Region-specific proteolysis differentially regulates type 1 inositol 1,4,5-trisphosphate receptor activity

The inositol 1,4,5 trisphosphate receptor (IP3R) is an intracellular Ca2+ release channel expressed predominately on the membranes of the endoplasmic reticulum. IP(3)R1 can be cleaved by caspase or calpain into at least two receptor fragments. However, the functional consequences of receptor fragmentation are poorly understood. Our previous work has demonstrated that IP(3)R1 channels, formed following either enzymatic fragmentation or expression of the corresponding complementary polypeptide chains, retain tetrameric architecture and are still activated by IP3 binding despite the loss of peptide continuity. In this study, we demonstrate that region-specific receptor fragmentation modifies channel regulation. Specifically, the agonist-evoked temporal Ca2+ release profile and protein kinase A modulation of Ca2+ release are markedly altered. Moreover, we also demonstrate that activation of fragmented IP(3)R1 can result in a distinct functional outcome. Our work suggests that proteolysis of IP(3)R1 may represent a novel form of modulation of IP(3)R1 channel function and increases the repertoire of Ca2+ signals achievable through this channel.