title: 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.
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States.
authors.forename: F A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States. Electronic address: WojcikiR@upstate.edu.
authors.forename: R J H
authors.initials: RJ
authors.lastname: Wojcikiewicz
mesh_terms: D000818:Animals; D004194:Disease; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D054875:Ubiquitination
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D046988:Proteasome Endopeptidase Complex
keywords: ER; IP(3)R; calcium intracellular release; neurodegenerative disease; ubiquitin ligase