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. IP₃R1 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 IP₃R1 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 IP₃R1 can result in a distinct functional outcome. Our work suggests that proteolysis of IP₃R1 may represent a novel form of modulation of IP₃R1 channel function and increases the repertoire of Ca²⁺ signals achievable through this channel.

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