When worlds collide: IP(3) receptors and the ERAD pathway.
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.
Wojcikiewicz
Richard J H
RJ
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. wojcikir@upstate.edu
Pearce
Margaret M P
MM
Sliter
Danielle A
DA
Wang
Yuan
Y
D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins; D015398:Signal Transduction; D054875:Ubiquitination
C418605:ERLIN1 protein, human; C121703:ERLIN2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins