Insulin receptor

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insulin receptor
Identifiers
Symbol(s)	INSR
Entrez	3643
OMIM	147670
RefSeq	NM_000208
UniProt	P06213
Other data
Locus	Chr. 19 p13.3-13.2

In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors.

Two alpha subunits and two beta subunits make up the insulin receptor. The beta subunits pass through the cellular membrane and are linked by disulfide bonds.

Tyrosine kinase receptors, including the insulin receptor, mediate their activity by causing the addition of a phosphate groups to particular tyrosines on certain proteins within a cell. The "substrate" proteins which are phosphorylated by the Insulin Receptor include a protein called "IRS-1" for "insulin receptor substrate 1". IRS-1 binding and phosphorylation eventually leads to an increase in glucose transporter (Glut4) molecules on the outer membrane of insulin-responsive tissues, including muscle cells, liver and adipose tissue, and therefore to an increase in the uptake of glucose from blood into these tissues. Briefly, the glucose transporter (Glut4), is transported from cellular vesicles to the cell surface, where it then can mediate the transport of glucose into the cell.

The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitvity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 - the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae which result from diabetes.

Patients with insulin resistance may display acanthosis nigricans.

A few patients with homozygous mutations in the INSR gene have been described which causes Donohue Syndrome or Leprechaunism. In most cases the outlook for these patients is poor with death occurring in the first year of life.

1 Regulation of Gene Expression
2 Stimulation of Glycogen Synthesis
3 See also
4 External links

[edit] Regulation of Gene Expression

The activated IRS-1 acts as a secondary messenger within the cell to stimulate the transcription of insulin-regulated genes. First, the protein Grb2 binds the P-Tyr residue of IRS-1 in its SH2 domain. Grb2 is then able to bind Sos, which in turn catalyzes the replacement of bound GDP with GTP on Ras, a G protein. This protein then begins a phosphorylation cascade, culminating in the activation of mitogen-activated protein kinase (MAPK), which enters the nucleus and phosphorylates various nuclear transcription factors (such as Elk1).

[edit] Stimulation of Glycogen Synthesis

Glycogen synthesis is also stimulated by the insulin receptor via IRS-1. In this case, it is the SH2 domain of PI-3 kinase (PI-3K) that binds the P-Tyr of IRS-1. Now activated, PI-3K can convert the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This indirectly activates a protein kinase, PKB, via phosphorylation. PKB then phosphorylates several target proteins, including glycogen synthase kinase 3 (GSK-3). GSK-3 is responsible for phosphorylating (and thus deactivating) glycogen synthase. When GSK-3 is phosphorylated, it is deactivated, and prevented from deactivating glycogen synthase. In this roundabout manner, insulin increases glycogen synthesis.