Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s – and in some cases

virus A virus is a wikt:submicroscopic, submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and ...

es – by the inward budding of the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

(

invagination Invagination is the process of a surface folding in on itself to form a cavity, pouch or tube. In developmental biology, invagination is a mechanism that takes place during gastrulation. This mechanism or cell movement happens mostly in the vegeta ...

). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.

Process

Although receptors and their

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...

s can be brought into the cell through a few mechanisms (e.g. caveolin and

lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular mem ...

clathrin Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. Wh ...

-mediated endocytosis remains the best studied. Clathrin-mediated endocytosis of many receptor types begins with the ligands binding to receptors on the cell plasma membrane. The ligand and receptor will then recruit adaptor proteins and clathrin

triskelion A triskelion or triskeles is an ancient motif consisting of a triple spiral exhibiting rotational symmetry. The spiral design can be based on interlocking Archimedean spirals, or represent three bent human legs. It is found in artefacts of t ...

s to the plasma membrane around where invagination will take place. Invagination of the plasma membrane then occurs, forming a clathrin-coated pit. Other receptors can nucleate a clathrin-coated pit allowing formation around the receptor. A mature pit will be cleaved from the plasma membrane through the use of membrane-binding and fission proteins such as

dynamin Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the " dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin ...

(as well as other

BAR domain In molecular biology, BAR domains are highly conserved protein dimerisation domains that occur in many proteins involved in membrane dynamics in a cell. The BAR domain is banana-shaped and binds to membrane via its concave face. It is cap ...

proteins), forming a clathrin-coated vesicle that then uncoats of clathrin and typically fuses to a sorting

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane c ...

. Once fused, the endocytosed cargo (receptor and/or ligand) can then be sorted to lysosomal, recycling, or other trafficking pathways.

Function

The function of receptor-mediated endocytosis is diverse. It is widely used for the specific uptake of certain substances required by the cell (examples include LDL via the LDL receptor or iron via

transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded ...

). The role of receptor-mediated endocytosis is well recognized up take downregulation of transmembrane signal transduction but can also promote sustained signal transduction. The activated receptor becomes internalised and is transported to late endosomes and

lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane ...

for degradation. However, receptor-mediated endocytosis is also actively implicated in transducing signals from the cell periphery to the nucleus. This became apparent when it was found that the association and formation of specific signaling complexes via clathrin-mediated endocytosis is required for the effective signaling of hormones (e.g.

EGF EGF may refer to: * E.G.F., a Gabonese company * East Grand Forks, Minnesota, a city * East Garforth railway station in England * Epidermal growth factor * Equity Group Foundation, a Kenyan charity * European Gendarmerie Force, a military unit of ...

). Additionally it has been proposed that the directed transport of active signaling complexes to the nucleus might be required to enable signaling, due to the fact that random

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

is too slow, and mechanisms permanently downregulating incoming signals are strong enough to shut down signaling completely without additional signal-transducing mechanisms.

Experiments

Using fluorescent or EM visible dyes to tag specific molecules in living cells, it is possible to follow the internalization of cargo molecules and the evolution of a clathrin-coated pit by fluorescence microscopy and immuno electron microscopy. Since the process is non-specific, the ligand can be a carrier for larger molecules. If the target cell has a known specific pinocytotic receptor, drugs can be attached and will be internalized. To achieve internalisation of

nanoparticles A nanoparticle or ultrafine particle is usually defined as a particle of matter that is between 1 and 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 10 ...

into cells, such as

T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...

, antibodies can be used to target the nanoparticles to specific receptors on the cell surface (such as

CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 pr ...

). This is one method of improving drug delivery to immune cells. The development of photoswitchable peptide inhibitors of protein-protein interactions involved in clathrin-mediated endocytosis (Traffic Lights peptides) and photoswitchable small molecule inhibitors of

(Dynazos) has been reported. These photopharmacological compounds allow spatiotemporal control of the endocytosis with light.

Characteristics

* Induction within minutes of exposure to excess ligand. * The formation of these vesicles is sensitive to inhibition by

wortmannin Wortmannin, a steroid metabolite of the fungi '' Penicillium funiculosum'', ''Talaromyces wortmannii'', is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''50) of a ...

* The initiation of vesicle formation can be delayed/inhibited by temperature variations

References

External links