Phosphatidylinositol 4,5-bisphosphate
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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 (
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PubChem CID
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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 their standard state (at 25 °C [77 °F], 100 kPa).
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Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor
PIP2 is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases from PI(4)P. In metazoans, PIP2 can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases from PI(5)P.[6]
The
Signaling pathways
PIP2 is a part of many cellular signaling pathways, including PIP2 cycle, PI3K signalling, and PI5P metabolism.[8] Recently, it has been found in the nucleus[9] with unknown function.
Functions
Cytoskeleton dynamics near membranes
PIP2 regulates the organization, polymerization, and branching of filamentous actin (F-actin) via direct binding to F-actin regulatory proteins.[10]
Endocytosis and exocytosis
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-specific phospholipase C into 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
PIP2 functions as an intermediate in the
Docking phospholipids
Class I PI 3-kinases phosphorylate PtdIns(4,5)P2 forming phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) and PtdIns(4,5)P2 can be converted from PtdIns4P. PtdIns4P, 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.[23][24]
- Examples of proteins activated by PtdIns(3,4,5)P3 are PDPK1, Btk1.
- One mechanism for direct effect of PtdIns(4,5)P2 is opening of growth hormone-releasing hormone.[25]
Potassium channels
G protein-coupled receptors
PtdIns(4,5)P2 has been shown to stabilize the active states of Class A
G protein-coupled receptor kinases
PIP2 has been shown to recruit
Regulation
PIP2 is regulated by many different components. One emerging hypothesis is that PIP2 concentration is maintained locally. Some of the factors involved in PIP2 regulation 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
- .
- S2CID 298052.
- S2CID 14678865.
- S2CID 252281018.
- S2CID 146810646.
- S2CID 4403301.
- PMID 12654002.
- PMID 25311266.
- PMID 21048195.
- PMID 10559185.
- ^
Eberhard, David A, et al. (1990). "Evidence that the inositol phospholipids are necessary for exocytosis. Loss of inositol phospholipids and inhibition of secretion in permeabilized cells caused by a bacterial phospholipase C and removal of ATP". Biochemical Journal. 268 (1): 15–25. PMID 2160809.
- ^
Hay, Jesse C, Thomas M (1993). "Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion". Nature. 366 (6455): 572–575. S2CID 4348488.
- ^
Hay, Jesse C, et al. (1995). "ATP-dependent inositide phosphorylation required for Ca2positive-activated secretion". Nature. 374 (6518): 173–177. S2CID 4365980.
- ^
Holz RW, et al. (2000). "A pleckstrin homology domain specific for phosphatidylinositol 4, 5-bisphosphate (PtdIns-4, 5-P2) and fused to green fluorescent protein identifies plasma membrane PtdIns-4, 5-P2 as being important in exocytosis". J. Biol. Chem. 275 (23): 17878–17885. PMID 10747966.
- ^ a b c
Gong LW, et al. (2005). "Phosphatidylinositol phosphate kinase type Iγ regulates dynamics of large dense-core vesicle fusion". PNAS. 102 (14): 5204–5209. PMID 15793002.
- ^ a b
Di Paolo G, et al. (2004). "Impaired PtdIns (4, 5) P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking". Nature. 431 (7007): 415–422. S2CID 4333681.
- ^
Waselle L, et al. (2005). "Role of phosphoinositide signaling in the control of insulin exocytosis". Molecular Endocrinology. 19 (12): 3097–3106. PMID 16081518.
- ^ a b
Milosevic I, et al. (2005). "Plasmalemmal phosphatidylinositol-4, 5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells". Journal of Neuroscience. 25 (10): 2557–2565. PMID 15758165.
- ^
Grishanin RN, et al. (2004). "CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP 2 binding protein". Neuron. 43 (4): 551–562. PMID 15312653.
- ^
Kabachinski G, et al. (2014). "CAPS and Munc13 utilize distinct PIP2-linked mechanisms to promote vesicle exocytosis". Molecular Biology of the Cell. 25 (4): 508–521. PMID 24356451.
- ^
Loewen CA, et al. (2006). "C2B polylysine motif of synaptotagmin facilitates a Ca2+-independent stage of synaptic vesicle priming in vivo". Molecular Biology of the Cell. 17 (12): 5211–5226. PMID 16987956.
- S2CID 20289175.
- ^
Won DH, et al. (2006). "PI (3, 4, 5) P3 and PI (4, 5) P2 lipids target proteins with polybasic clusters to the plasma membrane". Science. 314 (5804): 1458–1461. PMID 17095657.
- ^
Hammond G, et al. (2012). "PI4P and PI (4, 5) P2 are essential but independent lipid determinants of membrane identity". Science. 337 (6095): 727–730. PMID 22722250.
- ^ GeneGlobe -> GHRH Signaling[permanent dead link] Retrieved on May 31, 2009
- S2CID 36375203.
- PMID 21874019.
- PMID 29995853.
- PMID 27088923.
- S2CID 24745275.