1,4,5,-trisphosphate

In addition to the mechanism involving cycHc AMP, nonsugar sweeteners, eg, saccharin and a guanidine-type sweetener, have been found to enhance the production of another second messenger, inositol 1,4,5-trisphosphate (IP3), causing the closure of potassium channels and the release of... 

Inositol 1,4,5-trisphosphate (IP3) receptors are intracellular cation channels. They are expressed in most cells and predominantly within the membranes of the endoplasmic reticulum. They mediate release of Ca2+ from intracellular stores by the many receptors that stimulate IP3 formation. 

Bosanac I et al (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420 696-701... 

Bosanac I et al (2005) Crystal structure of the ligand binding suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor. Mol Cell 17 193-203... 

Hormonal factors and other stimuli by activating phospholipase C-(3 or -y isoforms stimulate the breakdown of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and diacylglycerol, a reaction called PI response. 

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

Sarcoplasmic reticulum (SR) is a form of the smoothfaced endoplasmic reticulum (ER) in muscles. It functions as an intracellular Ca2+ store for muscle contraction. Ca2+ is energetically sequestered into the SR by Ca2+-pump/sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) and released via Ca2+ release channels on stimuli (ryanodine receptor in striated muscles and inositol 1,4,5-trisphosphate receptor in most smooth muscles). Endoplasmic reticulum in non-muscle tissues also functions as an intracellular Ca2+ store. 

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

If a sugar is esterified with two or more phosphate groups, the compound is termed bisphosphate, trisphosphate etc. (e.g. fructofuranose 1,6-bisphosphate). The term diphosphate denotes an ester with diphosphoric acid, e.g. adenosine S -diphosphate. 

Covalent regulation. Following occupation and activation of the M2 acetyl choline receptors, phospholipase C (PLC), is activated and both inositol (l,4,5)-trisphosphate (IP3), and diacylglycerol (DAG), are formed by hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2). 

Inositol trisphosphate Receptor/G-protein cascades. As discussed above, IP3 is one of the products of the hydrolysis of PIP2. To say that it acts as a second messenger means that a rise in its concentration occurs as a result of some meaningful event and that the rise causes some other significant event. In terms of information flow, the signal immediately preceding the rise in IP3 is a rise in the concentration of active PLC. This rise is due to the binding of a subset of G-proteins... 

Vergara, J., Tsien, R.Y., Delay, M. (1985). Inositol 1,4, 5-trisphosphate Possible chemical link in excitation-contraction coupling in muscle. Proc. Natl. Acad. Sci. USA 82,6352-6356. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

The inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

Figure 43-7. Phospholipase C cleaves PIPj into diacylglycerol and inositol trisphosphate. R, generally is stearate, and Rj is usually arachido-nate. IP3 can be dephosphorylated (to the inactive I-1,4-P2) or phosphorylated (to the potentially active I-1,3,4,5-P4).

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