Phosphorylation of the rat Ins(1,4,5)P3 receptor at T930 within the coupling domain decreases its affinity to Ins(1,4,5)P3

The Ins(1,4,5)P-3 receptor acts as a central hub for Ca2+ signaling by integrating multiple signaling modalities into Ca2+ release from intracellular stores downstream of G-protein and tyrosine kinase-coupled receptor stimulation. As such, the Ins(1,4,5)P-3 receptor plays fundamental roles in cellular physiology. The regulation of the Ins(1,4,5)P-3 receptor is complex and involves protein-protein interactions, post-translational modifications, allosteric modulation, and regulation of its sub-cellular distribution. Phosphorylation has been implicated in the sensitization of Ins(1,4,5)P-3-dependent Ca2+ release observed during oocyte maturation. Here we investigate the role of phosphorylation at T-930, a residue phosphorylated specifically during meiosis. We show that a phosphomimetic mutation at T-930 of the rat Ins(1,4,5)P-3 receptor results in decreased Ins(1,4,5)P-3-dependent Ca2+ release and lowers the Ins(1,4,5)P-3 binding affinity of the receptor. These data, coupled to the sensitization of Ins(1,4,5)P-3-dependent Ca2+ release during meiosis, argue that phosphorylation within the coupling domain of the Ins(1,4,5)P-3 receptor acts in a combinatorial fashion to regulate Ins(1,4,5)P-3 receptor function.