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 bind ing to its receptor (InsP(3)R), an endoplasmic reticulum-localized Ca2+ rel ease channel. Patch clamp electrophysiology of Xenopus oocyte nuclei was us ed 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 e ndoplasmic reticulum membrane. Cytoplasmic ATP free-acid ([ATP](i)), but no t 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). Ac tivation was associated with a reduction of the half-maximal activating [Ca 2+](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 concentra tions. In contrast, ATP was without effect on maximum open probability or t he Hill coefficient for Ca2+ activation. Thus, ATP enhances gating of the I nsP(3)R by allosteric regulation of the Ca2+ sensitivity of the Ca2+ activa tion sites of the channel. By regulating the Ca2+-induced Ca2+ release prop erties of the InsP(3)R, ATP may play an important role in shaping cytoplasm ic Ca2+ signals, possibly linking cell metabolic state to important Ca2+ de pendent processes.