Inositol 1,4,5-trisphosphate InsP receptors

The general mechanism of Ca2+ wave propagation is believed to be as follows. An event occurs that results in a small rise of intracellular Ca2+ near an SR release receptor (either ryanodine receptor or inositol-1,4,5-trisphosphate [InsPs] receptor). The release of SR Ca2+ results in a local increase of cytoplasmic Ca2+. The nascent cytoplasmic Ca2+ then diffuses to adjacent release sites, causing further SR release. This process is a regenerative process and will remain so as long as the receptors are functional and the SR Ca2+ stores are sufficient. The Ca2+ wave can then be envisioned as a series of SR Ca2+ release events that are dependent upon local Ca2+ concentrations, receptor function, receptor density and diffusion of cytoplasmic Ca2+. The rate of propagation of the Ca2+ wave is possibly dependent upon any of these processes. 

Figure 3.7 A ligand fitting into a binding site. Binding of inositol 1,4,5-trisphosphate (InsPs) with its receptor. The lnsP3 receptor plays a key role in cellular and physiological processes, source Reprinted with permission from Bosanac, I., Alattia, J.R., Mai, T.K., et al. Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand, Nature, 420, pp. 696-700 (2002).

The synthesis of D-myo-inositol 1,4,5-trisphosphate (18) (InsP3) from methyl a-i)-glucopyranose (17), via a type 2 Perrier rearrangement, has been reported by Keddie et al. (Scheme 7). Biological evaluation of the synthetic InsPs showed that this compound evoked a selective Ca + release via activation of InsP receptors. 

Abbreviations used are as follows AR, adrenergic receptor [Ca ]i, intracellular calcium CEC, chloroethylclonidine DAG, diacylgiycerol EPI, epinephrine CNS, central nervous system HEK 293, human embryonic kidney 293 cells IPTG, isoproply-P-D-thiogalactoside InsP, inositol phosphate IP, inositol (1,4,5) trisphosphate NE, norepinephrine PI, phosphatidyl inositol PLA, phospholipase A, PLC, phospholipase C PLD, phospholipase D PKC, protein kinase C rMTC 6-23, rat medullary thyroid carcinoma cells VDCC, voltage-dependent Ca chaimel. 

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