The Endoplasmic Reticulum (ER) is a dynamic organelle that plays a critical role in a variety of processes, including Ca2+ storage and release, synthesis and folding of proteins, as well as post-translational proteín modification. These processes of signaling and biosynthesis are deeply inter-connected.

When the load of newly synthesized proteins exceeds the folding and/or processing capacity of the organelle, the ER enters into a stress condition. This activates a signal transduction pathway called the Unfolded Protein Response (UPR) that attempts to restore homeostasis in the ER.

An immediate response is the attenuation of protein translation via PERK (Protein kinase RNA [PKR]-like ER kinase), an ER membrane protein with a stress-sensing luminal domain connected by a transmembrane segment to a cytoplasmic-kinase domain. PERK is normally inactive due to the association of its luminal domain with the ER chaperone BiP. During ER stress, BiP is competitively titrated from the luminal domain of PERK by the excess of unfolded proteins. This dissociation causes PERK to undergo homo-oligomerization and trans-autophosphorylation within its cytosolic kinase domain, thereby increasing its activity.

If ER damage is persistent or excessive, UPR initiates an apoptotic response.

Paradoxically, UPR is designed to facilitate both homeostasis recovery and apoptosis, depending upon the severity and nature of the stressor.

It is well accepted that ER calcium depletion induces ER stress.  At this respect, we found that Ca2+, once in the cytosol, acts as a co-factor for the initiation of the UPR (Bollo et al 2010 Plos One, 5(8): e11925, Paredes et al 2013, Cell Calcium 53:286 y Chen Y et al 2016, Neurobiol Dis 94: 139). Particularly, we observed in astrocytes that an increase in cytosolic Ca2+ during the early phase of ER stress is associated with a calcium-dependent protective role of isoform β of Calcineurin (CNβ). This function is independent of its phosphatase activity and dependent on PERK. Therefore, CNβ-PERK pathway is required for astrogliosis after focal cerebral ischemia.


 Cytoprotective role of Calcineurin b in focal cerebral ischemia. A comprehensive model showing the mechanistic insights into protective role of CNβ explained on text.

Moreover, we demonstrated the participation of PERK signaling pathway in a GM2-gangliosidosis cell model (Virgolini et al 2019 Biochim Biophys Acta Mol Cell Res. 1866, 2: 225). Specifically, we showed that GM2 accumulation in the ER induce decrease in the luminal Ca2+ content. This in turn activates PERK signaling, which shows two phases: one acute, where Calcineurin is up regulated, and the other apoptotic. We also presented evidence showing that pharmacological as well as molecular modulation of PERK signaling changes the vulnerability of neurons to undergo neurite atrophy and apoptosis.