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
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
component of cell membranes. PtdIns(4,5)''P''
2 is enriched at the
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
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, f ...
s of PIP
2 are variable in different species and tissues, but the most common fatty acids are
stearic in position 1 and
arachidonic
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arach ...
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
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
* Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
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
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
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 hydrolysi ...
by
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(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
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...
. 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
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
(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
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first m ...
. In this cascade, DAG remains on the cell membrane and activates the signal cascade by activating
protein kinase C
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and ...
(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
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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 Class I PI 3-kinases are a subgroup of the enzyme family, phosphoinositide 3-kinase that possess a common protein domain structure, substrate specificity, and method of activation. Class I PI 3-kinases are further divided into two subclasses, class ...
phosphorylate PtdIns(4,5)''P''
2 forming
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
(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
In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas.
Function
PD ...
,
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
Growth may refer to:
Biology
* Auxology, the study of all aspects of human physical growth
* Bacterial growth
* Cell growth
* Growth hormone, a peptide hormone that stimulates growth
* Human development (biology)
* Plant growth
* Secondary gr ...
.
[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 (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
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the beta
adrenergic receptor
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...
, 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