Biomaterial Database

Calcium release activity and metabolism of inositol 1,4,5-trisphosphate in T cells. Modulation by novel inositol 1,4,5-trisphosphate 5-phosphatase inhibitors. 1994

S G Ward, and D Lampe, and C Liu, and B V Potter, and J Westwick

School of Pharmacy and Pharmacology, University of Bath, England.

Stimulation of the T cell antigen receptor/CD3 complex is followed by phospholipase C activation, phosphoinositol lipid metabolism and ultimately by a rapid rise in both myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] as well as cytosolic free calcium concentration. A 5-phosphatase plays a pivotal role in the subsequent metabolism of Ins(1,4,5)P3 and Ins(1,3,4,5)P4. Synthetic routes have been developed which have enabled the synthesis of both natural and unnatural inositol phosphates and this approach has yielded several compounds which have been shown to act as inhibitors of Ins(1,4,5)P3 5-phosphatase. These compounds offer considerable potential for investigation of the complex metabolism and function of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 in T cell activation and proliferation. We now report the time course and temperature sensitivity of Ins(1,4,5)P3-induced 45Ca2+ release in the permeabilised leukaemic T cell line Jurkat. Furthermore, we demonstrate that the metabolism of Ins(1,4,5)P3 in the presence of two novel 5-phosphatase inhibitors, namely L-myo-inositol 1,4,5-trisphosphorothioate [L-Ins(1,4,5)PS3] and myo-inositol 1,3,5-trisphosphorothioate [Ins(1,3,5)PS3], can be inhibited with concomitant elevation of the heparin-sensitive Ins(1,4,5)P3-induced release of 45Ca2+. These novel 5-phosphatase inhibitors provide a starting point for development of cell-permeable analogues which may be able to modulate cell function in intact cells and may be used as manipulative tools with which to elucidate the function of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 with respect to T cell activation.

UI	MeSH Term	Description	Entries
D007295	Inositol Phosphates	Phosphoric acid esters of inositol. They include mono- and polyphosphoric acid esters, with the exception of inositol hexaphosphate which is PHYTIC ACID.	Inositol Phosphate,Phosphate, Inositol,Phosphates, Inositol
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D010744	Phosphoric Monoester Hydrolases	A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate.	Phosphatase,Phosphatases,Phosphohydrolase,Phosphohydrolases,Phosphomonoesterase,Phosphomonoesterases,Phosphoric Monoester Hydrolase,Hydrolase, Phosphoric Monoester,Hydrolases, Phosphoric Monoester,Monoester Hydrolase, Phosphoric
D011948	Receptors, Antigen, T-Cell	Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (CD3 COMPLEX). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.	Antigen Receptors, T-Cell,T-Cell Receptors,Receptors, T-Cell Antigen,T-Cell Antigen Receptor,T-Cell Receptor,Antigen Receptor, T-Cell,Antigen Receptors, T Cell,Receptor, T-Cell,Receptor, T-Cell Antigen,Receptors, T Cell Antigen,Receptors, T-Cell,T Cell Antigen Receptor,T Cell Receptor,T Cell Receptors,T-Cell Antigen Receptors
D002118	Calcium	A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.	Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D006493	Heparin	A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts.	Heparinic Acid,alpha-Heparin,Heparin Sodium,Liquaemin,Sodium Heparin,Unfractionated Heparin,Heparin, Sodium,Heparin, Unfractionated,alpha Heparin
D000072181	Inositol Polyphosphate 5-Phosphatases	Phosphoinositide phosphatases that catalyze the removal of the 5' phosphate from INOSITOL 1,4,5-TRISPHOSPHATE or myo-inositol 1,3,4,5-tetrakisphosphate, resulting in inositol 1,4-bisphosphate and phosphate. They have important functions in the metabolism of INOSITOL PHOSPHATES and inositol 1,4,5-trisphosphate signaling pathways such as CALCIUM SIGNALING.	1,4,5-Triphosphate-1,2,4,5-Tetrakisphosphate 5-Phosphatase,Inositol 5-Phosphatase,Inositol Polyphosphate 5-Phosphatase,Inositol Triphosphate 5-Phosphatase,Inositol-1,4,5-Trisphosphate 5'-Phosphatase,Inositol-1,4,5-Trisphosphate 5-Phosphatase,Inositol-Polyphosphate 5-Phosphatase,Ins(1,4,5)P3 5'-Phosphatase,Inositol 5 Phosphatase,Inositol Polyphosphate 5 Phosphatase,Inositol Polyphosphate 5 Phosphatases,Inositol Triphosphate 5 Phosphatase
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships