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Abstract
Inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4] is an inhibitor of the conductance of the Ca2+-activated chloride channels in the plasma membrane. These ion channels are required for salt and fluid secretion from epithelial cells, for cell volume homeostasis, and for electrical excitability in neurons and smooth muscle. The enzyme ITPK1 (inositol 1,3,4-triphosphate 5/6 kinase) is the source of Ins(3,4,5,6)P4. It can phosphorylate both Ins(1,3,4)P3 at the 5 or 6 positions and Ins(3,4,5,6)P4 at the 1 position and can also dephosphorylate Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. A study now shows that these various enzyme activities manifested by ITPK1 provide a molecular mechanism that allows the receptor-activated changes in phospholipase C activity and consequent increases in the concentration of Ins(1,3,4)P3 to regulate the abundance of Ins(3,4,5,6)P4. ITPK1 sequesters a tightly bound nucleotide that can accept a phosphate from, or donate a phosphate directly to, an inositol polyphosphate without the nucleotide being released in the bulk medium. This phenomenon of "intersubstrate" transfer is found only in the human enzyme, which can use Ins(1,3,4)P3 to promote increased cellular concentrations of Ins(3,4,5,6)P4.
