Isoform-specific Regulation of the Inositol 1,4,5-Trisphosphate Receptor by O-Linked Glycosylation

Abstract

The inositol 1,4,5-trisphosphate receptor (InsP 3 R), an intracellular calcium channel, has three isoforms with >65% sequence homology, yet the isoforms differ in their function and regulation by post-translational modifications. We showed previously that

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…OGlcNAcylation of the IP 3 type I receptor decreased its activity, while the removal of O-GlcNAc restored its function (Rengifo et al 2007). Following this study, it was demonstrated that the IP 3 type III receptor is functionally regulated by O-GlcNAc, except that O-GlcNAcylation enhanced its activity while O-GlcNAc removal negated its function (Bimboese et al 2011). Thus, O-GlcNAcylation of IP 3 type I and III receptors regulates their function(s) in controlling Ca 2+ flux and ultimately attenuating Ca 2+ -dependent apoptosis (Rengifo et al 2007).…”

“…O-GlcNAc is thought to regulate these proteins in a manner analogous to protein phosphorylation. O-GlcNAc has been demonstrated to alter numerous protein functions that include: DNA binding and transactivation (Jackson and Tjian 1989;Ozcan et al 2010;Comer and Hart 1999;Gao et al 2003;Sayat et al 2008), protein-protein interactions (Lim and Chang 2010;Ise et al 2010;Guinez et al 2010;Guinez et al 2007;Guinez et al 2006), protein degradation (Cheng and Hart 2001;Han and Kudlow 1997;Zhang et al 2003), protein and enzyme activity Rengifo et al 2007;Zhang et al 2003;Dias et al 2009;Bimboese et al 2011), and protein localization (Sayat et al 2008;Dudognon et al 2004) among many others .…”

Functional Inositol 1,4,5-Trisphosphate Receptors Assembled from Concatenated Homo- and Heteromeric Subunits

“…Early reports have suggested that their sensitivity to Ca 2ϩ is greater for IP 3 R3 than IP 3 R1; however, all three subtypes show a bell-shaped Ca 2ϩ dependence with the optimum cytosolic [Ca 2ϩ ] around 200 nM (26,29,30). In addition, IP 3 R subtypes are modulated differentially by kinases, phosphatases, proteolysis, transcriptional, post-transcriptional, and post-translational modifications (31)(32)(33)(34)(35)(36)(37)(38)(39). Consequently, it is widely held that these differences may underlie subtype-specific Ca 2ϩ patterns, and it follows that the particular cellular complement of IP 3 Rs may therefore dictate the spatio-temporal patterns of Ca 2ϩ signals evoked in response to IP 3 formation in an individual cell (13, 35, 40 -42).…”

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

“…66 Also, the inositol 1,4,5-trisphosphate receptor in itself is modified by O-GlcNAc, and this modification regulates channel activity 67 in an isoformspecific manner. 68 O-GlcNAc transferase overexpression/glucose-induced increase in O-GlcNAc is associated with prolonged Ca 2+ transients and reduced sarcoplasmic reticulum/ ER Ca 2+ -ATPase protein expression in cardiomyocytes. When intracellular calcium stores are depleted, nonvoltage storeoperated Ca 2+ channels in the plasma membrane facilitate Ca 2+ entry into the cell.…”