Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''
2, also known simply as PIP
2 or PI(4,5)P
2, 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.
PIP2 also forms
lipid clusters that sort proteins.
PIP
2 is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases from
PI(4)P. In metazoans, PIP
2 can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases from
PI(5)P.
The
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s of PIP
2 are variable in different species and tissues, but the most common fatty acids are
stearic in position 1 and
arachidonic in 2.
Signaling pathways
PIP
2 is a part of many cellular signaling pathways, including
PIP2 cycle,
PI3K signalling, and PI5P metabolism. Recently, it has been found in the
nucleus with unknown function.
Functions
Cytoskeleton dynamics near membranes
PIP
2 regulates the organization, polymerization, and branching of filamentous actin (F-actin) via direct binding to F-actin regulatory proteins.
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.
[
]
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
,
[
] and phosphoinositol-4-monophosphatase 5 kinase type Iγ (PIPKγ)
,
[
]
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.
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)
,
[
] PIPKIγ knockout in chromaffin cell
[
] and in central nerve system,
[
] PIPKIγ knockdown in beta cell lines
,
[
] and over-expression of membrane-tethered inositol 5-phosphatase domain of synaptojanin 1
,
[
] all suggested vesicle (synaptic vesicle and LDCV) secretion were severely impaired after PI(4,5)P2 depletion or blockage. Moreover, some studies
showed an impaired/reduced RRP of those vesicles, though the docked vesicle number were not altered
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,
[
] Munc13
[
] and synaptotagmin1
[
] are likely to play a role in this PI(4,5)P2 dependent priming defect.
IP3/DAG pathway
PIP
2 functions as an intermediate in the
IP3/DAG pathway, which is initiated by ligands binding to G protein-coupled receptors activating the
Gq alpha subunit. PtdIns(4,5)''P''
2 is a substrate for
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
by
phospholipase C (PLC), a membrane-bound
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
activated through protein receptors such as α1
adrenergic receptors. PIP
2 regulates the function of many membrane proteins and ion channels, such as the
M-channel. The products of the PLC catalyzation of PIP
2 are
inositol 1,4,5-trisphosphate (Ins''P''
3; IP
3) and
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
(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. IP
3 enters the cytoplasm and activates IP
3 receptors on the smooth
endoplasmic reticulum (ER), which opens calcium channels on the smooth ER, allowing mobilization of calcium ions through specific Ca
2+ channels into the cytosol. Calcium participates in the cascade by activating other proteins.
Docking phospholipids
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.
[
][
]
*Examples of proteins activated by PtdIns(3,4,5)''P''
3 are
Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
,
PDPK1,
Btk1.
*One mechanism for direct effect of PtdIns(4,5)''P''
2 is opening of
Na+ channels as a minor function in growth hormone release by
growth hormone-releasing hormone.
[GeneGlobe -> GHRH Signaling]
Retrieved on May 31, 2009
Potassium channels
Inwardly rectifying potassium channels have been shown to require docking of PIP
2 for channel activity.
G protein-coupled receptors
PtdIns(4,5)''P''
2 has been shown to stabilize the active states of Class A
G protein-coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCRs) via direct binding, and enhance their selectivity toward certain G proteins.
G protein-coupled receptor kinases
PIP
2 has been shown to recruit
G protein-coupled receptor kinase 2
G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ''ADRBK1'' gene. GRK2 was initially called Beta-adrenergic receptor kinase (βARK or βARK1), and is a member of the G protein-coupled receptor kinase subfam ...
(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.
Regulation
PIP
2 is regulated by many different components. One emerging hypothesis is that PIP
2 concentration is maintained locally. Some of the factors involved in PIP
2 regulation are:
*
Lipid kinases, Lipid Phosphatase
* Lipid Transfer Proteins
*
Growth Factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
, Small GTPases
* Cell Attachment
* Cell-Cell Interaction
* Change in cell volume
* Cell differentiation state
* Cell stress
References
{{Phospholipids
Phospholipids