Phosphoinositides: In the 1950's it was shown that the neurotransmitter acetylcholine would stimulate the release of amylase in pancreatic cells and at the same time would promote the incorporation of inorganic phosphate into phosphatidic acid and phosphatidyl inositol. The activation of this pathway (the Phosphatidyl Inositol (PI) pathway) was assumed to have an important role in receptor mediated signalling. It is now known that many receptors are coupled to the PI pathway, including, noradrenergic, muscarinic, histaminergic, and others. It is generally accepted that receptors are coupled to the PI pathway via G-proteins. Agonist binding to the receptor results in activation of a phosphodiesterase (phospholipase C) that hydolyzes phosphatidylinositol,4,5-bisphosphate (PIP₂) to form inositol 1,4,5-triphosphate (IP₃) and diacylglycerol (DAG). IP₃ acts to release intracellular stores of Ca⁺⁺. The release of Ca⁺⁺ can result in a biological response via a direct effect or by activation of calmodulin, which is a small cytosolic protein that is present in most cells and acts to activate many enzymes. DAG can also produce a response by stimulating protein kinase C and activation of eicosinoids (e.g., prostaglandins).