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Cited by 54Endoplasmic Reticulum Stress and DiseaseIon Channels and ReceptorsUbiquitin and proteasome pathways

When worlds collide: IP3 receptors and the ERAD pathway

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Wojcikiewicz, Richard J.H., Pearce, Margaret M.P., Sliter, Danielle A., Wang, Yuan·2009·Cell Calcium
DOI 10.1016/j.ceca.2009.05.002PMC PMC2752845
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Abstract

While cell signaling devotees tend to think of the endoplasmic reticulum (ER) as a Ca(2+) store, those who study protein synthesis tend to see it more as site for protein maturation, or even degradation when proteins do not fold properly. These two worldviews collide when inositol 1,4,5-trisphosphate (IP(3)) receptors are activated, since in addition to acting as release channels for stored ER Ca(2+), IP(3) receptors are rapidly destroyed via the ER-associated degradation (ERAD) pathway, a ubiquitination- and proteasome-dependent mechanism that clears the ER of aberrant proteins. Here we review recent studies showing that activated IP(3) receptors are ubiquitinated in an unexpectedly complex manner, and that a novel complex composed of the ER membrane proteins SPFH1 and SPFH2 (erlin 1 and 2) binds to IP(3) receptors immediately after they are activated and mediates their ERAD. Remarkably, it seems that the conformational changes that underpin channel opening make IP(3) receptors resemble aberrant proteins, which triggers their binding to the SPFH1/2 complex, their ubiquitination and extraction from the ER membrane and finally, their degradation by the proteasome. This degradation of activated IP(3) receptors by the ERAD pathway serves to reduce the sensitivity of ER Ca(2+) stores to IP(3) and may protect cells against deleterious effects of over-activation of Ca(2+) signaling pathways.

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Cited by

Sorted by citations

Authors
Wojcikiewicz, R. J. H., Pearce, M. M. P., Sliter, D. A., & Wang, Y.
Affiliations
SUNY Upstate Medical University (US)
Corresponding author
Wojcikiewicz, Richard J.H.
ORCID
Venue
Cell Calcium
Publisher
Elsevier BV
Published
2009-09
Volume
46
Issue
3
Pages
147-153
ISSN
0143-4160 (ISSN-L)
DOI
10.1016/j.ceca.2009.05.002
PMC
PMC2752845
OpenAlex
W2012109738
Cited by
54
References
3
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 1 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 7
FWCI
0.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Calcium (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • Pharmaceutical Research and Manufacturers of America Foundation
  • National Institute for Health and Care Research
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK049194)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
IP3 receptor, ER-associated degradation, ubiquitination, proteasome, endoplasmic reticulum calcium stores, protein degradation, channel conformational change, calcium signaling, protein maturation
MeSH terms
Endoplasmic Reticulum, Humans, Membrane Proteins, Nerve Tissue Proteins, Signal Transduction, Calcium Signaling, Inositol 1,4,5-Trisphosphate Receptors, Ubiquitination

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