The inositol pyrophosphate disphosphoinositol pentakisphosphate (PP-InsP(3)/InsP(7)) is formed in mammals by two recently cloned inositol hexakiphosphate kinases, InsP(6)K1 and InsP(6)K2 (Saiardi, A., Erdjument-Bromage, H., Snowman, A. M., Tempst, P., and Snyder, S. H. (1999) Curr. Biol. 9, 1323-1326). We now report the identification, cloning, and characterization of a third InsP(7) forming en...

Inositol 1,4,5-trisphosphate receptors (InsP(3)R) play a key role in intracellular calcium (Ca(2+)) signaling. Three InsP(3)R isoforms are expressed in mammals. Type 1 InsP(3)R (InsP(3)R1) is a predominant neuronal isoform. Neuronal InsP(3)R1 is one of the major substrates of protein kinase A (PKA) phosphorylation. In our previous study (Tang, T. S., Tu, H., Wang, Z., and Bezprozvanny, I. (2003...

The inositol 1,4,5-trisphosphate receptor (InsP(3)R) is activated by InsP(3) binding to amino-terminal ligand binding domain (InsP(3)R-N). Recently we reported functional coupling of phosphatidylinositol (4, 5)-bisphosphate (PIP(2)) to the InsP(3)R. Specific binding of PIP(2) to InsP(3)R-N domain was postulated as a part of the InsP(3)R-PIP(2) functional coupling model. Here we utilized bacteri...

The inositol 1,4,5-trisphosphate (InsP(3)) receptor (InsP(3)R) is a ligand-gated intracellular Ca(2+) release channel that plays a central role in modulating cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)). The fungal metabolite adenophostin A (AdA) is a potent agonist of the InsP(3)R that is structurally different from InsP(3) and elicits distinct calcium signals in cells. We have investig...

The inositol trisphosphate (InsP(3)) receptor (InsP(3)R) is a ubiquitously expressed intracellular Ca(2+) channel that mediates complex cytoplasmic Ca(2+) signals, regulating diverse cellular processes, including synaptic plasticity. Activation of the InsP(3)R channel is normally thought to require binding of InsP(3) derived from receptor-mediated activation of phosphatidylinositol lipid hydrol...

Schizosaccharomyces pombe Aps1 is an enzyme that degrades both diadenosine oligophosphates (Ap(n)A, n =5 or 6) and diphosphoinositol polyphosphates [diphosphoinositol pentakisphosphate (PP-InsP(5)) and bisdiphosphoinositol tetrakisphosphate ([PP](2)-InsP(4))] in vitro. The in vivo substrates of Aps1 are unknown. We report here the identification of Ap(5)A, PP-InsP(5), [PP](2)-InsP(4) and a nove...

Modulation of the inositol 1,4,5-trisphosphate (InsP(3)) receptors (InsP(3)R) by cytosolic calcium (Ca(2+)) plays an essential role in Ca(2+) signalling, but structural determinants and mechanisms responsible for the InsP(3)R regulation by Ca(2+) are poorly understood. In the present study, we expressed rat InsP(3)R type 1 (InsP(3)R1) in Spodoptera frugiperda cells using a baculovirus-expressio...

Inositol (1,4,5) trisphosphate (Ins(1,4,5)P(3)) is a well-known messenger molecule that releases calcium from intracellular stores. Homologues with up to six phosphates have been characterized and recently, homologues with seven or eight phosphate groups, including pyrophosphates, have been identified. These homologues are diphosphoinositol pentakisphosphate (PP-InsP(5)/InsP(7)) and bis(diphosp...

Nuclear calcium (Ca(2+)) regulates a number of important cellular processes, including gene transcription, growth, and apoptosis. However, it is unclear whether Ca(2+) signaling is regulated differently in the nucleus and cytosol. To investigate this possibility, we examined subcellular mechanisms of Ca(2+) release in the HepG2 liver cell line. The type II isoform of the inositol 1,4,5-trisphos...

The syntheses of four D-myo-inositol 1,4,5-trisphosphate (InsP(3)) derivatives, incorporating phosphate bioisosteres at the 5-position, are reported. The methyl phosphate ester and sulfate derivatives retain InsP(3) receptor (InsP(3)R) agonist activity; the compounds that possess a methylphosphonate or a carboxymethyl moiety are InsP(3)R antagonists.