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

Abstract

Phosphatidylinositol(4,5) bisphosphate (PI(4,5)P2) 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)P2 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)P2 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)P2 as a substrate to make second messengers. Activation of PI3K generates PI(3,4,5)P3 (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)P2 to generate the second messengers, diacylglycerol (DAG), an activator of protein kinase C and inositol(1,4,5)trisphosphate (IP3/I(1,4,5)P3) which facilitates an increase in intracellular Ca2+. Decreases in PI(4,5)P2 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)P2 in nanodomains at the membrane allows for these multiple processes to occur concurrently.

TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

“…It is not only the increase in the products of PLC activity that should be considered, but also the reduction in localised PIP 2 that can result from PLC activation. PIP 2 plays a crucial role in regulating a number of cellular processes or molecules, including actin polymerisation, endocytosis, exocytosis, ion channels and G-protein-coupled receptors [78,79]. Another consequence of PIP 2 hydrolysis is the production of protons, which can lead to localised decreases in the juxtamembrane pH [80,81].…”

Altered Proteomic Profile of Adipose Tissue-Derived Mesenchymal Stem Cell Exosomes from Cats with Severe Chronic Gingivostomatitis

“…On the one hand, eight proteins were only present in the exosomes that were derived from the fAd-MSCs isolated from the FCGS patients, while five proteins could only be found in the samples from the healthy cats. The exosomal proteins that were identified exclusively in diseased animals were related to the regulation of biological processes, such as tissue remodeling, inflammation, defense against infectious agents, and metabolism [ 48 , 49 , 50 , 51 ]. The proteins that were missing in the FCGS group were involved in the immune response, inflammation, chromatin structure modulation, transcription, replication, recombination, DNA repair, and gene silencing [ 52 , 53 ].…”

Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration

“…The PI(3,5)P 2 synthesis enzyme FIG4 acts as a risk factor for ALS. Bernier et al (2013b), Khuong et al (2013), Heras-Sandoval et al (2014, Maekawa et al (2014), Schlam et al (2015), Sekar and Taghibiglou (2018), Katan and Cockcroft (2020) and Desale and Chinnathambi (2021) from the post-mortem prefrontal cortex and incubated with PI(4,5)P 2 before the addition of dopamine to activate PLC. These membranes demonstrated reduced PLC activity, characterized by decreased PI(4,5)P 2 metabolism, within the PD samples (Wallace and Claro, 1993).…”