Cell surface receptor

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(Redirected from
Transmembrane receptor
)
The seven-transmembrane α-helix structure of a G-protein-coupled receptor

Cell surface receptors (membrane receptors, transmembrane receptors) are

extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change
through the cell membrane.

Structure and mechanism

Many membrane receptors are transmembrane proteins. There are various kinds, including glycoproteins and lipoproteins.[2] Hundreds of different receptors are known and many more have yet to be studied.[3][4] Transmembrane receptors are typically classified based on their tertiary (three-dimensional) structure. If the three-dimensional structure is unknown, they can be classified based on membrane topology. In the simplest receptors, polypeptide chains cross the lipid bilayer once, while others, such as the G-protein coupled receptors, cross as many as seven times. Each 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.[5][6]

Mechanism

Two models have been proposed to explain transmembrane receptors' mechanism of action.

Domains

plasma membrane
I = intracellular space

Transmembrane receptors in

plasma membrane
can usually be divided into three parts.

Extracellular domains

The extracellular domain is just externally from the cell or

FGF23
).

Transmembrane domains

Two most abundant classes of transmembrane receptors are

single-pass transmembrane proteins.[8][9] In some receptors, such as the nicotinic acetylcholine receptor, the transmembrane domain forms a protein pore through the membrane, or around the 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 7TM superfamily
, the transmembrane domain includes a ligand binding pocket.

Intracellular domains

The intracellular (or cytoplasmic) 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 enzyme-linked receptors, the intracellular domain has enzymatic activity. Often, this is tyrosine kinase activity. The enzymatic activity can also be due to an enzyme associated with the intracellular domain.

Signal transduction

External reactions and internal reactions for signal transduction (click to enlarge)

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:

  • 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.[11]
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 enzyme-linked receptor; and The G protein-coupled receptor
.

Ion channel-linked 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 the

cell excitability.[12]

The 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 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.[13][14]

Enzyme-linked receptors

Sketch of an enzyme-linked receptor structure (structure of IGF-1R) (click to enlarge)

As of 2009, there are 6 known types of

guanylyl cyclases and histidine kinase associated receptors. Receptor tyrosine kinases have the largest population and widest application. The majority of these molecules are receptors for growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF) and hormones such as insulin
. Most of these receptors will dimerize after binding with their ligands, in order to activate further signal transductions. For example, after the epidermal growth factor (EGF) receptor binds with its ligand EGF, the two receptors dimerize and then undergo phosphorylation of the 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

G protein-coupled receptors comprise a large protein family of transmembrane receptors. They are found only in eukaryotes.[15] The ligands which bind and activate these receptors include: photosensitive compounds, odors, pheromones, hormones, and neurotransmitters. These vary in size from small molecules to peptides and large proteins. 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: the cAMP signaling pathway and the phosphatidylinositol signaling pathway.[17] Both are mediated via 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 guanosine diphosphate (GDP), which is displaced by 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

hepatoma.[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 of 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【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.

Structure-based drug design

Flow charts of two strategies of structure-based drug design

Through methods such as

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.[20][21][22]

Other examples

See also

References

  1. ^ "9.3: Signaling Molecules and Cellular Receptors - Types of Receptors". Biology LibreTexts. 12 July 2018. Retrieved 24 July 2023.
  2. S2CID 44727052
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  8. ^ Superfamilies of single-pass transmembrane receptors in Membranome database
  9. ^ Superfamilies of single-pass transmembrane protein ligands and regulators of receptors in Membranome database
  10. PMID 2158859
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  16. ^ Filmore, David (2004). "It's a GPCR world". Modern Drug Discovery. 2004 (November): 24–28.
  17. S2CID 33992382
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External links