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J Biol Chem, Vol. 274, Issue 32, 22231-22237, August 6, 1999
ATP Regulation of Type 1 Inositol 1,4,5-Trisphosphate Receptor
Channel Gating by Allosteric Tuning of Ca2+ Activation
Don-On Daniel
Mak ,
Sean
McBride , and
J. Kevin
Foskett §
From the Department of Physiology and
§ Institute for Human Gene Therapy, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6100
Inositol 1,4,5-trisphosphate
(InsP3) mobilizes intracellular Ca2+ by
binding to its receptor (InsP3R), 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 InsP3R channels in native endoplasmic reticulum
membrane. Cytoplasmic ATP free-acid ([ATP]i), but not the
MgATP complex, activated gating of the InsP3-liganded InsP3R, 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 InsP3R 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
InsP3R, ATP may play an important role in shaping
cytoplasmic Ca2+ signals, possibly linking cell metabolic
state to important Ca2+-dependent processes.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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