ATP regulation of type 1 inositol 1,4,5-trisphosphate receptor channel gating by allosteric tuning of Ca2+ activation

Inositol 1,4,5-trisphosphate (InsP(3)) mobilizes intracellular Ca2+ by binding to its receptor (InsP(3)R), an endoplasmic reticulum-localized Ca2+ release channel. Patch clamp electrophysiology of Xenopus oocyte nuclei was used to study the effects of cytoplasmic ATP concentration on the cytoplasmic Ca2+ ([Ca2+](i)) dependence of single type 1 InsP(3)R channels in native endoplasmic reticulum membrane. Cytoplasmic ATP free-acid ([ATP](i)), but not the MgATP complex, activated gating of the InsP(3)-liganded InsP(3)R, by stabilizing open channel state(s) and destabilizing the closed state(s). Activation was associated with a reduction of the half-maximal activating [Ca2+](i) from 500 +/- 50 nM in 0 [ATP](i) to 29 +/- 4 nM in 9.5 mM [ATP](i), with apparent ATP affinity = 0.27 +/- 0.04 mM, similar to in vivo concentrations. In contrast, ATP was without effect on maximum open probability or the Hill coefficient for Ca2+ activation. Thus, ATP enhances gating of the InsP(3)R by allosteric regulation of the Ca2+ sensitivity of the Ca2+ activation sites of the channel. By regulating the Ca2+-induced Ca2+ release properties of the InsP(3)R, ATP may play an important role in shaping cytoplasmic Ca2+ signals, possibly linking cell metabolic state to important Ca2+ dependent processes.