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J Biol Chem. 2017 Jul 14;292(28):11714-11726. doi: 10.1074/jbc.M117.789917. Epub 2017 May 19.

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

Author information

1
From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642.
2
From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642 david_yule@urmc.rochester.edu.

Abstract

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.

KEYWORDS:

PKA; calcium; calcium signaling; calpain; caspase; inositol 1,4,5 trisphosphate receptor (IP3R)

PMID:
28526746
PMCID:
PMC5512067
DOI:
10.1074/jbc.M117.789917
[Indexed for MEDLINE]
Free PMC Article

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