Chapter 4 - Inositol 1,4,5-Trisphosphate Receptor Ubiquitination

Abstract

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are large (∼300kDa) proteins that associate into tetrameric ion channels in the endoplasmic reticulum (ER) membrane. Activation and opening of the channel upon binding of IP3 and Ca(2+) allows the flow of Ca(2+) ions from stores within the ER lumen to the cytosol, thereby promoting a number of Ca(2+)-dependent cellular events, such as secretion, neurotransmitter release, and cell division. Intriguingly, it appears that the same conformational change that IP3Rs undergo during activation makes them a target for degradation by the ubiquitin-proteasome pathway and that this mode of processing allows the cell to tune its internal Ca(2+) response to extracellular signals. Here, we review recent studies showing that activated IP3Rs interact with an array of proteins that mediate their degradation, that IP3Rs are modified by a complex array of ubiquitin conjugates, that this ubiquitination and degradation functions to regulate IP3-mediated Ca(2+) responses in the cell, and that mutations to different proteins involved in IP3R degradation result in a set of similar diseases.

Keywords: ER; IP(3)R; calcium intracellular release; neurodegenerative disease; ubiquitin ligase.