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Title: Biphenyl 2,3',4,5',6-pentakisphosphate, a novel inositol polyphosphate surrogate, modulates Ca2+ responses in rat hepatocytes
Authors: Vandeput, Fabrice ×
Combettes, Laurent
Mills, Stephen J
Backers, Katrien
Wohlkönig, Alexandre
Parys, Jan
De Smedt, Humbert
Missiaen, Ludwig
Dupont, Geneviève
Potter, Barry V L
Erneux, Christophe #
Issue Date: May-2007
Publisher: The Federation of American Societies for Experimental Biology
Series Title: FASEB Journal vol:21 issue:7 pages:1481-1491
Abstract: Benzene polyphosphates containing phosphate groups on one ring are Ins(1,4,5)P3 5-phosphatase inhibitors when evaluated against type-I Ins(1,4,5)P3 5-phosphatase. A novel biphenyl derivative, biphenyl 2,3',4,5',6-pentakisphosphate, with five phosphate groups on two rings was synthesized: It inhibited the activity of two inositol 5-phosphatases: type I and SHIP2 with Ins(1,3,4,5)P4 as substrate. The inhibition was competitive with respect to the substrate. IC50 value measured in rat hepatocytes, which contains the native Ins(1,4,5)P3 5-phosphatase, was in the micromolar range at 1.0 microM Ins(1,4,5)P3 as substrate. Biphenyl 2,3',4,5',6-pentakisphosphate did not affect the activity of Ins(1,4,5)P3 3-kinase A in the 5-100 microM range. Surprisingly, experimental evidence supports an effect of biphenyl 2,3',4,5',6-pentakisphosphate at the level of the Ins(1,4,5)P3 receptor. Finally, when injected into rat hepatocytes, the analog affected the frequency of Ca2+ oscillations in a positive or negative way depending on its concentration. At very high concentrations of the analog, Ca2+ oscillations were even suppressed. These data were interpreted as a dual effect of the biphenyl 2,3',4,5',6-pentakisphosphate on cytosolic [Ca2+] increases: an activation effect through an increase in Ins(1,4,5)P3 level via Ins(1,4,5)P3 5-phosphatase inhibition and an inhibitory effect, which was exerted directly on the Ins(1,4,5)P3 receptor. Thus, our data show for the first time that the frequency of Ca2+ oscillations in response to a Ca2+-mobilizing agonist can be controlled by inhibitors of type-I Ins(1,4,5)P3 5-phosphatase.
URI: 
ISSN: 0892-6638
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
× corresponding author
# (joint) last author

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