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WIREs Membr Transp Signal

Inositol 1,4,5‐trisphosphate receptor degradation pathways

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We know where cellular proteins come from, but know very little about where they go. This is a fairly accurate generalization, since a great deal of emphasis has been placed on understanding the synthesis of proteins, the regulation of their synthesis, and if appropriate, their posttranslational modification, assembly into complexes, and insertion into membranes. In contrast, very little attention has been paid to the details of protein turnover—cellular proteins only have a limited lifetime and are somehow degraded to be replaced by new copies, but how? This generalization is certainly applicable to inositol 1,4,5‐trisphosphate (IP3) receptors. In summary, it seems that under resting conditions, IP3 receptors are slowly disposed of in a nonspecific manner that may involve trafficking to lysosomes, whereas activated IP3 receptors are rapidly and selectively degraded by the ubiquitin‐proteasome pathway. WIREs Membr Transp Signal 2012, 1:126–135. doi: 10.1002/wmts.4

Figure 1.

Inositol 1,4,5‐trisphosphate (IP3) receptor downregulation in three mammalian cell lines. αT3‐1, Rat1, and AR42J cells were incubated with 100 nM gonadotropin‐releasing hormone (GnRH), 10 nM endothelin‐1 and 200 nM cholecystokinin, respectively, for the times indicated and cell lysates were probed for IP3 receptor content. The IP3 receptor downregulation shown is representative of that seen in a range of mammalian cell lines13,14,19–23,32 and primary cultures.24–27,32 (Reprinted with permission from Ref 23. Copyright 2011 ASBMB)

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Figure 2.

The endoplasmic reticulum‐associated degradation (ERAD) pathway in mammalian cells. ERAD of membrane or luminal proteins containing some kind of aberration (stars), either within or outside the membrane bilayer, can be thought of as a four‐step process consisting of (1) recognition, (2) retrotranslocation, (3) ubiquitination, and (4) proteasomal degradation. It is probable that these steps are integrated, as multiprotein complexes that carry out more than one step are being defined; e.g., complexes centered on HMG‐CoA reductase degradation protein 1 (HRD1), an ER membrane‐located E3, likely recognize, retrotranslocate, and ubiquitinate ERAD substrates.34–36

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Figure 3.

Inositol 1,4,5‐trisphosphate (IP3) receptor structure and ubiquitination. (a) A schematic representation of mouse IP3R1, showing the overall domain structure and the 12 ubiquitination sites (K916, 962, 1571, 1771, 1884, 1885, 1886, 1899, 1901, 1924, 2118, and 2257) indicated by ‘K's’ in the main diagram or by arrows in the expanded regions.23,50 Also indicated are sites at which trypsin preferentially cleaves IP3R1 and which are thought to be surface‐exposed loops (arrowheads), a glycine‐rich region, the caspase‐3 cleavage site, ATP‐ and calmodulin‐binding sites, the ‘Ca2+ sensor’, and sites of PKA‐mediated phosphorylation.2 Note that the ubiquitination sites are near exposed loops or regulatory sites. (b) Relative amounts of ubiquitin in chains linked via K48 or K63 or other lysines to IP3R1 in stimulated αT3‐1 cells (Reprinted with permission from Ref 50. Copyright 2008 ASBMB). (c) Effects of over‐expression of wild‐type or mutant ubiquitins on IP3R1 downregulation in αT3‐1 cells. The normal downregulation seen in cells over‐expressing wild‐type ubiquitin is inhibited by over‐expression of K48R ubiquitin (which blocks the formation of K48‐linked ubiquitin chains), but is unaffected by over‐expression of K63R ubiquitin (which blocks the formation of K63‐linked ubiquitin chains) (Reprinted with permission from Ref 23. Copyright 2011 ASBMB). (d) Depicted are possible arrangements of ubiquitin moieties on IP3R1 tetramers, taking into account the knowledge that modified individual subunits are tagged, on average, with eight ubiquitin moieties, that approximately half the ubiquitin moieties are involved in chains, and that K48 and K63‐linked ubiquitin chains are homogeneous and are segregated to different subunits. At present, it has not been established which of the two possible arrangements is correct.

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Figure 4.

Summary of IP3 degradation pathways. IP3 receptors are destroyed via one of two routes—either fast degradation of activated receptors mediated by the endoplasmic reticulum‐associated degradation (ERAD) pathway, or slow degradation under basal conditions that likely involves ER exit and transfer to lysosomes (see text for details).

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Intracellular Channels and Receptors > Inositol-1,4,5 trisphosphate (IP3) Receptors

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