In 1988,Lewis C. Cantley published a paper describing the discovery of a novel type of phosphoinositide kinase with the unprecedented ability to phosphorylate the 3' position of the inositol ring resulting in the formation of phosphatidylinositol-3-phosphate (PI3P).[1] Working independently, Alexis Traynor-Kaplan and coworkers published a paper demonstrating that a novel lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP3) occurs naturally in humanneutrophils with levels that increased rapidly following physiologic stimulation with chemotactic peptide.[2] Subsequent studies demonstrated thatin vivo the enzyme originally identified by Cantley's group prefers PtdIns(4,5)P2 as a substrate, producing the product PIP3.[3]
PIP3 functions to activate downstream signaling components, the most notable one being the protein kinaseAkt, which activates downstream anabolic signaling pathways required for cell growth and survival.[4]
PIP3 plays a critical role outside the cytosol, notably at the postsynaptic terminal of hippocampal cells. Here, PIP3 has been implicated in regulating synaptic strengthening andAMPA expression, contributing tolong-term potentiation. Moreover, PIP3 suppression disrupts normal AMPA expression on the neuron membrane and instead leads to the accumulation of AMPA on dendritic spines, commonly associated withsynaptic depression.[9]
PIP3 interacts with proteins to mediatesynaptic plasticity. Of these proteins,Phldb2 has been shown to interact with PIP3 to induce and maintain long-term potentiation. In the absence of such an interaction, memory consolidation is impaired.[10]
