ENANTIOMERS OF MYO-INOSITOL-1,3,4-TRISPHOSPHATE AND MYO-INOSITOL-1,4,6-TRISPHOSPHATE - STEREOSPECIFIC RECOGNITION BY CEREBELLAR AND PLATELET MYO-INOSITOL-1,4,5-TRISPHOSPHATE RECEPTORS

The naturally occurring tetrakisphosphate myo-inositol-1,3,4,6-tetraki sphosphate [Ins(1,3,4,6)P-4] was able to release Ca2+ from the intrace llular stores of permeabilized rabbit platelets but was 40-fold less p otent than D-myo-inositol-1,4,5-trisphosphate [Ins(1,4,5)P-3]. The Ca2 + releasing activity of Ins(1,3,4,6)P-4 was rationalized by envisaging two alternative receptor binding orientations in which the vicinal D- 1,6-bisphosphate of Ins(1,3,4,6)P-4 mimics the D-4,5-bisphosphate in t he Ins(1,4,5)P-3 binding conformation. This rationalization predicted that Ins(1,4,5)P-3 regioisomers [i.e., D-myo-inositol-1,4,6-trisphosph ate [D-Ins(1,4,6)P-3] and D-myo-inositol-1,3,6-trisphosphate [D-Ins(1, 3,6)P-3]] should also possess Ca2+-releasing activity. The unambiguous total synthesis of the enantiomers of Ins(1,4,6)P-3 [i.e., D-Ins(1,4, 6)P-3 and D-Ins(3,4,6)P-3] and the enantiomers of Ins(1,3,4)P-3 [i.e., D-Ins(1,3,6)P-3 and D-Ins(1,3,4)P-3] allowed an examination of this p rediction. D-Ins(1,4,6)P-3 released Ca2+ from the intracellular stores of permeabilized platelets and was only 2-3-fold less potent than Ins (1,4,5)P-3. D-Ins(1,3,6)P-3 [alternative nomenclature, L-Ins(1,3,4)P-3 ] also released Ca2+ but was 12-fold less potent than Ins(1,4,5)P-3. B oth D-Ins(1,4,6)P-3 and D-Ins(1,3,6)P-3 displaced specifically bound [ H-3]Ins(1,4,5)P-3 from the Ins(1,4,5)P-3 receptor on rat cerebellar me mbranes. In contrast, however, D-Ins(3,4,6)P-3 [alternative nomenclatu re, L-Ins(1,4,6)P-3] and D-Ins(1,3,4)P-3 neither possessed Ca2+-releas ing activity nor displaced [H-3]Ins(1,4,5)P-3. The ability of D-Ins(1, 3,6)P-3 to release Ca2+ in permeabilized platelets is in contrast to i ts apparent lack of Ca2+-mobilizing activity previously reported in ra t basophilic leukemic cells. The possibility that this is a reflection of the different Ins(1,4,5)P-3 receptor subtypes possessed by these t wo cell types is discussed.