Insulin receptor

• OMIM: 147 670
• UniProt: P06213

The insulin receptor (IR ) ( Gen: INSR ) is that membrane protein to which undistributed insulin binds and thereby exerts its effect. The IR is produced in all chordates and expressed by almost all cells in varying numbers. The red blood cells expressing for example, only a few hundred receptors, liver cells and fat cells, however, several hundred thousand. Mutations in the INSR gene are responsible for hereditary insulin resistance, the Rabson - Mendenhall syndrome, which Donahue syndrome, insulin-dependent diabetes mellitus, familial hypoglycemia and diabetes mellitus with acanthosis nigricans.

Structure

The insulin receptors are located within the cell membrane and thus belong to the group of transmembrane receptors or integral membrane proteins.

Is a hetero - tetramer, which is composed of each two α - and β - subunits: an extracellular α - subunit and a cell membrane -spanning β subunit, from which a large part is located inside the cell. The α - and β - subunits are covalently connected through disulfide bonds to each other. The β - subunit have a so-called tyrosine kinase activity. This means that they are able to phosphorylate tyrosine residues. The phosphate group originates from a molecule of ATP.

Insulin binding and autophosphorylation

If an insulin molecule is bound by the two α subunits, there is a conformational change. The two β - subunits approach each other and phosphorylate each other. Therefore, it is a trans - autophosphorylation. The kinase domains of the β subunits experienced by the phosphorylation of a conformational change and are thereby activated ..

, The tyrosine kinase of the insulin receptor taken for insulin binding and activation of its active state, multiple receptor subunits are phosphorylated near the kinase domain and now provide binding sites for intracellular substrates (such as insulin receptor substrate, IRS) dar. IRS are known as adapter proteins between the insulin receptor and the protein, the signal cascade passes (eg Phosphoinosidkinase -3).

Furthermore, is within a few minutes instead of endocytosis of the entire area, making the kinase activity of the receptor is carried into the cytosol. After done action of the receptor is recycled.

Ultimately triggers the binding of insulin to its receptor, a number of kinase cascades ( cascade of phosphorylation ), which can be described by signal paths.

Activated signaling pathways

The insulin signal is coupled by the formation of signaling complexes at various intracellular signaling cascades. These signaling pathways initiated diverse processes in the cell, such as the glucose rapid processing, the lipid and protein metabolism as well as the gene expression required for this purpose.

MAP kinase cascade

This way enabled the protein synthesis by the phosphorylation of SHC transforming protein, GRB2, SOS - modulated activation of Ras and Raf below, and then the MAP kinase cascade.

Insulin receptor substrate - cascade

Above above IRS adapter proteins phosphoinositide- 3-kinase is activated, which in turn leads to PI3 cascade activation of protein kinase B ( PKB), which phosphorylates a number of target proteins. Phosphorylation of glycogen synthase kinase - 3 is disabled, thereby running phosphorylation of glycogen synthase, UDP is omitted, whereby it is activated. Phosphorylated possible phosphorylation of insulin -stimulated protein kinase ( ISPK, RSK2 ) and activates the protein phosphatase PP1G. PP1G dephosphorylated glycogen synthase, which is hereby enabled again. By this process, glucose is added to the glycogen (in the case of high energy charged).

PKB also causes vesicles with the other on the cell surface does not exist glucose transporter 4 ( GLUT4 ) fuse with the cell membrane in muscle and fat cells. This GLUT4 is functional and it can be increasingly used glucose for energy. Through this mechanism, the blood glucose level is lowered quickly and effectively. But GLUT4 is also activated even by a different route.

SH2 adapter protein cascade

Phosphorylation of SH2 - adapter protein 2 (APS ) and further activation of Cbl, GRF2, Tc10, CIP4 / 2 amplifies the mobilization of GLUT4 vesicles with the following massive import of glucose into the cell.

Thus, the described way cause a fall in blood glucose level by

• Promotion of glucose uptake ( GLUT4 translocation to the cell surface )
• Promoting glucose - storage ( glycogen synthesis) in the liver and muscles

This signal is supported by switching glucose - consuming ways. Other supportive measures consist in turning off glucose -forming ways, such as by degradation of the second messenger cAMP via phosphodiesterase.

Recycling of the internalized receptor

The enzyme bound to phosphorylated insulin receptor molecule is located in a floating cytosolic vesicles whose endocytosis is complete after five minutes. The vesicles are out of proton pump already insulin- degrading enzymes. Due to the proton pump, the pH in the vesicles of 7.4 to 6.0, whereby the insulin receptor from separated and is degraded lowers. After no more insulin maintains the signal protein tyrosine phosphatases are able to dephosphorylate the receptor. Acidic environment causes the vesicle finally, to integrate with the recycled receptor back to the cell membrane.