The insulin receptors are protein structure exposed on the extracellular side of the plasma membrane of many cells in the human body and other mammals. The natural ligand for this receptor is insulin.
Insulin is a hormone synthesized by the β cells of the islets of Langerhans of the endocrine portion of the pancreas, an organ located in the abdominal cavity that synthesizes enzymes and digestive hormones.
The insulin synthesized and released by the pancreas binds to its receptor on the plasmatic membrane of white blood cells and, as a consequence of this ligand-receptor union, a series of intracellular processes are triggered that end up promoting the entry of glucose into these cells.
Insulin is responsible for activating many anabolic or synthetic reactions related to the metabolism of carbohydrates, fats and proteins.
Insulin receptors are glycoproteins formed by four subunits with their amino and carboxyl terminals in the cytoplasmic region. When these receptors bind to insulin, they cluster together and endocytose.
In obesity and type II diabetes, the number of insulin receptors decreases and this explains in part the insulin resistance that accompanies these pathological conditions.
Features of Insulin receptors
Insulin receptors are part of a family of membrane receptors that have binding sites for protein hormones. These types of hormones cannot cross cell membranes, so their metabolic effects are carried out through their receptors.
Insulin is a peptide hormone related to the promotion of synthesis reactions called anabolic reactions, related to the metabolism of carbohydrates, fats and proteins.
Many cells have insulin receptors, particularly muscle cells, liver cells, and adipose tissue cells. However, other cells that apparently are not insulin target cells also have insulin receptors.
The entry of glucose into cells, in some tissues, depends on insulin, since in them the proteins responsible for the facilitated diffusion of glucose are found in small pieces of membrane forming intracellular vesicles.
When insulin binds to its receptor in these types of insulin-dependent cells, glucose transporters located in intracellular vesicles move and appear on the surface of the cell membrane when these vesicles fuse with that membrane.
Skeletal muscle and adipose tissue cells are, among others, an example of this mechanism.
Insulin receptors have a relatively short half-life of about 7 to 12 hours, so they are constantly being synthesized and broken down. In mammals, the concentration of receptors is approximately 20,000 receptors per cell.
When insulin binds to the receptor, a conformational change of the receptor occurs, neighboring receptors move, microaggregates are produced, and then the receptor is internalized. At the same time, the signals that will amplify the responses are generated.
Colored dimeric insulin receptor. Domains L1 (blue), CR (cyan), L2 (green), FnIII-1 (yellow), FnIII-2 (orange), FnIII-3 (red). Fletcher01 [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]
The gene encoding the insulin receptor is found on chromosome 19 and has 22 exons. This receptor is formed by four subunits of glycoproteins linked by disulfide bridges.
It is initially synthesized in the endoplasmic reticulum as a single polypeptide chain of about 1382 amino acids which is then phosphorylated and cleaved to form α and β subunits.
The four insulin receptor subunits are two alpha (α) with a molecular weight of 140,000 Da and two smaller beta (β) with an approximate molecular weight of 95,000 Da.
The α subunits are extracellular and are exposed on the outer surface of the cell membrane. β-subunits, on the other hand, span the membrane and are exposed or project onto the inner surface of the membrane (facing the cytoplasm).
In the α subunits it is the insulin binding site. In the p units, there is a binding site for ATP that activates the kinase function of this subunit and induces receptor autophosphorylation on the tyrosine residues of the p subunit.
These receptors are part of a family of receptors associated with cytoplasmic enzymes such as tyrosine kinase, an enzyme that is activated when insulin binds to the receptor and initiates a process of phosphorylation and dephosphorylation of a series of enzymes responsible for the effects. insulin metabolism.
Functions of Insulin receptors
Mechanism of action of insulin. Excreted by the pancreas, insulin circulates in the blood (λ = 30 min) before binding to an insulin receptor (IR). Luuis12321 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
The α subunit of insulin receptors has the insulin binding site. When this unit binds to its ligand, conformational changes occur in the structure of the receptor that activate the β subunits responsible for signal transduction mechanisms and therefore the effects of insulin.
In the cytoplasmic domains of the receptor, a tyrosine kinase is activated that initiates signal transmission through a kinase cascade. The first thing that happens is phosphorylation or autophosphorylation of the insulin receptor, and then so-called insulin receptor substrates or IRS are phosphorylated.
Four insulin receptor substrates called IRS-1, IRS-2, IRS-3 and IRS-4 have been described. Phosphorylation of these occurs on tyrosine, serine and threonine residues. Each of these substrates is related to different kinase cascades involved in the metabolic effects of insulin.
- IRS-1 appears to be related to insulin’s effect on cell growth.
- IRS-2 is related to the metabolic effects of the hormone, such as increased synthesis of glycogen, lipids and proteins, and the translocation of proteins such as receptor proteins and glucose transport proteins.
Diabetes is a disease that affects a very high percentage of the world’s population and is related to defects in insulin production, but also to a deficient function of insulin receptors.
There are two types of diabetes: type I diabetes or juvenile diabetes, which is insulin dependent, and type II diabetes or adult diabetes, which is not insulin dependent.
Type I diabetes is due to insufficient insulin production and is accompanied by hyperglycemia and ketoacidosis. Type II diabetes is related to genetic factors that affect insulin production and the function of its receptors and is accompanied by hyperglycemia without ketoacidosis.