Inositol tetrakisphosphate, calcium

Similarly, each molecule of IP will continue to keep the endoplasmic reticulum calcium channel open until it is phosphorylated to inactive inositol tetrakisphosphate, thus maintaining a flow of calcium ions into the cytosol. Each molecule of calcium-calmodulin will bind to, and activate, a molecule of protein kinase for as long as the cytosol calcium concentration remains high. It is only as the calcium is pumped back into the endoplasmic reticulum that the calcium concentration falls low enough for calmodulin to lose its bound calcium and be inactivated. Again each molecule of phosphorylated enzyme will catalyse the metabolism of many thousands of mol of substrate per second, until it is dephosphorylated by phosphoprotein phosphatase. 

Fig. 3. The interrelated changes in the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and Ca2+ during activation of the cell by a typical Ca2+-dependent hormone. R, receptor G, guanine regulatory protein PLC, phospholipase C DG, diacylglycerol CK, protein kinase C [Ca2+]sm, the Ca2+ concentration in a cellular domain just beneath the plasma membrane (striped area) Insl,4,SP3, inositol 1,4,5-trisphosphate Insl,3,4,5P4, inositol 1,3,4,5-tetrakisphosphate [Ca2+]c, cytosolic Ca2+ concentration CaM, calmodulin arrows (=>), fluxes of Ca2+ across membranes s=>, energy-dependent fluxes CaY, a calcium pool in specialized compartment of the endoplasmic reticulum. See text for discussion.

Recently, an additional IP3 isomer, inositol 1,3,4-trisphosphate (1,3,4-IP3), which is ineffective in releasing calcium from the ER, has been identified. Unlike 1,4,5-IP3, 1,3,4-IP3 is thought not to be a product of the direct hydrolysis of an isomer of PIP2, but rather a result of the action of a 5-phosphatase on a more polar inositol phosphate, inositol 1,3,4,5-tetrakisphosphate (IP4) [34], At this time neither 1,3,4-IP3 nor its precursor IP4, which is formed as a result of a 3-kinase-catalysed phosphorylation of 1,4,5-IP3, has a clear physiological role, although IP4 has been implicated in the regulation of plasma membrane calcium influx (see Rasmussen and Barrett, Chapter 4). 

Carew, M.A., Yang, X.N., Schultz, C. and Shears, S.B., 2000, myo-Inositol 3,4,5,6-tetrakisphosphate inhibits an apical calcium-activated chloride conductance in polarized monolayers of a cystic fibrosis cell line. J. Biol. Chem., 275 26906-26913. 

Ho, M.W., Kaetzel, M. A., Armstrong, D.L. and Shears, S.B., 2001, Regulation of a human chloride channel, a paradigm for integrating input from calcium, type II calmodulin-dependent protein kinase, and inositol 3,4,5,6-tetrakisphosphate. J. Biol. Chem. 276 18673-18680. 

Ismailov, I.I., Fuller, C.M., Berdiev, B.K., Shlyonsky, V.G., Benos, DJ. and Barrett, K.E., 1996, A biologic function for an orphan messenger D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels. Proc. Natl. Acad. Sci. USA 93 10505-10509. 

Tsubokawa, H., Oguro, K., Robinson, H.P., Masuzawa, T., and Kawai, N., 1996, Intracellular inositol 1,3,4,5-tetrakisphosphate enhances the calcium current in hippocampal CA1 neurones of the gerbil after ischaemia. J. Physiol. 497(Pt 1) 67-78. 

Ho MWYS, Shears SB. Regulation of calcium-activated chloride channels by inositol 3,4,5,6 tetrakisphosphate. Curr. Top. Membranes. 2002 53 345-363. 

IP.1 is also converted to inositol l.3.4..5-tetrakisphosphate (IP4). IP.) also ads as an intracellular messenger, resulting in an influx of extracellular calcium. IP4 is converted to IP.d 1.3.4). which Is Jepho.sphorylaled stepwise to imwilul 1.4-diphosphate, inositol I-phosphate, then ino.sitol. The inositol is then incorporated into DAG to form pho.sphatidylinositol (PI). PI is sequentially phosphorylatcd to formphos-phatidylino.sitol 4-phosphatc (PIP) and PIP-. 

The role of D-w o-inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4] in the uncoupling of chloride anion secretion from intracellular calcium levels was confirmed with experiments using a membrane-permeable analogue. After cell penetration, derivative (54) with the four phosphate groups masked as acyloxymethyl esters and the two hydroxy groups as butanoyl esters, was cleaved by intracellular esterases to give Ins(3,4,5,6)P4 which caused inhibition of chloride anion secretion [75],... 

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