What is Inositol Trisphosphate?

Inositol trisphosphate, commonly abbreviated as InsP₃ or IP₃, is a small signaling molecule that cells use as a secondary messenger in a signaling pathway. It is comprised of a central six-carbon ring with three hydroxyl (OH) groups and three phosphate (PO₄)^2- groups, with one group extending from each of the carbon atoms in the ring. The phosphate groups are attached to the first, fourth, and fifth carbon atoms, giving the molecule the more specific name of inositol 1,4,5-trisphosphate.

While generated in the cell membrane, it is a polar molecule with a charge of -6. It is, therefore, able to leave the membrane to travel through the cytoplasm. This action is necessary for the molecule to bind to its receptor, a glycoprotein calcium ion channel in the membrane of a separate organelle — either the endoplasmic reticulum or the sarcoplasmic reticulum.

Inositol trisphosphate plays an essential role in the pathway initiated by the alpha-1 (a₁) adrenergic receptors, which cause smooth muscle contraction in response to epinephrine. This pathway constricts blood vessels in the skin, digestive system, kidneys, and some parts of the brain during the body’s fight-or-flight response. It occurs in the central nervous system as well as the peripheral nervous system.

The pathway in which inositol trisphosphate is involved begins with the release of a ligand or hormone into the bloodstream. The hormone initiates the signaling pathway by binding to a G-protein coupled receptor (GPCR), a protein embedded in the cell membrane and connected to the G-protein. When bound to the hormone, the receptor undergoes a conformational change, activating the G-protein, which binds to guanosine triphosphate (GTP) for energy. The activated G-protein travels through the cell membrane to bind to and activate the enzyme phospholipase C. This enzyme breaks up the membrane phospholipid molecule phosphatidylinositol 4,5-bisphosphate into two smaller molecules: diacylglycerol and inositol trisphosphate.

Diacylglycerol stays in the membrane, while inositol trisphosphate travels through the cell’s cytoplasm to bind to a calcium channel on the membrane of one of the cell’s organelles. Depending on the type of cell, inositol trisphosphate will bind to the channel either on the surface of the endoplasmic reticulum or on the sarcoplasmic reticulum. In both cases, inositol trisphosphate will open the channel, releasing calcium 2+ ions into the cell. These ions team up with the diacylglycerol in the membrane to bind to and activate another enzyme, protein kinase C, which phosphorylates other proteins and creates the cell’s overall response to the hormone messenger.