Phosphatidylinositol 4,5-bisphosphate: Difference between revisions

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'''Phosphatidylinositol 4,5-bisphosphate''' or '''PtdIns(4,5)''P''₂''', also known simply as '''PIP₂ or PI(4,5)P₂''', is a minor [[phospholipid]] component of cell membranes. PtdIns(4,5)''P''₂ is enriched at the [[plasma membrane]] where it is a substrate for a number of important signaling proteins.<ref name=Strachan>{{cite book | vauthors = Strachan T, Read AP | title = Leptospira. ''In:'' Human Molecular Genetics | edition = 2nd | publisher = Wiley-Liss | year = 1999 | id = [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hmg.table.888 (via NCBI Bookshelf)] | isbn = 0-471-33061-2 | url-access = registration | url = https://archive.org/details/humanmolecularge0002stra }}</ref> PIP2 also forms [[PIP2 domain|lipid clusters]]<ref>{{cite journal |last1=van den Bogaart |first1=G |last2=Meyenberg |first2=K |last3=Risselada |first3=HJ |last4=Amin |first4=H |last5=Willig |first5=KI |last6=Hubrich |first6=BE |last7=Dier |first7=M |last8=Hell |first8=SW |last9=Grubmüller |first9=H |last10=Diederichsen |first10=U |last11=Jahn |first11=R |title=Membrane protein sequestering by ionic protein-lipid interactions. |journal=Nature |date=23 October 2011 |volume=479 |issue=7374 |pages=552–5 |doi=10.1038/nature10545 |pmid=22020284|pmc=3409895 |bibcode=2011Natur.479..552V |hdl=11858/00-001M-0000-0012-5C28-1 |s2cid=298052 }}</ref> that sort proteins.<ref>{{cite journal |last1=Petersen |first1=EN |last2=Chung |first2=HW |last3=Nayebosadri |first3=A |last4=Hansen |first4=SB |title=Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D. |journal=Nature Communications |date=15 December 2016 |volume=7 |pages=13873 |doi=10.1038/ncomms13873 |pmid=27976674|pmc=5171650 |bibcode=2016NatCo...713873P |s2cid=14678865 }}</ref><ref>{{cite journal |last1=Yuan |first1=Z |last2=Pavel |first2=MA |last3=Wang |first3=H |last4=Kwachukwu |first4=JC |last5=Mediouni |first5=S |last6=Jablonski |first6=JA |last7=Nettles |first7=KW |last8=Reddy |first8=CB |last9=Valente |first9=ST |last10=Hansen |first10=SB |title=Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture. |journal=Communications Biology |date=14 September 2022 |volume=5 |issue=1 |pages=958 |doi=10.1038/s42003-022-03841-8 |pmid=36104427|pmc=9472185 |s2cid=252281018 }}</ref><ref>{{cite journal |last1=Robinson |first1=CV |last2=Rohacs |first2=T |last3=Hansen |first3=SB |title=Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. |journal=Trends in Biochemical Sciences |date=September 2019 |volume=44 |issue=9 |pages=795–806 |doi=10.1016/j.tibs.2019.04.001 |pmid=31060927|pmc=6729126 |s2cid=146810646 }}</ref>

PIP₂ is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases from [[Phosphatidylinositol 4-phosphate|PI(4)P]]. In metazoans, PIP₂ can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases from [[Phosphatidylinositol 5-phosphate|PI(5)P]].<ref>{{cite journal | last1 = Rameh | first1 = LE | last2 = Tolias | first2 = K | last3 = Duckworth | first3 = BC | last4 = Cantley | first4 = LC | date = Nov 1997 | title = A new pathway for synthesis of phosphatydilinositol-4,5-bisphosphate | journal = Nature | volume = 390 | issue = 6656| pages = 192–6 | doi = 10.1038/36621 | pmid = 9367159 | bibcode = 1997Natur.390..192R | s2cid = 4403301 }}</ref>

The [[fatty acid]]s of PIP₂ are variable in different species and tissues, but the most common fatty acids are [[stearic acid|stearic]] in position 1 and [[arachidonic]] in 2.<ref>{{Cite journal |vauthors=Tanaka T, Iwawaki D, Sakamoto M, Takai Y, Morishige J, Murakami K, Satouchi K | title = 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 | journal = Eur J Biochem | volume = 270 | date = April 2003 | issue = 7 | pages = 1466–73 | doi = 10.1046/j.1432-1033.2003.03512.x | pmid = 12654002 | doi-access = free }}</ref>

== Signaling pathways ==

PIP₂ is a part of many cellular signaling pathways, including [[PI(4,5)P2 Cycle|PIP₂ cycle]], [[PI3K/AKT/mTOR pathway|PI3K signalling]], and PI5P metabolism.<ref>{{cite journal|pmc=4359101 | pmid=25311266 | doi=10.1016/j.jbior.2014.09.007 | volume=57 | title=Exploring phosphatidylinositol 5-phosphate 4-kinase function | journal=Adv Biol Regul | pages=193–202 | vauthors=Bulley SJ, Clarke JH, Droubi A, Giudici ML, Irvine RF| year=2015 }}</ref> Recently, it has been found in the [[Cell nucleus|nucleus]]<ref>{{cite journal|pmc=3033679 | pmid=21048195 | doi=10.1074/mcp.M110.003376 | volume=10 | issue=2 | title=Identification of nuclear phosphatidylinositol 4,5-bisphosphate-interacting proteins by neomycin extraction | journal=Mol Cell Proteomics | page=M110.003376 | vauthors=Lewis AE, Sommer L, Arntzen MØ, Strahm Y, Morrice NA, Divecha N, D'Santos CS| year=2011 | doi-access=free }}</ref> with unknown function.

=== Cytoskeleton dynamics near membranes ===

PIP₂ regulates the organization, polymerization, and branching of filamentous actin (F-actin) via direct binding to F-actin regulatory proteins.<ref>{{cite journal|last1=Sun|first1=Hui|last2=Yamamoto|first2=Masaya|last3=Mejillano|first3=Marisan|last4=Yin|first4=Helen|title=Gelsolin, a Multifunctional Actin Regulatory Protein|journal=The Journal of Biological Chemistry|date=November 19, 1999|volume=274|issue=47|pages=33179–82|pmid=10559185|doi=10.1074/jbc.274.47.33179|doi-access=free}}</ref>

=== 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.

<ref name="Emberhard1990">

{{cite journal

|vauthors=Eberhard, David A, et al

| title = 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.

| journal = Biochemical Journal

| year = 1990

| doi = 10.1042/bj2680015

| pmid = 2160809

| volume=268

| issue = 1

| pages=15–25

| pmc=1131385}}

</ref>

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

,<ref name="Hay1993">

{{cite journal

|vauthors= Hay, Jesse C, Thomas M

| title = Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion

| journal = Nature

| year = 1993

| doi = 10.1038/366572a0

| pmid = 8255295

| volume=366

| issue = 6455

| pages=572–575

| s2cid = 4348488

}}</ref> and phosphoinositol-4-monophosphatase 5 kinase type Iγ (PIPKγ)

,<ref name="Hay1995">

{{cite journal

|vauthors= Hay, Jesse C, et al.

| title = ATP-dependent inositide phosphorylation required for Ca2positive-activated secretion.

| journal = Nature

| year = 1995

| doi = 10.1038/374173a0

| pmid = 7877690

| volume=374

| issue = 6518

| pages=173–177

| s2cid = 4365980

}}

</ref>

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.{{cn|date=October 2023}}

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)

,<ref name="Holz 2000">

{{cite journal

|vauthors= Holz RW, et al

| title = 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

| journal = J. Biol. Chem.

| year = 2000

| doi = 10.1074/jbc.M000925200

| pmid = 10747966

| volume=275

| issue = 23

| pages=17878–17885

| doi-access= free

}}</ref> PIPKIγ knockout in chromaffin cell

<ref name="gong2005">

{{cite journal

|vauthors= Gong LW, et al

| title = Phosphatidylinositol phosphate kinase type Iγ regulates dynamics of large dense-core vesicle fusion.

| journal = PNAS

| year = 2005

| doi = 10.1073/pnas.0501412102

| pmid = 15793002

| volume=102

| issue = 14

| pages=5204–5209

| pmc= 555604

| doi-access = free

| bibcode = 2005PNAS..102.5204G

}}

</ref> and in central nerve system,<ref name="Di Paolo G2004">

{{cite journal

|vauthors= Di Paolo G, et al

| title = Impaired PtdIns (4, 5) P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.

| journal = Nature

| year = 2004

| doi = 10.1038/nature02896

| pmid = 15386003

| volume=431

| issue = 7007

| pages=415–422

| s2cid = 4333681

}}

</ref> PIPKIγ knockdown in beta cell lines

,<ref name="Waselle L2005">

{{cite journal

|vauthors= Waselle L, et al

| title = Role of phosphoinositide signaling in the control of insulin exocytosis.

| journal = Molecular Endocrinology

| year = 2005

| doi = 10.1210/me.2004-0530

| pmid = 16081518

| volume=19

| issue = 12

| pages=3097–3106

| doi-access= free

}}

</ref> and over-expression of membrane-tethered inositol 5-phosphatase domain of synaptojanin 1

,<ref name="Milosevic2005">

{{cite journal

|vauthors= Milosevic I, et al

| title = Plasmalemmal phosphatidylinositol-4, 5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells.

| journal = Journal of Neuroscience

| year = 2005

| doi = 10.1523/JNEUROSCI.3761-04.2005

| volume=25

| issue = 10

| pages=2557–2565

| pmid = 15758165

| pmc = 6725155

| doi-access= free

}}

</ref> all suggested vesicle (synaptic vesicle and LDCV) secretion were severely impaired after PI(4,5)P2 depletion or blockage. Moreover, some studies<ref name="Milosevic2005"/><ref name="Di Paolo G2004"/><ref name="gong2005"/> showed an impaired/reduced RRP of those vesicles, though the docked vesicle number were not altered<ref name="gong2005"/> 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,<ref name="Grishanin RN2004">

{{cite journal

|vauthors= Grishanin RN, et al

| title = CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP 2 binding protein

| journal = Neuron

| year = 2004

| doi = 10.1016/j.neuron.2004.07.028

| volume=43

| issue = 4

| pages=551–562

| pmid = 15312653

| doi-access= free

}}

</ref> Munc13<ref name="Kabachinski G2014">

{{cite journal

|vauthors= Kabachinski G, et al

| title = CAPS and Munc13 utilize distinct PIP2-linked mechanisms to promote vesicle exocytosis

| journal = Molecular Biology of the Cell

| year = 2014

| doi = 10.1091/mbc.E12-11-0829

| pmid = 24356451

| volume=25

| issue = 4

| pages=508–521

| pmc=3923642

}}

</ref> and synaptotagmin1<ref name="Loewen CA2006">

{{cite journal

|vauthors= Loewen CA, et al

| title = C2B polylysine motif of synaptotagmin facilitates a Ca2+-independent stage of synaptic vesicle priming in vivo

| journal = Molecular Biology of the Cell

| year = 2006

| doi = 10.1091/mbc.E06-07-0622

| pmid = 16987956

| pmc = 1679685

| volume=17

| issue = 12

| pages=5211–5226

}}

</ref> 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 [[IP3/DAG pathway|IP₃/DAG pathway]], which is initiated by ligands binding to G protein-coupled receptors activating the [[Gq alpha subunit|G_q alpha subunit]]. PtdIns(4,5)''P''₂ is a substrate for [[hydrolyze|hydrolysis]] by [[phospholipase C]] (PLC), a membrane-bound [[enzyme]] activated through protein receptors such as α1 [[adrenergic receptors]]. PIP₂ regulates the function of many membrane proteins and ion channels, such as the [[M current|M-channel]]. The products of the PLC catalyzation of PIP₂ are [[inositol 1,4,5-trisphosphate]] (Ins''P''₃; IP₃) and [[diglyceride|diacylglycerol]] (DAG), both of which function as [[second messenger system|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.<ref>{{Cite journal|last1=Rusten|first1=Tor Erik|last2=Stenmark|first2=Harald|date=April 2006|title=Analyzing phosphoinositides and their interacting proteins|journal=Nature Methods|volume=3|issue=4|pages=251–258|doi=10.1038/nmeth867|pmid=16554828|s2cid=20289175|issn=1548-7091}}</ref>

{{Further|phosphatidylinositol (3,4,5)-trisphosphate}}

[[Class I PI 3-kinases]] phosphorylate PtdIns(4,5)''P''₂ forming [[phosphatidylinositol (3,4,5)-trisphosphate]] (PtdIns(3,4,5)''P''₃) and PtdIns(4,5)''P''₂ can be converted from PtdIns4P. PtdIns4P, PtdIns(3,4,5)''P''₃ and PtdIns(4,5)''P''₂ 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.<ref name="DoHeo2006">

{{cite journal

|vauthors=Won DH, et al

| title = PI (3, 4, 5) P3 and PI (4, 5) P2 lipids target proteins with polybasic clusters to the plasma membrane.

| journal = Science

| volume = 314

| pages = 1458–1461

| year = 2006

| doi = 10.1126/science.1134389

| pmid = 17095657

| issue = 5804

| pmc= 3579512

}}</ref><ref name="Hammond2012">

{{cite journal

|vauthors=Hammond G, et al

| title = PI4P and PI (4, 5) P2 are essential but independent lipid determinants of membrane identity

| journal = Science

| volume = 337

| pages = 727–730

| year = 2012

| doi = 10.1126/science.1222483

| pmid = 22722250

| issue = 6095

| pmc= 3646512

}}</ref>

* Examples of proteins activated by PtdIns(3,4,5)''P''₃ are [[Protein kinase B|Akt]], [[PDPK1]], [[Bruton's tyrosine kinase|Btk]]1.

* One mechanism for direct effect of PtdIns(4,5)''P''₂ is opening of [[sodium channel|Na⁺ channel]]s as a minor function in growth hormone release by [[growth hormone-releasing hormone]].<ref name=GeneGlobe>[https://www1.qiagen.com/GeneGlobe/PathwayView.aspx?pathwayID=199 GeneGlobe -> GHRH Signaling]{{dead link|date=March 2018 |bot=InternetArchiveBot |fix-attempted=yes }} Retrieved on May 31, 2009</ref>

===Potassium channels===

[[Inward-rectifier potassium ion channel|Inwardly rectifying potassium channels]] have been shown to require docking of PIP₂ for channel activity.<ref>{{cite journal|last=Soom|first=M|title=Multiple PtdIns(4,5)P₂ binding sites in Kir2.1 inwardly rectifying potassium channels|journal=FEBS Letters|volume=490|issue=1–2|pages=49–53|doi=10.1016/S0014-5793(01)02136-6|pmid=11172809|year=2001|s2cid=36375203|doi-access=free}}</ref><ref>{{cite journal|last1=Hansen|first1=SB|last2=Tao|first2=X|last3=MacKinnon|first3=R|title=Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.|journal=Nature|date=28 August 2011|volume=477|issue=7365|pages=495–8|pmid=21874019|doi=10.1038/nature10370|pmc=3324908}}</ref>

=== G protein-coupled receptors ===

PtdIns(4,5)''P''₂ has been shown to stabilize the active states of Class A [[G protein–coupled receptor|G protein-coupled receptors]] (GPCRs) via direct binding, and enhance their selectivity toward certain G proteins.<ref>{{Cite journal|last1=Yen|first1=Hsin-Yung|last2=Hoi|first2=Kin Kuan|last3=Liko|first3=Idlir|last4=Hedger|first4=George|last5=Horrell|first5=Michael R.|last6=Song|first6=Wanling|last7=Wu|first7=Di|last8=Heine|first8=Philipp|last9=Warne|first9=Tony|date=2018-07-11|title=PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling|journal=Nature|volume=559|issue=7714|pages=423–427|doi=10.1038/s41586-018-0325-6|pmid=29995853|pmc=6059376|issn=0028-0836}}</ref>

=== G protein-coupled receptor kinases ===

PIP₂ has been shown to recruit [[Beta adrenergic receptor kinase-2|G 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 efficient [[phosphorylation]] of the beta [[adrenergic receptor]], a type of GPCR.<ref>{{Cite journal|last1=Yang|first1=Pei|last2=Homan|first2=Kristoff T.|last3=Li|first3=Yaoxin|last4=Cruz-Rodríguez|first4=Osvaldo|last5=Tesmer|first5=John J.G.|last6=Chen|first6=Zhan|date=2016-05-24|title=Effect of Lipid Composition on Membrane Orientation of the G protein-coupled Receptor Kinase 2-Gβ1γ2 Complex|journal=Biochemistry|volume=55|issue=20|pages=2841–2848|doi=10.1021/acs.biochem.6b00354|issn=0006-2960|pmc=4886744|pmid=27088923}}</ref>

===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:<ref>{{cite journal|last=Hilgemann|first=D. W.|title=The Complex and Intriguing Lives of PIP2 with Ion Channels and Transporters|journal=Science's STKE|volume=2001|issue=111|pages=19re–19|doi=10.1126/stke.2001.111.re19|pmid=11734659|year=2001|s2cid=24745275}}</ref>

* [[Phosphoinositide 3-kinase|Lipid kinases]], Lipid Phosphatase

* Lipid Transfer Proteins

* [[Growth factor|Growth Factors]], Small GTPases

* Cell Attachment

* Cell-Cell Interaction

* Change in cell volume

* Cell differentiation state

* Cell stress

<references />

==Further reading==

{{refbegin | 2}}

*{{cite journal |vauthors= Mansat M, Kpotor AO, Chicanne G, Picot M, Mazars A, Flores-Flores R, Payrastre B, Hnia K, Viaud J |title= MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 16 |pages= 8910–5 |year= 2024 |pmid= 38805272|doi= 10.1073/pnas.2217971121| doi-access=free |pmc= 11161799 }}

{{refend}}

[[Category:Phospholipids]]