Cell surface receptors (membrane receptors,transmembrane receptors) arereceptors that are embedded in theplasma membrane ofcells.[1] They act incell signaling by receiving (binding to)extracellular molecules. They are specializedintegral membrane proteins that allow communication between the cell and theextracellular space. The extracellular molecules may behormones,neurotransmitters,cytokines,growth factors,cell adhesion molecules, ornutrients; they react with the receptor to induce changes in themetabolism and activity of a cell. In the process ofsignal transduction,ligand binding affects acascading chemical change through the cell membrane.
Many membrane receptors aretransmembrane proteins. There are various kinds, includingglycoproteins andlipoproteins.[2] Hundreds of different receptors are known and many more have yet to be studied.[3][4] Transmembrane receptors are typically classified based on theirtertiary (three-dimensional) structure. If the three-dimensional structure is unknown, they can be classified based onmembrane topology. In the simplest receptors,polypeptide chains cross thelipid bilayer once, while others, such as theG-protein coupled receptors, cross as many as seven times. Eachcell 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.[5][6]
Two models have been proposed to explain transmembrane receptors' mechanism of action.
Transmembrane receptors inplasma membrane can usually be divided into three parts.
The extracellular domain is just externally from the cell ororganelle. 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, aneurotransmitter,hormone, or atomic ions may each bind to the extracellular domain as a ligand coupled to receptor.Klotho is an enzyme which effects a receptor to recognize the ligand (FGF23).[citation needed]
Two most abundant classes of transmembrane receptors areGPCR andsingle-pass transmembrane proteins.[8][9] In some receptors, such as thenicotinic acetylcholine receptor, the transmembrane domain forms a protein pore through the membrane, or around theion 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 the7TM superfamily, the transmembrane domain includes a ligand binding pocket.[citation needed]
The intracellular (orcytoplasmic) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamental paths for this interaction:[citation needed]
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.[10][11]
Signal transduction through membrane receptors requires four parts:
Membrane receptors are mainly divided by structure and function into 3 classes: Theion channel linked receptor; Theenzyme-linked receptor; and TheG protein-coupled receptor.
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 thecell excitability.[12]
Theacetylcholine 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 oneacetylcholine 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.[13][14]
As of 2009, there are 6 known types ofenzyme-linked receptors: Receptortyrosine kinases; Tyrosine kinase associated receptors; Receptor-liketyrosine phosphatases; Receptorserine/threoninekinases; Receptorguanylyl cyclases andhistidine kinase associated receptors. Receptor tyrosine kinases have the largest population and widest application. The majority of these molecules are receptors forgrowth factors such asepidermal growth factor (EGF),platelet-derived growth factor (PDGF),fibroblast growth factor (FGF),hepatocyte growth factor (HGF),nerve growth factor (NGF) andhormones such asinsulin.Most of these receptors will dimerize after binding with their ligands, in order to activate further signal transductions. For example, after theepidermal growth factor (EGF) receptor binds with its ligand EGF, the two receptors dimerize and then undergophosphorylation of thetyrosine residues in the enzyme portion of each receptor molecule. This will activate the tyrosine kinase and catalyze further intracellular reactions.[citation needed]
G protein-coupled receptors comprise a largeprotein family of transmembrane receptors. They are found only ineukaryotes.[15] Theligands which bind and activate these receptors include: photosensitive compounds,odors,pheromones,hormones, andneurotransmitters. These vary in size from small molecules topeptides and largeproteins. G protein-coupled receptors are involved in many diseases, and thus are the targets of many modern medicinal drugs.[16]
There are two principal signal transduction pathways involving the G-protein coupled receptors: thecAMP signaling pathway and thephosphatidylinositol signaling pathway.[17] Both are mediated viaG 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 boundguanosine diphosphate (GDP), which is displaced byguanosine 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.[citation needed]
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 receptorTM4SF5 influences the migration of hepatic cells andhepatoma.[18] Also, the cortical NMDA receptor influences membrane fluidity, and is altered in Alzheimer's disease.[19] 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 ofpoliovirus, 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【myristic acid=CH3(CH2)12COOH】. 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.[citation needed]
Through methods such asX-ray crystallography andNMR spectroscopy, the information about 3D structures of target molecules has increased dramatically, and so has structural information about the ligands. This drives rapid development ofstructure-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.[20][21][22]
