Inhibition in cortical circuits

photobleaching reveal that the half-life of stress-granule-associated RNA-binding proteins is very brief, on the order of seconds to minutes, despite the fact that time-lapse microscopy reveals that individual stress granules persist for hours. This rapid shuttling of protein and RNA within stress granules suggests that their mRNP contents are continually sorted via fleeting associations with the translational machinery. Unlike other types of RNA granule, such as germ cell granules or neuronal granules, stress granules are not sites of long-term mRNP storage. What are the core components of stress granules? Stress granules are primarily composed of the stalled 48S complexes containing bound mRNAs derived from disassembling polysomes. These contain poly(A) + RNA bound to early initiation factors (such as eIF4E, eIF3, eIF4A, eIFG) and small, but not large, ribosomal subunits. In addition to these core components, stress granules contain an eclectic assembly of proteins that vary with cell type and with the nature and duration of the stress involved. RNA-binding proteins, transcription factors, RNA helicases, nucleases, kinases and signaling molecules have been reported to accumulate in stress granules. In some cases, recruitment of signaling proteins into stress granules influences cell survival. More recently, stress granules have been shown to contain the Argonaute proteins, microRNAs, a number of mRNA-editing enzymes, and proteins required for transposon activity. What are their speculated functions? The dynamic nature of stress granules suggests that they are sites of mRNA triage, wherein individual mRNAs are dynamically sorted for storage, degradation, or translation during stress and recovery. Short-lived mRNAs bearing adenine– uridine-rich destabilizing elements in their 3' untranslated regions bind to TTP and BRF1/2, proteins that promote interactions between stress granules and processing bodies (P-bodies) and induce mRNA decay. It is therefore likely that stress granules can regulate the stability of selected mRNAs. Beyond mRNP sorting, the recruitment of other signaling molecules into stress granules suggests that they link mRNP sorting with other signaling events. Cells that express a non-phosphorylatable form of eIF2α (S51A) cannot assemble stress granules in response to arsenite-induced oxidative stress and are hypersensitive to the toxic effects of low doses of arsenite. Whether this is due to defective stress-induced translational silencing or defective stress granule assembly is not yet clear. In other cases, the sequestration of signaling molecules not directly linked to RNA metabolism (such as TRAF2, RACK1 and FAST) in stress granules has been shown to regulate the survival of stressed cells. Any known …