Biphenyl 2,3',4,5',6-pentakisphosphate, a Novel Inositol Polyphosphate Surrogate, Modulates Ca2+ Responses in Rat Hepatocytes.
From: Institut de Recherche Interdisciplinaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: May 2007
- ISSN: 1530-6860
- Volume: 21
- Issue: 7
- Pages: 1481-91
- Medium: Internet
- Language: English
- Citation (JAMA): Vandeput Fabrice, Combettes Laurent, Mills Stephen J, et al. Biphenyl 2,3',4,5',6-pentakisphosphate, a Novel Inositol Polyphosphate Surrogate, Modulates Ca2+ Responses in Rat Hepatocytes.. FASEB J. May 2007;21:1481-91
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.
Mesh Headings (Keywords): Animals, Biphenyl Compounds, Calcium, Cell Line, Female, Hepatocytes, Microinjections, Phosphates, Rats, Rats, Wistar, Spodoptera
Check for Full Text / PubMed Unique Identifier (PMID): 17264160
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