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Biphenyl 2,3′,4,5′,6‐pentakisphosphate, a novel inositol polyphosphate surrogate, modulates Ca 2+ responses in rat hepatocytes
Author(s) -
Vandeput Fabrice,
Combettes Laurent,
Mills Stephen J.,
Backers Katrien,
Wohlkönig Alexandre,
Parys Jan B.,
De Smedt Humbert,
Missiaen Ludwig,
Dupont Geneviève,
Potter Barry V. L.,
Erneux Christophe
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7691com
Subject(s) - polyphosphate , chemistry , inositol , phosphatase , stereochemistry , biphenyl , substrate (aquarium) , inositol phosphate , phosphate , biochemistry , enzyme , receptor , biology , ecology , organic chemistry
Benzene polyphosphates containing phosphate groups on one ring are Ins(1,4,5)P 3 5‐phosphatase inhibitors when evaluated against type‐I Ins(1,4,5)P 3 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)P 4 as substrate. The inhibition was competitive with respect to the substrate. IC 50 value measured in rat hepatocytes, which contains the native Ins(1,4,5)P 3 5‐phosphatase, was in the micromolar range at 1.0 μM Ins(1,4,5)P 3 as substrate. Biphenyl 2,3′,4,5′,6‐pentakisphosphate did not affect the activity of Ins(1,4,5)P 3 3‐kinase A in the 5‐100 μM range. Surprisingly, experimental evidence supports an effect of biphenyl 2,3′,4,5′,6‐pentakisphosphate at the level of the Ins(1,4,5)P 3 receptor. Finally, when injected into rat hepatocytes, the analog affected the frequency of Ca 2+ oscillations in a positive or negative way depending on its concentration. At very high concentrations of the analog, Ca 2+ oscillations were even suppressed. These data were interpreted as a dual effect of the biphenyl 2,3′,4,5′,6‐pentakisphosphate on cytosolic [Ca 2+ ] increases: an activation effect through an increase in Ins(1,4,5)P 3 level via Ins(1,4,5)P 3 5‐phosphatase inhibition and an inhibitory effect, which was exerted directly on the Ins(1,4,5)P 3 receptor. Thus, our data show for the first time that the frequency of Ca 2+ oscillations in response to a Ca 2+ ‐mobilizing agonist can be controlled by inhibitors of type‐I Ins(1,4,5)P 3 5‐phosphatase.—Vandeput, F., Combettes, L., Mills, S. J., Backers, K., Wohlkönig, A., Parys, J. B., De Smedt, H., Missiaen, L., Dupont, G., Potter, B. V. L., Erneux, C. Biphenyl 2,3′,4,5′,6‐pentakisphosphate, a novel inositol polyphosphate surrogate, modulates Ca2+ responses in rat hepatocytes. FASEB J. 21, 1481–1491 (2007)