Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP
3 or Ins3P or IP
3 is an
inositol phosphate
Inositol phosphates are a group of mono- to hexaphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.
The group comprises:
* inosito ...
signaling molecule. It is made by
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 ...
of
phosphatidylinositol 4,5-bisphosphate
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 o ...
(PIP
2), a
phospholipid that is located in the
plasma membrane, by
phospholipase C (PLC).
Together with
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), IP
3 is a
second messenger molecule used in
signal transduction in
biological cell
The cell is the basic structural and functional unit of life forms. Every cell consists of a cytoplasm enclosed within a membrane, and contains many biomolecules such as proteins, DNA and RNA, as well as many small molecules of nutrients an ...
s. While DAG stays inside the membrane, IP
3 is soluble and diffuses through the cell, where it binds to
its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP
3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.
Properties
Chemical formula and molecular weight
IP
3 is an organic molecule with a
molecular mass
The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quanti ...
of 420.10 g/mol. Its
empirical formula
In chemistry, the empirical formula of a chemical compound is the simplest whole number ratio of atoms present in a compound. A simple example of this concept is that the empirical formula of sulfur monoxide, or SO, would simply be SO, as is the ...
is C
6H
15O
15P
3. It is composed of an
inositol ring with three
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
groups bound at the 1, 4, and 5 carbon positions, and three
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydro ...
groups bound at positions 2, 3, and 6.
Chemical properties
Phosphate groups can exist in three different forms depending on a solution's
pH. Phosphorus atoms can bind three oxygen atoms with single bonds and a fourth oxygen atom using a double/dative bond. The pH of the solution, and thus the form of the phosphate group determines its ability to bind to other molecules. The binding of phosphate groups to the inositol ring is accomplished by phosphor-ester binding (see
phosphoric acids and phosphates
A phosphoric acid, in the general sense, is a phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is bonded to four oxygen (O) atoms, one of them through a double bond, arranged as the corners of a tetrahedron. ...
). This bond involves combining a
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydro ...
group from the inositol ring and a free phosphate group through a
dehydration reaction
In chemistry, a dehydration reaction is a chemical reaction that involves the loss of water from the reacting molecule or ion. Dehydration reactions are common processes, the reverse of a hydration reaction.
Dehydration reactions in organic ch ...
. Considering that the average physiological pH is approximately 7.4, the main form of the phosphate groups bound to the inositol ring
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
is PO
42−. This gives IP
3 a net negative charge, which is important in allowing it to dock to its receptor, through binding of the phosphate groups to positively charged residues on the receptor. IP
3 has three
hydrogen bond donors in the form of its three hydroxyl groups. The hydroxyl group on the 6th carbon atom in the inositol ring is also involved in IP
3 docking.
Binding to its receptor
![IP3 moleucle](https://upload.wikimedia.org/wikipedia/commons/7/76/IP3_moleucle.png)
The docking of IP
3 to its receptor, which is called the
inositol trisphosphate receptor
Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiol ...
(InsP3R), was first studied using deletion
mutagenesis
Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...
in the early 1990s. Studies focused on the
N-terminus side of the IP
3 receptor. In 1997 researchers localized the region of the IP
3 receptor involved with binding of IP
3 to between
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues 226 and 578 in 1997. Considering that IP
3 is a negatively charged molecule, positively charged amino acids such as
arginine and
lysine were believed to be involved. Two arginine residues at position 265 and 511 and one lysine residue at position 508 were found to be key in IP
3 docking. Using a modified form of IP
3, it was discovered that all three phosphate groups interact with the receptor, but not equally. Phosphates at the 4th and 5th positions interact more extensively than the phosphate at the 1st position and the hydroxyl group at the 6th position of the inositol ring.
Discovery
The discovery that a
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
can influence phosphoinositide
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
was made by
Mabel R. Hokin (1924–2003) and her then husband Lowell E. Hokin in 1953, when they discovered that
radioactive
Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is consi ...
32P phosphate was incorporated into the
phosphatidylinositol
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
of
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
slices when stimulated with
acetylcholine. Up until then
phospholipids
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 t ...
were believed to be inert structures only used by cells as building blocks for construction of the plasma membrane.
Over the next 20 years, little was discovered about the importance of PIP
2 metabolism in terms of cell signaling, until the mid-1970s when Robert H. Michell hypothesized a connection between the
catabolism of PIP
2 and increases in
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
(Ca
2+) levels. He hypothesized that receptor-activated hydrolysis of PIP
2 produced a molecule that caused increases in intracellular calcium mobilization. This idea was researched extensively by Michell and his colleagues, who in 1981 were able to show that PIP
2 is hydrolyzed into DAG and IP
3 by a then unknown
phosphodiesterase
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many ot ...
. In 1984 it was discovered that IP
3 acts as a secondary messenger that is capable of traveling through the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
to the
endoplasmic reticulum (ER), where it stimulates the release of calcium into the cytoplasm.
Further research provided valuable information on the IP
3 pathway, such as the discovery in 1986 that one of the many roles of the calcium released by IP
3 is to work with DAG to activate
protein kinase C (PKC). It was discovered in 1989 that
phospholipase C (PLC) is the phosphodiesterase responsible for hydrolyzing PIP
2 into DAG and IP
3. Today the IP
3 signaling pathway is well mapped out, and is known to be important in regulating a variety of calcium-dependent cell signaling pathways.
Signaling pathway
Increases in the intracellular Ca
2+ concentrations are often a result of IP
3 activation. When a
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
binds to a
G protein-coupled receptor
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 ...
(GPCR) that is coupled to a Gq
heterotrimeric G protein
Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structu ...
, the α-subunit of Gq can bind to and induce activity in the PLC
isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
PLC-β, which results in the cleavage of PIP
2 into IP
3 and DAG.
[Biaggioni I., Robertson D. (2011). Chapter 9. Adrenoceptor Agonists & Sympathomimetic Drugs. In: B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 11e. Retrieved October 11, 2011 from .]
If a
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
(RTK) is involved in activating the pathway, the isozyme PLC-γ has
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP
2 into DAG and IP
3. This occurs in cells that are capable of responding to
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 ...
such as
insulin, because the growth factors are the ligands responsible for activating the RTK.
[Barrett KE, Barman SM, Boitano S, Brooks H. Chapter 2. Overview of Cellular Physiology in Medical Physiology. In: K.E. Barrett, S.M. Barman, S. Boitano, H. Brooks (Eds), Ganong's Review of Medical Physiology, 23e. . ]
IP
3 (also abbreviated Ins(1,4,5)P
3 is a
soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubi ...
molecule and is capable of
diffusing
Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) of ...
through the cytoplasm to the ER, or the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...
(SR) in the case of
muscle cells, once it has been produced by the action of PLC. Once at the ER, IP
3 is able to bind to the Ins(1,4,5)P
3 receptor Ins(1,4,5)P
3R which is a ligand-gated Ca
2+ channel that is found on the surface of the ER. The binding of IP
3 (the ligand in this case) to Ins(1,4,5)P
3R triggers the opening of the Ca
2+ channel, and thus release of Ca
2+ into the cytoplasm.
In heart muscle cells this increase in Ca
2+ activates the
ryanodine receptor-operated channel on the SR, results in further increases in Ca
2+ through a process known as calcium-induced calcium release. IP
3 may also activate Ca
2+ channels on the cell membrane indirectly, by increasing the intracellular Ca
2+ concentration.
Function
Human
IP
3's main functions are to mobilize Ca
2+ from storage
organelles and to regulate
cell proliferation and other cellular reactions that require free calcium. In
smooth muscle cell
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
s, for example, an increase in concentration of cytoplasmic Ca
2+ results in the contraction of the muscle cell.
In the nervous system, IP
3 serves as a second messenger, with the
cerebellum containing the highest concentration of IP
3 receptors. There is evidence that IP
3 receptors play an important role in the induction of plasticity in cerebellar
Purkinje cells
Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
Structure
T ...
.
Sea urchin eggs
The
slow block to polyspermy in the
sea urchin is mediated by the PIP
2 secondary messenger system. Activation of the binding receptors activates PLC, which cleaves PIP
2 in the egg plasma membrane, releasing IP
3 into the egg cell cytoplasm. IP
3 diffuses to the ER, where it opens Ca
2+ channels.
Research
Huntington's disease
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
occurs when the cytosolic protein
Huntingtin
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also fo ...
(Htt) has an additional 35
glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
residues added to its amino terminal region. This modified form of Htt is called Htt
exp. Htt
exp makes Type 1 IP
3 receptors more sensitive to IP
3, which leads to the release of too much Ca
2+ from the ER. The release of Ca
2+ from the ER causes an increase in the cytosolic and
mitochondrial concentrations of Ca
2+. This increase in Ca
2+ is thought to be the cause of
GABAergic MSN degradation.
Alzheimer's disease
Alzheimer's disease involves the progressive degeneration of the brain, severely impacting mental faculties. Since the Ca
2+ hypothesis of Alzheimer's was proposed in 1994, several studies have shown that disruptions in Ca
2+ signaling are the primary cause of Alzheimer's disease.
Familial Alzheimer's disease
Early-onset Alzheimer's disease, also called younger-onset Alzheimer's, is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive ...
has been strongly linked to mutations in the
presenilin 1 (PS1),
presenilin 2 (PS2), and
amyloid precursor protein
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse format ...
(APP)
genes. All of the mutated forms of these genes observed to date have been found to cause abnormal Ca
2+ signaling in the ER. Mutations in PS1 have been shown to increase IP
3-mediated Ca
2+ release from the ER in several animal models.
Calcium channel blockers have been used to treat Alzheimer's disease with some success, and the use of
lithium to decrease IP
3 turnover has also been suggested as a possible method of treatment.
See also
*
Adenophostin
*
Inositol
*
Inositol phosphate
Inositol phosphates are a group of mono- to hexaphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.
The group comprises:
* inosito ...
*
''myo''-Inositol
*
Myo-inositol trispyrophosphate
Myo-inositol trispyrophosphate (ITPP) is an inositol phosphate, a pyrophosphate, a drug candidate, and a putative performance-enhancing substance, which exerts its biological effects by increasing tissue oxygenation.
Chemistry
ITPP is a pyrophosp ...
*
Inositol pentakisphosphate
Inositol pentakisphosphate (abbreviated IP5) is a molecule derived from inositol tetrakisphosphate by adding a phosphate group with the help of Inositol-polyphosphate multikinase (IPMK). It is believed to be one of the many second messengers in ...
*
Inositol hexaphosphate
Phytic acid is a six-fold dihydrogenphosphate ester of inositol (specifically, of the ''myo'' isomer), also called inositol hexakisphosphate (IP6) or inositol polyphosphate. At physiological pH, the phosphates are partially ionized, resulting in ...
*
Inositol trisphosphate receptor
Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiol ...
*
ITPR1
Inositol 1,4,5-trisphosphate receptor type 1 is a protein that in humans is encoded by the ''ITPR1'' gene.
Interactions
ITPR1 has been shown to interact with:
* AHCYL1,
* CA8,
* EPB41L1
* FKBP1A,
* MRVI1,
* PRKG1,
* RHOA
Transform ...
*
ITPKC
ITPKC is one of 3 human genes that encode for an Inositol-trisphosphate 3-kinase. This gene that has been associated with Kawasaki disease. Kawasaki disease is an acute febrile illness that involves the inflammation of blood vessels throughout t ...
References
External links
*
{{DEFAULTSORT:Inositol Triphosphate
Signal transduction
Inositol
Phosphate esters