We have previously found that for permeabilized L1210 cells, low micromolar concentrations of Ins(1,3,4,5)P4 added prior to Ins(2,4,5)P3 enhance the effects of suboptimal concentrations of Ins(2,4,5)P3 in causing Ca2+ release from InsP3-sensitive Ca2+ stores [Cullen, Irvine and Dawson (1990) Biochem. J. 271, 549–553]. If this was due either to some conversion of added Ins(1,3,4,5)P4 into Ins(1,4,5)P3 by the 3-phosphatase, or to Ins(1,3,4,5)P4 acting as a weak (or partial) agonist on the InsP3 receptor it would be expected that, in the presence of thimerosal to sensitize the InsP3 receptor, the dose–response curve to Ins(1,3,4,5)P4 would be left-shifted by the same extent as that of Ins(1,4,5)P3. This was found not to be the case; the dose–response curve to Ins(1,3,4,5)P4 was not shifted at all by thimerosal. Furthermore, L-Ins(1,3,4,5)P4, which can displace radiolabelled D-Ins(1,3,4,5)P4 but not D-Ins(1,4,5)P3 from their respective high-affinity binding sites, mimicked the effects of D-Ins(1,3,4,5)P4 in enhancing the slow phase of Ins(2,4,5)P3-stimulated Ca2+ release. Ins(1,3,4,5)P4 caused an increase in magnitude of the slow phase of InsP3-stimulated Ca2+ release leaving the magnitude of the fast phase unaltered, in contrast to increasing Ins(2,4,5)P3 concentrations which increased the size of both phases. In addition, Ins(1,3,4,5)P4 decreased the rate constant for the slow phase of Ca2+ release These findings point strongly to the conclusion that InsP4 is not working directly via the InsP3 receptor but indirectly via an InsP4 receptor.
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Research Article|
March 15 1996
Synergistic effects of inositol 1,3,4,5-tetrakisphosphate on inositol 2,4,5-triphosphate-stimulated Ca2+ release do not involve direct interaction of inositol 1,3,4,5-tetrakisphosphate with inositol triphosphate-binding sites
Jeff W. LOOMIS-HUSSELBEE;
Jeff W. LOOMIS-HUSSELBEE
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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Peter J. CULLEN;
Peter J. CULLEN
§
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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Uschi E. DREIKHAUSEN;
Uschi E. DREIKHAUSEN
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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Robin F. IRVINE;
Robin F. IRVINE
†Inositide Laboratory, The Babraham Institute, Babraham, Cambridge CB2 4AT, U.K.
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Alan P. DAWSON
Alan P. DAWSON
‡
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
‡To whom correspondence should be addressed.
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Publisher: Portland Press Ltd
Received:
May 09 1995
Revision Received:
October 27 1995
Accepted:
November 08 1995
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 314 (3): 811–816.
Article history
Received:
May 09 1995
Revision Received:
October 27 1995
Accepted:
November 08 1995
Citation
Jeff W. LOOMIS-HUSSELBEE, Peter J. CULLEN, Uschi E. DREIKHAUSEN, Robin F. IRVINE, Alan P. DAWSON; Synergistic effects of inositol 1,3,4,5-tetrakisphosphate on inositol 2,4,5-triphosphate-stimulated Ca2+ release do not involve direct interaction of inositol 1,3,4,5-tetrakisphosphate with inositol triphosphate-binding sites. Biochem J 15 March 1996; 314 (3): 811–816. doi: https://doi.org/10.1042/bj3140811
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