Phosphatidylinositol 4,5-bisphosphate

Phosphatidylinositol 4,5-bisphosphate

Names
IUPAC name 1,2-Diacyl-sn-glycero-3-phospho-(1-D-myo-inositol 4,5-bisphosphate)
Identifiers
CAS Number	245126-95-8
ChemSpider	21169207
Jmol 3D model	Interactive image
PubChem	5497157
InChI InChI=1S/C47H85O19P3/c1-3-5-7-9-11-13-15-17-19-20-22-24-26-28-30-32-34-36-41(49)63-39(37-61-40(48)35-33-31-29-27-25-23-21-18-16-14-12-10-8-6-4-2)38-62-69(59,60)66-45-42(50)43(51)46(64-67(53,54)55)47(44(45)52)65-68(56,57)58/h11,13,17,19,22,24,28,30,39,42-47,50-52H,3-10,12,14-16,18,20-21,23,25-27,29,31-38H2,1-2H3,(H,59,60)(H2,53,54,55)(H2,56,57,58)/p-5/b13-11-,19-17-,24-22-,30-28-/t39?,42-,43+,44+,45-,46-,47-/m1/s1 Key: CNWINRVXAYPOMW-WJUYXORRSA-I InChI=1/C47H85O19P3/c1-3-5-7-9-11-13-15-17-19-20-22-24-26-28-30-32-34-36-41(49)63-39(37-61-40(48)35-33-31-29-27-25-23-21-18-16-14-12-10-8-6-4-2)38-62-69(59,60)66-45-42(50)43(51)46(64-67(53,54)55)47(44(45)52)65-68(56,57)58/h11,13,17,19,22,24,28,30,39,42-47,50-52H,3-10,12,14-16,18,20-21,23,25-27,29,31-38H2,1-2H3,(H,59,60)(H2,53,54,55)(H2,56,57,58)/p-5/b13-11-,19-17-,24-22-,30-28-/t39?,42-,43+,44+,45-,46-,47-/m1/s1 Key: CNWINRVXAYPOMW-XHXVUCGABS
SMILES O=P([O-])([O-])O[C@@H]1[C@@H](O)[C@H](OP([O-])(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)[C@H](O)[C@H](O)[C@H]1OP([O-])([O-])=O
Properties
Chemical formula	C47H80O19P3
Molar mass	1042.05 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P₂, also known simply as PIP₂, is a minor phospholipid component of cell membranes. PtdIns(4,5)P₂ is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins.^[1]

PtdIns(4,5)P₂ is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases from PI(4)P. In metazoans, PtdIns(4,5)P₂ can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases from PI(5)P.^[2]

The fatty acids of PtdIns(4,5)P₂ are variable in different species and tissues, but studies show the most common fatty acids are stearic in position 1 and arachidonic in 2.^[3]

Functions

IP₃/DAG pathway

PIP₂ functions as an intermediate in the [IP₃/DAG pathway], which is initiated by ligands binding to G protein-coupled receptors activating the G_q alpha subunit. PtdIns(4,5)P₂ is a substrate for hydrolysis by phospholipase C (PLC), a membrane-bound enzyme activated through protein receptors such as α1 adrenergic receptors. PtdIns(4,5)P₂ regulates the function of many membrane proteins and ion channels, such as the M-channel. The products of the PLC catalyzation of PtdIns(4,5)P₂ are inositol 1,4,5-trisphosphate (InsP₃; IP₃) and diacylglycerol (DAG), both of which function as second messengers. In this cascade, DAG remains on the cell membrane and activates the signal cascade by activating protein kinase C (PKC). PKC in turn activates other cytosolic proteins by phosphorylating them. The effect of PKC could be reversed by phosphatases. IP₃ enters the cytoplasm and activates IP₃ receptors on the smooth endoplasmic 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.

Docking phospholipids

Class I PI 3-kinases phosphorylate PtdIns(4,5)P₂ forming phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P₃). Both PtdIns(3,4,5)P₃ and PtdIns(4,5)P₂ not only act as substrates for enzymes but also serve as docking phospholipids that bind specific domains that promote the recruitment of proteins to the plasma membrane and subsequent activation of signaling cascades.

• Examples of proteins activated by PtdIns(3,4,5)P₃ are AKT, PDPK1, Btk1.
• One mechanism for direct effect of PtdIns(4,5)P₂ is opening of Na⁺ channels as a minor function in growth hormone release by growth hormone-releasing hormone.^[4]

Potassium channels

Inwardly rectifying potassium channels have been shown to require docking of PtdIns(4,5)P₂ for channel activity.^[5][6]

Regulation

PtdIns(4,5)P₂ is regulated by many different components. One emerging hypothesis is that PtdIns(4,5)P₂ concentration is maintained locally. Some of the factors involved in PtdIns(4,5)P₂ regulation are:^[7]

• 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

Additional images

References

1. Strachan T, Read AP (1999). Leptospira. In: Human Molecular Genetics (2nd ed.). Wiley-Liss. (via NCBI Bookshelf) ISBN 0-471-33061-2.
2. Rameh, LE; Tolias, K; Duckworth, BC; Cantley, LC (Nov 1997). "A new pathway for synthesis of phosphatydilinositol-4,5-bisphosphate". Nature 390 (6656): 192–6. doi:10.1038/36621. PMID 9367159.
3. 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. PMID 12654002.
4. GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009
5. Soom, M. "Multiple PtdIns(4,5)P₂ binding sites in Kir2.1 inwardly rectifying potassium channels". FEBS Letters 490 (1-2): 49–53. doi:10.1016/S0014-5793(01)02136-6.
6. Hansen, SB; Tao, X; MacKinnon, R (28 August 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.". Nature 477 (7365): 495–8. PMID 21874019.
7. Hilgemann, D. W. "The Complex and Intriguing Lives of PIP2 with Ion Channels and Transporters". Science's STKE 2001 (111): 19re–19. doi:10.1126/stke.2001.111.re19.