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

The inositol 1,4,5 trisphosphate receptor (IPR) is an intracellular Ca release channel expressed predominately on the membranes of the endoplasmic reticulum. IPR1 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 IPR1 channels, formed following either enzymatic fragmentation or expression of the corresponding complementary polypeptide chains, retain tetrameric architecture and are still activated by IP 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 Ca release profile and protein kinase A modulation of Ca release are markedly altered. Moreover, we also demonstrate that activation of fragmented IPR1 can result in a distinct functional outcome. Our work suggests that proteolysis of IPR1 may represent a novel form of modulation of IPR1 channel function and increases the repertoire of Ca signals achievable through this channel.