Biphenyl 2,3',4,5',6-pentakisphosphate, a novel inositol polyphosphate surrogate, modulates Ca2+ responses in rat hepatocytes.
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.
Vandeput
Fabrice
F
Institut de Recherche Interdisciplinaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium.
Combettes
Laurent
L
Mills
Stephen J
SJ
Backers
Katrien
K
Wohlkönig
Alexandre
A
Parys
Jan B
JB
De Smedt
Humbert
H
Missiaen
Ludwig
L
Dupont
Geneviève
G
Potter
Barry V L
BV
Erneux
Christophe
C
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008845:Microinjections; D010710:Phosphates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018411:Spodoptera
D001713:Biphenyl Compounds; D010710:Phosphates; C519883:biphenyl 2,3',4,5',6-pentakisphosphate; D002118:Calcium