The discovery that a hormone can influence phosphoinositide metabolism was made by Mabel R. Hokin (1924–2003) and her husband Lowell E. Hokin in 1953, when they discovered that radioactive P phosphate was incorporated into the phosphatidylinositol of pancreas slices when stimulated with acetylcholine. Up until then phospholipids were believed to be inert structures only used by cells as building blocks for construction of the plasma membrane.
Over the next 20 years, little was discovered about the importance of PIP metabolism in terms of cell signaling, until the mid-1970s when Robert H. Michell hypothesized a connection between the catabolism of PIP and increases in intracellular calcium (Ca) levels. He hypothesized that receptor-activated hydrolysis of PIP produced a molecule that caused increases in intracellular calcium mobilization. This idea was researched extensively by Michell and his colleagues, who in 1981 were able to show that PIP is hydrolyzed into DAG and IP by a then unknown phosphodiesterase. In 1984 it was discovered that IP acts as a secondary messenger that is capable of traveling through the cytoplasm to the endoplasmic reticulum (ER), where it stimulates the release of calcium into the cytoplasm.
Further research provided valuable information on the IP pathway, such as the discovery in 1986 that one of the many roles of the calcium released by IP is to work with DAG to activate protein kinase C (PKC). It was discovered in 1989 that phospholipase C (PLC) is the phosphodiesterase responsible for hydrolyzing PIP into DAG and IP. Today the IP signaling pathway is well mapped out, and is known to be important in regulating a variety of calcium-dependent cell signaling pathways.