Answer to Hormones Question H-03
The insulin receptor is a transmembrane protein formed by two subunits linked by disulfide bonds. It is possible to distinguish in the receptor an extracellular domain, related to the binding of insulin, a transmembrane domain, and an intramembrane domain, that shows activity of tyrosine kinase.
When the insulin binds to the receptor (insulin binds to the two peptide chains of the dimer) a conformational chain that activates the tyrosin kinase domain is produced. This domain phosphorylates various tyrosin residues in the receptor (autophosphorylation) and in other proteins (Insulin Receptor Substrates –IRS) that act as “second messengers” of insulin (IRs1, IRs2, IRs3 and IRS4).
The phosphorylation of the tyrosin residues in the IRSs “attracts” proteins containing SH2 domains (domains that bind to phosphorylated tyrosine) activating them.
(For the whole Receptor Itinerary, visit Signal Transduction at the Wellcome Trust Sanger Institute)
The interaction between insulin and its receptor and the resulting activation of IRSs trigger changes at different levels:
a) At a membrane level
b) At a genetic level
c) At an enzymatic level
At a membrane level the activated IRSs provoke phosphorylations and conformational changes in other proteins, resulting in an increase in the quantity of glucose transporters in the plasma membrane in adipose and muscular tissues.
At a genetic level they increase the expression of genes that codify some regulatory enzymes of glycolysis, pentose phosphate shunt, and fatty acid and neutral fats synthesis, while decreases the expression of genes that codify some enzymes of gluconeogenesis.
At an enzymatic level the IRSs produce covalent modification of other enzymes. modifying their activity: these IRS proteins provokes conformational changes and activation on enzymes like protein kinases, that produce further covalent modifications in other proteins.
IRS-1 in particular has a very important role in triggering insulin effects:
1.- it promotes the fusion of cytosolic vesicles that contain GLUT4, with the plasma membrane, increasing the concentration of GLUT4 in this membrane in adipose and muscular tissues and consequently the uptake of glucose.
2.- Triggers a phosphorylation cascade that produce the activation of MAPK (Mutagen Activated Protein Kinase) that enters the nucleus and activates, by phosphorylation, various transcription factors.
3.- Trough a different mechanism that include the participation of Protein Kinase 3 (PK3), prevents the deactivation of glycogen synthase, favoring glycogenesis.
For more information about insulin receptors and mechanism of action of insulin, I would recommend to visit these sites:
Very detailed information can be found in: