Editing Inositol trisphosphate

{{Chembox
| Name = 1D-myo-inositol 1,4,5-trisphosphate 
| ImageFile = Inositol 1,4,5-trisphosphate.svg
| ImageSize = 200px
| ImageCaption = The inositol trisphosphate trianion
| IUPACName = [(1''R'',2''S'',3''R'',4''R'',5''S'',6''R'')-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate
| OtherNames = IP<sub>3</sub>; Triphosphoinositol; Inositol 1,4,5-trisphosphate
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 4222
| CASNo = 85166-31-0
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = MU34XVK5NR
| PubChem = 439456
| ChemSpiderID = 388562
| SMILES = [C@H]1([C@@H]([C@H]([C@@H]([C@H]([C@@H]1OP(=O)(O)O)O)OP(=O)(O)O)OP(=O)(O)O)O)O
| InChI = 1/C6H15O15P3/c7-1-2(8)5(20-23(13,14)15)6(21-24(16,17)18)3(9)4(1)19-22(10,11)12/h1-9H,(H2,10,11,12)(H2,13,14,15)(H2,16,17,18)/t1-,2+,3+,4-,5-,6-/m1/s1
| InChIKey = MMWCIQZXVOZEGG-XJTPDSDZBF
| StdInChI = 1S/C6H15O15P3/c7-1-2(8)5(20-23(13,14)15)6(21-24(16,17)18)3(9)4(1)19-22(10,11)12/h1-9H,(H2,10,11,12)(H2,13,14,15)(H2,16,17,18)/t1-,2+,3+,4-,5-,6-/m1/s1
| StdInChIKey = MMWCIQZXVOZEGG-XJTPDSDZSA-N
  }}
|Section2={{Chembox Properties
| Formula = C<sub>6</sub>H<sub>15</sub>O<sub>15</sub>P<sub>3</sub>
| MolarMass = 420.096 g/mol
| Appearance = 
| Density = 
| MeltingPt = 
| BoilingPt = 
| Solubility =
  }}
|Section3={{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt =
  }}
}}

'''Inositol trisphosphate''' or '''inositol 1,4,5-trisphosphate''' abbreviated '''InsP<sub>3</sub>''' or '''Ins3P''' or '''IP<sub>3</sub>''' is an [[inositol phosphate]] signaling molecule. It is made by [[hydrolysis]] of [[phosphatidylinositol 4,5-bisphosphate]] (PIP<sub>2</sub>), a [[phospholipid]] that is located in the [[plasma membrane]], by [[phospholipase C]] (PLC).
Together with [[diglyceride|diacylglycerol]] (DAG), IP<sub>3</sub> is a [[second messenger]] molecule used in [[signal transduction]] in [[cell (biology)|biological cell]]s. While DAG stays inside the membrane, IP<sub>3</sub> is soluble and diffuses through the cell, where it binds to [[Inositol trisphosphate receptor|its receptor]], which is a calcium channel located in the endoplasmic reticulum. When IP<sub>3</sub> binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

==Properties ==

===Chemical formula and molecular weight===
IP<sub>3</sub> is an organic molecule with a [[molecular mass]] of 420.10 g/mol. Its [[empirical formula]] is C<sub>6</sub>H<sub>15</sub>O<sub>15</sub>P<sub>3</sub>. It is composed of an [[inositol]] ring with three [[phosphate]] groups bound at the 1, 4, and 5 carbon positions, and three [[hydroxyl]] groups bound at positions 2, 3, and 6.<ref>{{PubChem|439456}}</ref>

===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]]). This bond involves combining a [[hydroxyl]] group from the inositol ring and a free phosphate group through a [[dehydration reaction]]. Considering that the average physiological pH is approximately 7.4, the main form of the phosphate groups bound to the inositol ring [[in vivo]] is PO<sub>4</sub><sup>2−</sup>. This gives IP<sub>3</sub> 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<sub>3</sub> 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<sub>3</sub> docking.<ref>{{cite journal|doi=10.1016/j.bbamcr.2004.09.016|title=Structural insights into the regulatory mechanism of IP3 receptor|year=2004|last1=Bosanac|first1=Ivan|last2=Michikawa|first2=Takayuki|last3=Mikoshiba|first3=Katsuhiko|last4=Ikura|first4=Mitsuhiko|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|volume=1742|issue=1–3|pages=89–102|pmid=15590059|doi-access=}}</ref>

===Binding to its receptor===
[[File:IP3 moleucle.png|thumb|IP<sub>3</sub> anion with oxygen atoms (red) and the hydrogen atoms involved in docking to InsP3R (dark blue) indicated]]
The docking of IP<sub>3</sub> to its receptor, which is called the [[inositol trisphosphate receptor]] (InsP3R), was first studied using deletion [[mutagenesis]] in the early 1990s.<ref>{{Cite journal|pmid=2174351|year=1990|last1=Mignery|first1=GA|last2=Südhof|first2=TC|title=The ligand binding site and transduction mechanism in the inositol-1,4,5-triphosphate receptor|volume=9|issue=12|pages=3893–8|pmc=552159|journal=The EMBO Journal|doi=10.1002/j.1460-2075.1990.tb07609.x}}</ref> Studies focused on the [[N-terminus]] side of the IP<sub>3</sub> receptor. In 1997 researchers localized the region of the IP<sub>3</sub> receptor involved with binding of IP<sub>3</sub> to between [[amino acid]] residues 226 and 578 in 1997. Considering that IP<sub>3</sub> 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<sub>3</sub> docking. Using a modified form of IP<sub>3</sub>, 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.<ref>{{cite journal|doi=10.1016/j.tibs.2004.02.010|title=IP3 receptors: The search for structure|year=2004|last1=Taylor|first1=Colin W.|last2=Da Fonseca|first2=Paula C.A.|last3=Morris|first3=Edward P.|journal=Trends in Biochemical Sciences|volume=29|issue=4|pages=210–9|pmid=15082315|url=http://www.phy.ohiou.edu/~braslavs/Biophysics/Articles/Ghanim/ip3receptors.pdf|access-date=2017-10-27|archive-date=2017-08-08|archive-url=https://web.archive.org/web/20170808142233/http://www.phy.ohiou.edu/%7Ebraslavs/Biophysics/Articles/Ghanim/ip3receptors.pdf|url-status=dead}}</ref>

==Discovery==
The discovery that a [[hormone]] can influence phosphoinositide [[metabolism]] was made by [[Mabel Hokin|Mabel R. Hokin]] (1924–2003) and her husband Lowell E. Hokin in 1953, when they discovered that [[radioactive]] <sup>32</sup>P phosphate was incorporated into the [[phosphatidylinositol]] of [[pancreas]] slices when stimulated with [[acetylcholine]]. Up until then [[phospholipids]] were believed to be inert structures only used by cells as building blocks for construction of the plasma membrane.<ref>{{cite journal |last1= Hokin |first1= LE |last2= Hokin |first2= MR |title= Enzyme secretion and the incorporation of <sup>32</sup>P into phosphlipids of pancreas slices |journal= Journal of Biological Chemistry |volume= 203 |pages= 967–977 |year= 1953 |pmid= 13084667 |issue= 2|doi= 10.1016/S0021-9258(19)52367-5 |doi-access= free }}</ref>

Over the next 20 years, little was discovered about the importance of PIP<sub>2</sub> metabolism in terms of cell signaling, until the mid-1970s when Robert H. Michell hypothesized a connection between the [[catabolism]] of PIP<sub>2</sub> and increases in [[intracellular]] [[calcium]] (Ca<sup>2+</sup>) levels. He hypothesized that receptor-activated hydrolysis of PIP<sub>2</sub> produced a molecule that caused increases in intracellular calcium mobilization.<ref>{{cite journal |last1= Michell |first1= RH |title= Inositol phospholipids and cell surface receptor function |journal= Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes |volume= 415 |issue= 1 |pages= 81–147 |year= 1975 |pmid= 164246 |doi=10.1016/0304-4157(75)90017-9}}</ref> This idea was researched extensively by Michell and his colleagues, who in 1981 were able to show that PIP<sub>2</sub> is hydrolyzed into DAG and IP<sub>3</sub> by a then unknown [[phosphodiesterase]]. In 1984 it was discovered that IP<sub>3</sub> acts as a secondary messenger that is capable of traveling through the [[cytoplasm]] to the [[endoplasmic reticulum]] (ER), where it stimulates the release of calcium into the cytoplasm.<ref>{{cite journal |last1= Michell |first1= RH |last2= Kirk |first2= CJ |last3= Jones |first3= LM |last4= Downes |first4= CP |last5= Creba |first5= JA |title= The stimulation of inositol lipid metabolism that accompanies calcium mobilization in stimulated cells: defined characteristics and unanswered questions |journal= [[Philosophical Transactions of the Royal Society B]] |volume= 296 |issue= 1080 |pages= 123–137 |year= 1981 |doi= 10.1098/rstb.1981.0177|pmid= 6121338 |bibcode= 1981RSPTB.296..123M |doi-access=  }}</ref>

Further research provided valuable information on the IP<sub>3</sub> pathway, such as the discovery in 1986 that one of the many roles of the calcium released by IP<sub>3</sub> is to work with DAG to activate [[protein kinase C]] (PKC).<ref>{{cite journal |last1= Nishizuka |first1= Y |title= Studies and perspectives of protein kinase C |journal= Science |volume= 233 |issue= 4761 |pages= 305–312 |year= 1986 |doi= 10.1126/science.3014651 |pmid= 3014651|bibcode= 1986Sci...233..305N }}</ref> It was discovered in 1989 that [[phospholipase C]] (PLC) is the phosphodiesterase responsible for hydrolyzing PIP<sub>2</sub> into DAG and IP<sub>3</sub>.<ref>{{cite journal |last1= Rhee |first1= SG |last2= Suh |first2= PG |last3= Ryu |first3= SH |last4= Lee |first4= SY |title= Studies of inositol phospholipid-specific phospholipase C |journal= Science |volume= 244 |issue= 4904 |pages= 546–550 |year= 1989 |doi= 10.1126/science.2541501 |pmid= 2541501|bibcode= 1989Sci...244..546R |url= https://zenodo.org/record/1231012 }}</ref> Today the IP<sub>3</sub> signaling pathway is well mapped out, and is known to be important in regulating a variety of calcium-dependent cell signaling pathways.

==Signaling pathway==
[[Image:PIP2 cleavage to IP3 and DAG.jpg|thumb|PLC cleavage of PIP<sub>2</sub> to IP<sub>3</sub> and DAG initiates intracellular calcium release and PKC activation.]]
Increases in the intracellular Ca<sup>2+</sup> concentrations are often a result of IP<sub>3</sub> activation. When a [[ligand]] binds to a [[G protein-coupled receptor]] (GPCR) that is coupled to a Gq [[heterotrimeric G protein]], the α-subunit of Gq can bind to and induce activity in the PLC [[isozyme]] PLC-β, which results in the cleavage of PIP<sub>2</sub> into IP<sub>3</sub> and DAG.<ref name="Biaggioni">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 {{cite web |url=http://www.accessmedicine.com/content.aspx?aID=4520412 |title=AccessMedicine &#124; Case Study |access-date=2011-11-30 |url-status=dead |archive-url=https://web.archive.org/web/20110930100935/http://www.accessmedicine.com/content.aspx?aID=4520412 |archive-date=2011-09-30 }}.</ref>

If a [[receptor tyrosine kinase]] (RTK) is involved in activating the pathway, the isozyme PLC-γ has [[tyrosine]] residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP<sub>2</sub> into DAG and IP<sub>3</sub>. This occurs in cells that are capable of responding to [[growth factors]] such as [[insulin]], because the growth factors are the ligands responsible for activating the RTK.<ref name="Barrett">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. {{cite web|url=http://www.accessmedicine.com/content.aspx?aID%3D5243085 |title=AccessMedicine &#124; Objectives |access-date=2011-11-30 |url-status=dead |archive-url=https://web.archive.org/web/20120614133549/https://www.accessmedicine.com/content.aspx?aID=5243085 |archive-date=2012-06-14 }}. </ref>

IP<sub>3</sub> (also abbreviated Ins(1,4,5)P<sub>3</sub> is a [[soluble]] molecule and is capable of [[diffusing]] through the cytoplasm to the ER, or the [[sarcoplasmic reticulum]] (SR) in the case of [[muscle]] cells, once it has been produced by the action of PLC. Once at the ER, IP<sub>3</sub> is able to bind to the Ins(1,4,5)P<sub>3</sub> receptor Ins(1,4,5)P<sub>3</sub>R which is a ligand-gated Ca<sup>2+</sup> channel that is found on the surface of the ER. The binding of IP<sub>3</sub> (the ligand in this case) to Ins(1,4,5)P<sub>3</sub>R triggers the opening of the Ca<sup>2+</sup> channel, and thus release of Ca<sup>2+</sup> into the cytoplasm.<ref name= "Barrett"/> In heart muscle cells this increase in Ca<sup>2+</sup> activates the [[ryanodine receptor]]-operated channel on the SR, results in further increases in Ca<sup>2+</sup> through a process known as calcium-induced calcium release. IP<sub>3</sub> may also activate Ca<sup>2+</sup> channels on the cell membrane indirectly, by increasing the intracellular Ca<sup>2+</sup> concentration.<ref name = "Biaggioni"/>

==Function==

===Human===
{{see also|Functions of calcium in humans}}
IP<sub>3</sub>'s main functions are to mobilize Ca<sup>2+</sup> from storage [[organelle]]s and to regulate [[cell proliferation]] and other cellular reactions that require free calcium. In [[smooth muscle cell]]s, for example, an increase in concentration of cytoplasmic Ca<sup>2+</sup> results in the contraction of the muscle cell.<ref>{{cite journal |last1= Somlyo |first1= AP |last2= Somlyo |first2= AV |title= Signal transduction and regulation in smooth muscle |journal= [[Nature (journal)|Nature]] |volume= 372 |issue= 6503 |pages= 231–6 |year= 1994 |pmid= 7969467 |doi= 10.1038/372231a0|bibcode= 1994Natur.372..231S |s2cid= 4362367 }}</ref>

In the nervous system, IP<sub>3</sub> serves as a second messenger, with the [[cerebellum]] containing the highest concentration of IP<sub>3</sub> receptors.<ref>{{cite journal |last1= Worley |first1= PF |last2= Baraban |first2= JM |last3= Snyder |first3= SH |title= Inositol 1,4,5-trisphosphate receptor binding: autoradiographic localization in rat brain |journal= [[J. Neurosci.]] |volume= 9 |issue= 1 |pages= 339–46 |year= 1989 |pmid= 2536419|doi= 10.1523/JNEUROSCI.09-01-00339.1989 |pmc= 6569993 }}</ref> There is evidence that IP<sub>3</sub> receptors play an important role in the induction of plasticity in cerebellar [[Purkinje cells]].<ref>{{cite journal |last1= Sarkisov |first1= DV |last2= Wang |first2= SS |title= Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor |journal= [[J. Neurosci.]] |volume= 28 |issue= 1 |pages= 133–42 |year= 2008 |pmid= 18171931 |doi= 10.1523/JNEUROSCI.1729-07.2008|pmc= 6671165 |doi-access= free }}</ref>

=== Sea urchin eggs ===
The [[Egg activation#Fast and slow block to polyspermy|slow block to polyspermy]] in the [[sea urchin]] is mediated by the PIP<sub>2</sub> secondary messenger system. Activation of the binding receptors activates PLC, which cleaves PIP<sub>2</sub> in the egg plasma membrane, releasing IP<sub>3</sub> into the egg cell cytoplasm. IP<sub>3</sub> diffuses to the ER, where it opens Ca<sup>2+</sup> channels.

==Research==

===Huntington's disease===
[[Huntington's disease]] occurs when the cytosolic protein [[Huntingtin]] (Htt) has an additional 35 [[glutamine]] residues added to its amino terminal region. This modified form of Htt is called Htt<sup>exp</sup>. Htt<sup>exp</sup> makes Type 1 IP<sub>3</sub> receptors more sensitive to IP<sub>3</sub>, which leads to the release of too much Ca<sup>2+</sup> from the ER. The release of Ca<sup>2+</sup> from the ER causes an increase in the cytosolic and [[mitochondrial]] concentrations of Ca<sup>2+</sup>. This increase in Ca<sup>2+</sup> is thought to be the cause of [[gamma-aminobutyric acid|GABA]]ergic MSN degradation.<ref name= "Bezprozvanny">{{cite journal | last1 = Bezprozvanny | first1 = I. | last2 = Hayden | first2 = M.R. | year = 2004 | title = Deranged neuronal calcium signaling and Huntington disease | journal = Biochemical and Biophysical Research Communications | volume = 322 | issue = 4| pages = 1310–1317 | doi=10.1016/j.bbrc.2004.08.035| pmid = 15336977 }}</ref>

=== Alzheimer's disease===
[[Alzheimer's disease]] involves the progressive degeneration of the brain, severely impacting mental faculties.<ref>Alzheimer's Society of Canada. (2009). Alzheimer's Disease:What is Alzheimer's? Retrieved from: http://www.alzheimer.ca/english/disease/whatisit-intro.htm {{Webarchive|url=https://web.archive.org/web/20111205113228/http://www.alzheimer.ca/english/disease/whatisit-intro.htm |date=2011-12-05 }}</ref> Since the Ca<sup>2+</sup> hypothesis of Alzheimer's was proposed in 1994, several studies have shown that disruptions in Ca<sup>2+</sup> signaling are the primary cause of Alzheimer's disease. [[Early onset Alzheimer's|Familial Alzheimer's disease]] has been strongly linked to mutations in the [[presenilin 1]] (PS1), [[presenilin 2]] (PS2), and [[amyloid precursor protein]] (APP) [[genes]]. All of the mutated forms of these genes observed to date have been found to cause abnormal Ca<sup>2+</sup> signaling in the ER. Mutations in PS1 have been shown to increase IP<sub>3</sub>-mediated Ca<sup>2+</sup> 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_(medication) | lithium]] to decrease IP<sub>3</sub> turnover has also been suggested as a possible method of treatment.<ref>{{cite journal | last1 = Stutzmann | first1 = G. E. | year = 2005 | title = Calcium Dysregulation, IP3 Signaling, and Alzheimer's Disease | journal = Neuroscientist | volume = 11 | issue = 2| pages = 110–115 | doi = 10.1177/1073858404270899 | pmid = 15746379| s2cid = 20512555 }}</ref><ref>{{cite journal | last1 = Berridge | first1 = M. J. | year = 2016 | title = The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease | journal = Physiological Reviews | volume = 96 | issue = 4| pages = 1261–1296 | doi=10.1152/physrev.00006.2016 | pmid = 27512009| doi-access = free }}</ref>

==See also==
{{div col|colwidth=22em}}
* [[Adenophostin]]
* [[Inositol]]
* [[Inositol phosphate]]
* [[myo-Inositol|''myo''-Inositol]]
* [[Myo-inositol trispyrophosphate]]
* [[Inositol pentakisphosphate]]
* [[Inositol hexaphosphate]]
* [[Inositol trisphosphate receptor]]
* [[ITPR1]]
* [[ITPKC]]
{{div col end}}

==References==
{{reflist|30em}}

==External links==
* {{MeshName|Inositol+1,4,5-Trisphosphate}}

{{Lipid_signaling}}
{{Calcium_signaling}}
{{Phospholipids}}

{{DEFAULTSORT:Inositol Triphosphate}}
[[Category:Signal transduction]]
[[Category:Inositol]]
[[Category:Phosphate esters]]
[[Category:Second messenger system]]