RGD Reference Report - Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) has InsP(3)-independent gating and disrupts intracellular Ca(2+) homeostasis. - Rat Genome Database

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Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) has InsP(3)-independent gating and disrupts intracellular Ca(2+) homeostasis.

Authors: Kopil, CM  Vais, H  Cheung, KH  Siebert, AP  Mak, DO  Foskett, JK  Neumar, RW 
Citation: Kopil CM, etal., J Biol Chem. 2011 Oct 14;286(41):35998-6010. Epub 2011 Aug 22.
RGD ID: 6480675
Pubmed: PMID:21859719   (View Abstract at PubMed)
PMCID: PMC3195633   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.254177   (Journal Full-text)

The type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1) is a ubiquitous intracellular Ca(2+) release channel that is vital to intracellular Ca(2+) signaling. InsP(3)R1 is a proteolytic target of calpain, which cleaves the channel to form a 95-kDa carboxyl-terminal fragment that includes the transmembrane domains, which contain the ion pore. However, the functional consequences of calpain proteolysis on channel behavior and Ca(2+) homeostasis are unknown. In the present study we have identified a unique calpain cleavage site in InsP(3)R1 and utilized a recombinant truncated form of the channel (capn-InsP(3)R1) corresponding to the stable, carboxyl-terminal fragment to examine the functional consequences of channel proteolysis. Single-channel recordings of capn-InsP(3)R1 revealed InsP(3)-independent gating and high open probability (P(o)) under optimal cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) conditions. However, some [Ca(2+)](i) regulation of the cleaved channel remained, with a lower P(o) in suboptimal and inhibitory [Ca(2+)](i). Expression of capn-InsP(3)R1 in N2a cells reduced the Ca(2+) content of ionomycin-releasable intracellular stores and decreased endoplasmic reticulum Ca(2+) loading compared with control cells expressing full-length InsP(3)R1. Using a cleavage-specific antibody, we identified calpain-cleaved InsP(3)R1 in selectively vulnerable cerebellar Purkinje neurons after in vivo cardiac arrest. These findings indicate that calpain proteolysis of InsP(3)R1 generates a dysregulated channel that disrupts cellular Ca(2+) homeostasis. Furthermore, our results demonstrate that calpain cleaves InsP(3)R1 in a clinically relevant injury model, suggesting that Ca(2+) leak through the proteolyzed channel may act as a feed-forward mechanism to enhance cell death.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cardiac arrest  ISOItpr1 (Rattus norvegicus)6480675; 6480675protein:increased expression:cerebellum (rat)RGD 
cardiac arrest  IEP 6480675protein:increased expression:cerebellum (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Itpr1  (inositol 1,4,5-trisphosphate receptor, type 1)

Genes (Mus musculus)
Itpr1  (inositol 1,4,5-trisphosphate receptor 1)

Genes (Homo sapiens)
ITPR1  (inositol 1,4,5-trisphosphate receptor type 1)


Additional Information