Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane

Abstract

Phosphatidylinositol(4,5) bisphosphate (PI(4,5)P ₂) has become a major focus in biochemistry, cell biology and physiology owing to its diverse functions at the plasma membrane. As a result, the functions of PI(4,5)P ₂ can be explored in two separate and distinct roles – as a substrate for phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K) and as a primary messenger, each having unique properties. Thus PI(4,5)P ₂ makes contributions in both signal transduction and cellular processes including actin cytoskeleton dynamics, membrane dynamics and ion channel regulation. Signalling through plasma membrane G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and immune receptors all use PI(4,5)P ₂ as a substrate to make second messengers. Activation of PI3K generates PI(3,4,5)P ₃ (phosphatidylinositol(3,4,5)trisphosphate), a lipid that recruits a plethora of proteins with pleckstrin homology (PH) domains to the plasma membrane to regulate multiple aspects of cellular function. In contrast, PLC activation results in the hydrolysis of PI(4,5)P ₂ to generate the second messengers, diacylglycerol (DAG), an activator of protein kinase C and inositol(1,4,5)trisphosphate (IP ₃/I(1,4,5)P ₃) which facilitates an increase in intracellular Ca ²⁺. Decreases in PI(4,5)P ₂ by PLC also impact on functions that are dependent on the intact lipid and therefore endocytosis, actin dynamics and ion channel regulation are subject to control. Spatial organisation of PI(4,5)P ₂ in nanodomains at the membrane allows for these multiple processes to occur concurrently.