Phosphatidylinositol 4,5-bisphosphate
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Names | |
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IUPAC name
1,2-Diacyl-sn-glycero-3-phospho-(1-D-myo-inositol 4,5-bisphosphate)
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Identifiers | |
3D model (JSmol)
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ChemSpider | |
PubChemCID
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CompTox Dashboard(EPA)
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Properties | |
C47H80O19P3 | |
Molar mass | 1042.05 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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Phosphatidylinositol 4,5-bisphosphateorPtdIns(4,5)P2,also known simply asPIP2or PI(4,5)P2,is a minorphospholipidcomponent of cell membranes. PtdIns(4,5)P2is enriched at theplasma membranewhere it is a substrate for a number of important signaling proteins.[1]PIP2 also formslipid clusters[2]that sort proteins.[3][4][5]
PIP2is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases fromPI(4)P.In metazoans, PIP2can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases fromPI(5)P.[6]
Thefatty acidsof PIP2are variable in different species and tissues, but the most common fatty acids arestearicin position 1 andarachidonicin 2.[7]
Signaling pathways
[edit]PIP2is a part of many cellular signaling pathways, includingPIP2cycle,PI3K signalling,and PI5P metabolism.[8]Recently, it has been found in thenucleus[9]with unknown function.
Functions
[edit]Cytoskeleton dynamics near membranes
[edit]PIP2regulates the organization, polymerization, and branching of filamentous actin (F-actin) via direct binding to F-actin regulatory proteins.[10]
Endocytosis and exocytosis
[edit]The first evidence that indicated phosphoinositides(PIs) (especially PI(4,5)P2) are important during the exocytosis process was in 1990. Emberhard et al. [11] found that the application of PI-specificphospholipase Cinto digitonin-permeabilized chromaffin cells decreased PI levels, and inhibited calcium-triggered exocytosis. This exocytosis inhibition was preferential for an ATP-dependent stage, indicating PI function was required for secretion. Later studies identified associated proteins necessary during this stage, such as phosphatidylinositol transfer protein ,[12]and phosphoinositol-4-monophosphatase 5 kinase type Iγ (PIPKγ) ,[13] which mediates PI(4,5)P2 restoration in permeable cell incubation in an ATP-dependent way. In these later studies, PI(4,5)P2 specific antibodies strongly inhibited exocytosis, thus providing direct evidence that PI(4,5)P2 plays a pivotal role during the LDCV (Large dense core vesicle) exocytosis process.[citation needed]
Through the use of PI-specific kinase/phosphatase identification and PI antibody/drug/blocker discovery, the role of PI (especially PI(4,5)P2) in secretion regulation was extensively investigated. Studies utilizing PHPLCδ1 domain over-expression (acting as PI(4,5)P2 buffer or blocker) ,[14]PIPKIγ knockout in chromaffin cell [15]and in central nerve system,[16]PIPKIγ knockdown in beta cell lines ,[17]and over-expression of membrane-tethered inositol 5-phosphatase domain of synaptojanin 1 ,[18]all suggested vesicle (synaptic vesicle and LDCV) secretion were severely impaired after PI(4,5)P2 depletion or blockage. Moreover, some studies[18][16][15]showed an impaired/reduced RRP of those vesicles, though the docked vesicle number were not altered[15]after PI(4,5)P2 depletion, indicating a defect at a pre-fusion stage (priming stage). Follow-up studies indicated that PI(4,5)P2 interactions with CAPS,[19]Munc13[20]and synaptotagmin1[21]are likely to play a role in this PI(4,5)P2 dependent priming defect.
IP3/DAG pathway
[edit]PIP2functions as an intermediate in theIP3/DAG pathway,which is initiated by ligands binding to G protein-coupled receptors activating theGqalpha subunit.PtdIns(4,5)P2is a substrate forhydrolysisbyphospholipase C(PLC), a membrane-boundenzymeactivated through protein receptors such asα1 adrenergic receptors.PIP2regulates the function of many membrane proteins and ion channels, such as theM-channel.The products of the PLC catalyzation of PIP2areinositol 1,4,5-trisphosphate(InsP3;IP3) anddiacylglycerol(DAG), both of which function assecond messengers.In this cascade, DAG remains on the cell membrane and activates the signal cascade by activatingprotein kinase C(PKC). PKC in turn activates other cytosolic proteins by phosphorylating them. The effect of PKC could be reversed by phosphatases. IP3enters the cytoplasm and activates IP3receptors on the smoothendoplasmic reticulum(ER), which opens calcium channels on the smooth ER, allowing mobilization of calcium ions through specific Ca2+channels into the cytosol. Calcium participates in the cascade by activating other proteins.[22]
Docking phospholipids
[edit]Class I PI 3-kinasesphosphorylate PtdIns(4,5)P2formingphosphatidylinositol (3,4,5)-trisphosphate(PtdIns(3,4,5)P3) and PtdIns(4,5)P2can be converted from PtdIns4P. PtdIns4P, PtdIns(3,4,5)P3and PtdIns(4,5)P2not only act as substrates for enzymes but also serve asdocking phospholipidsthat bind specific domains that promote the recruitment of proteins to the plasma membrane and subsequent activation of signaling cascades.[23][24]
- Examples of proteins activated by PtdIns(3,4,5)P3areAkt,PDPK1,Btk1.
- One mechanism for direct effect of PtdIns(4,5)P2is opening ofNa+channelsas a minor function in growth hormone release bygrowth hormone-releasing hormone.[25]
Potassium channels
[edit]Inwardly rectifying potassium channelshave been shown to require docking of PIP2for channel activity.[26][27]
G protein-coupled receptors
[edit]PtdIns(4,5)P2has been shown to stabilize the active states of Class AG protein-coupled receptors(GPCRs) via direct binding, and enhance their selectivity toward certain G proteins.[28]
G protein-coupled receptor kinases
[edit]PIP2has been shown to recruitG protein-coupled receptor kinase 2(GRK2) to the membrane by binding to the large lobe of GRK2. This stabilizes GRK2 and also orients it in a way that allows for more efficientphosphorylationof the betaadrenergic receptor,a type of GPCR.[29]
Regulation
[edit]PIP2is regulated by many different components. One emerging hypothesis is that PIP2concentration is maintained locally. Some of the factors involved in PIP2regulation are:[30]
- Lipid kinases,Lipid Phosphatase
- Lipid Transfer Proteins
- Growth Factors,Small GTPases
- Cell Attachment
- Cell-Cell Interaction
- Change in cell volume
- Cell differentiation state
- Cell stress
References
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- ^Tanaka T, Iwawaki D, Sakamoto M, Takai Y, Morishige J, Murakami K, Satouchi K (April 2003)."Mechanisms of accumulation of arachidonate in phosphatidylinositol in yellowtail. A comparative study of acylation systems of phospholipids in rat and the fish species Seriola quinqueradiata".Eur J Biochem.270(7): 1466–73.doi:10.1046/j.1432-1033.2003.03512.x.PMID12654002.
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- ^Yen, Hsin-Yung; Hoi, Kin Kuan; Liko, Idlir; Hedger, George; Horrell, Michael R.; Song, Wanling; Wu, Di; Heine, Philipp; Warne, Tony (2018-07-11)."PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling".Nature.559(7714): 423–427.doi:10.1038/s41586-018-0325-6.ISSN0028-0836.PMC6059376.PMID29995853.
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Further reading
[edit]- Mansat M, Kpotor AO, Chicanne G, Picot M, Mazars A, Flores-Flores R, Payrastre B, Hnia K, Viaud J (2024)."MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion".Proc. Natl. Acad. Sci. U.S.A.97(16): 8910–5.doi:10.1073/pnas.2217971121.PMC11161799.PMID38805272.