The suppressor domain of inositol 1,4,5-trisphosphate receptor plays an essential role in the protection against apoptosis

The N-terminal 1-225 amino acids (aa) of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) function as a suppressor/coupling domain. In this study we used IP3R-deficient B-lymphocytes to investigate the effects of modifications in this domain on IP3 binding and Ca2+-release activity. Although the N-terminal 1-225 aa of IP3R3 had the same role as in IP3R1, the suppression of IP3 binding for IP3R1 was lost when the suppressor/coupling domains were exchanged between the two isoforms. Resulting chimeric receptors showed a higher sensitivity to IP3-induced activation (IICR). Deletion of 11 aa in IP3R1 ([Δ76-86]-IP3R1) or replacing aa 76-86 of the IP3R1 in the suppressor/coupling domain by 13 aa of IP3R3 ([75-87 T3]-IP3R1) also resulted in increased IP3 binding and sensitivity of IICR. These residues constitute the only part of the suppressor/coupling domain that is strikingly different between the two isoforms. Expression of [Δ76-86]-IP3R1 and of [75-87 T3]-IP3R1 increased the propensity of cells to undergo staurosporine-induced apoptosis, but had no effect on the Ca2+ content in the endoplasmic reticulum. In the cell model used, our observations suggest that the sensitivity of the Ca2+-release activity of IP3R1 to IP3 influences the sensitivity of the cells to apoptotic stimuli and that the suppressor/coupling domain may have an anti-apoptotic function by attenuating the sensitivity of IICR.