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RA Wilcox, RA Challiss, C Liu, BV Potter and SR Nahorski
Department of Pharmacology and Therapeitucs, University of Leicester, UK.
myo-Inositol-1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]-induced Ca2+ mobilization was examined in saponin-permeabilized SH-SY5Y cells using myo-inositol hexakisphosphate-supplemented buffer to prevent Ins(1,3,4,5)P4-3-phosphatase-catalyzed back-conversion of exogenous Ins(1,3,4,5)P4 to myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P3]. The Ins(1,3,4,5)P4 concentration-response curve for Ca2+ release in SH-SY5Y cells exhibited an EC50 of 2.5 microM, compared with 52 nM for Ins(1,4,5)P3, with the maximally effective concentration of Ins(1,3,4,5)P4 (100 microM) mobilizing the entire Ins(1,4,5)P3- sensitive pool. Both Ins(1,3,4,5)P4- and Ins(1,4,5)P3-induced Ca2+ mobilizations were heparin sensitive. Further, L-chiro-inositol-2,3,5- trisphosphorothioate, a recently identified low intrinsic activity Ins(1,4,5)P3 receptor partial agonist, shifted both the Ins(1,4,5)P3 and Ins(1,3,4,5)P4 concentration-response curves significantly rightward, with similar potencies. However, binding studies demonstrate that L-chiro-inositol-2,3,5-trisphosphorothioate interacts very poorly (IC50 > 30 microM) with specific Ins(1,3,4,5)P4 binding sites that have been previously characterized in pig cerebellum. Carbachol-pretreated SH-SY5Y cells (1 mM, > or 6 hr) exhibit a decrease in Ins(1,4,5)P3 receptor number, accompanied by both a rightward shift and a reduced maximal Ca2+ release in their Ins(1,4,5)P3 concentration-response curve. Here both Ins(1,4,5)P3 and Ins(1,3,4,5)P4 concentration-response curves were found to exhibit identically reduced maximal Ca2+ release responses and about 4-fold rightward shifts in EC50 values. Together, these observations provide compelling evidence for our hypothesis that Ins(1,3,4,5)P4 exhibits weak but full agonist status at Ins(1,4,5)P3 receptor-operated Ca2+ channels in SH-SY5Y cells.
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