ATP Regulation of Type-1 Inositol 1,4,5-Trisphosphate Receptor Activity Does Not Require Walker A-type ATP-binding Motifs

ATP is known to increase the activity of the type-1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1). This effect is attributed to the binding of ATP to glycine rich Walker A-type motifs present in the regulatory domain of the receptor. Only two such motifs are present in neuronal S2+ splice variant of InsP(3)R1 and are designated the ATPA and ATPB sites. The ATPA site is unique to InsP(3)R1, and the ATPB site is conserved among all three InsP(3)R isoforms. Despite the fact that both the ATPA and ATPB sites are known to bind ATP, the relative contribution of these two sites to the enhancing effects of ATP on InsP(3)R1 function is not known. We report here a mutational analysis of the ATPA and ATPB sites and conclude neither of these sites is required for ATP modulation of InsP(3)R1. ATP augmented InsP(3)-induced Ca2+ release from permeabilized cells expressing wild type and ATP-binding site-deficient InsP(3)R1. Similarly, ATP increased the single channel open probability of the mutated InsP(3)R1 to the same extent as wild type. ATP likely exerts its effects on InsP(3)R1 channel function via a novel and as yet unidentified mechanism.