0089400060498 | issue =7–8}}</ref><ref name="CBDDreview">{{cite journal |author1=Schneider G. |author2=Fechner U. | title = Computer-based de novo design of drug-like molecules | journal = Nature Reviews Drug Discovery | year=2005 | volume=4 | pages=649–663 | doi = 10.1038/nrd1799 | pmid =16056391 | issue =8}}</ref><ref>{{cite journal | author = Jorgensen W.L. | s2cid = 1307935 | title = The Many Roles of Computation in Drug Discovery | journal = Science | year=2004 | volume=303 | pages=1813–1818 | doi = 10.1126/science.1096361 | pmid = 15031495 | issue = 5665}}</ref>

===Other examples===
* [[Biology:Adrenergic receptor|Adrenergic receptor]]
* [[Biology:Olfactory receptor|Olfactory receptor]]s
* [[Biology:Receptor tyrosine kinase|Receptor tyrosine kinase]]s
* [[Biology:Epidermal growth factor receptor|Epidermal growth factor receptor]]
* Insulin Receptor
* Fibroblast growth factor receptors,
* High affinity neurotrophin receptors
* Ephrin receptors
* Integrins
* Low Affinity Nerve Growth Factor Receptor
* [[Biology:NMDA receptor|NMDA receptor]]
* Several Immune receptors
** [[Biology:Toll-like receptor|Toll-like receptor]]
** T cell receptor
** [[Biology:CD28|CD28]]
** [[Biology:SCIMP protein|SCIMP protein]]

== See also ==
* Neuromodulators
* Second messenger
* [[Biology:Signalling lymphocyte activation molecule family|Signalling lymphocyte activation molecule family]]

== References ==
{{Reflist|2}}

==External links==
*[http://www.iuphar-db.org IUPHAR GPCR Database] {{Webarchive|url=https://web.archive.org/web/20190323064157/http://iuphar-db.org/ |date=2019-03-23 }}
* {{MeshName|Cell+Surface+Receptors}}

{{Cell signaling}}
{{Cell surface receptors}}
{{G protein-coupled receptors}}
{{Ligand-gated ion channels}}

[[Category:Transmembrane receptors]]
[[Category:Cell signaling]]

de:Rezeptor#Membranrezeptoren

{{Sourceattribution|Cell surface receptor}}