Abstract
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca(2+) channels that are widely expressed in animal cells, where they mediate the release of Ca(2+) from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca(2+) release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca(2+) release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.
Highlights
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are almost ubiquitously expressed in animal cells.[1,2] IP3Rs are essential links between receptors in the plasma membrane that stimulate phospholipase C and release of Ca2+ from the endoplasmic reticulum (ER)
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are widely expressed in animal cells, where they mediate the release of Ca2+ from intracellular stores evoked by extracellular stimuli
The three subtypes of IP3Rs expressed in vertebrates (IP3R1-3) are closely related proteins and they are each regulated by both (1,4,5)IP3 (1, Fig. 1) and Ca2+, but they differ in their sensitivity to other forms of regulation and in their subcellular and tissue distributions.[1]
Summary
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that are almost ubiquitously expressed in animal cells.[1,2] IP3Rs are essential links between receptors in the plasma membrane that stimulate phospholipase C and release of Ca2+ from the endoplasmic reticulum (ER). The resulting cytosolic Ca2+ signals regulate many diverse cellular processes.[3] The three subtypes of IP3Rs expressed in vertebrates (IP3R1-3) are closely related proteins and they are each regulated by both (1,4,5)IP3 (1, Fig. 1) and Ca2+, but they differ in their sensitivity to other forms of regulation and in their subcellular and tissue distributions.[1]. (1,3,4,6)IP4, which retains the essential pharmacophore of an IP3R agonist (Fig. 1B), stimulates Ca2+ release via IP3R, but its affinity is between 10 and 100-fold lower than that of 2504 | Org. Biomol.
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