Haven't studied it well enough to speak about it but it appears to be very informative at first look.
3. Mechanisms of neuroprotection by Sig-1R activation 3.1. Influence of Sig-1R on Ca2+ homeostasis As a consequence of its cellular localization, distribution, and characteristics as a molecular chaperone, the Sig-1R can modulate multiple intracellular pathways and signalling cascades involving Ca2+ ions (Fig. 1, Fig. 2). Since Ca2+ toxicity plays a pivotal role in cell death after stroke and neurodegenerative diseases, the Sig-1R-mediated effect on Ca2+ homeostasis may therefore be of crucial importance for its protective actions on the brain. At the MAM, Sig-1Rs are involved in the regulation of Ca2+ mobilization from ER stores. In addition, Sig-1Rs contribute to the stability of inositol trisphosphate receptor (IP3R) channels to ensure proper Ca2+ transport between the two organelles (9), (17). Furthermore, Sig-1Rs stimulate phospholipase C (PLC) resulting in increased levels of IP3 in the cytoplasm (40) with subsequent release of Ca2+ from the ER via activation of IP3R channels (41). Furthermore, the acid sensing ion channel Ia (42), (43), voltage sensitive Ca2+ channels (44), as well as AMPA and NMDA receptors (45), modulate intracellular Ca2+ levels and are regulated by Sig-1Rs. Neuroprotection by Sig-1R agonists could therefore be provided by preventing detrimental elevations of intracellular Ca2+-mediated effects by these channels. Under these conditions, activated Sig-1Rs are involved in normalizing intracellular ischaemia- or acidosis-evoked Ca2+ overloads (46), (47), an effect blocked by selective Sig-1R antagonists BD1047 and BD1063 (46). ......
4. Sig-1Rs and tissue repair 4.1. Sig-1R and molecular trafficking The brain rapidly responds to cell death by proliferation of glial cells, and subsequently by remodelling (plasticity) of synapses and neuronal connections to compensate for lost brain functions (54) (Fig. 1). In this context, gliosis and inflammation, as well as receptor trafficking, spine remodelling and axonal outgrowth, are important recovery-promoting processes where the Sig-1R has been implicated (Fig. 2).
The recovery of brain function after injury depends on recuperation of surviving or healthy neurons afflicted by injury or disease (Fig. 1). Recovery can be accomplished by obliterating factors hampering synaptic transmission such as inflammatory mediators, toxic substances released from dying or dead neurons, or by spontaneous activation of plasticity-promoting processes. The area surrounding the brain infarct after stroke is highly dynamic, involving astrocytes, oligodendrocytes, neuronal progenitor cells, microglia and macrophages in tissue repair. The synergistic action of these cells secures the removal of dead or injured neurons, reutilization of cellular constituents, lipids in particular, and the formation of a ”scar” that encapsulates the infarct, preventing the diffusion of toxic substances that may propagate damage and cause further dysfunction of surviving neurons in its vicinity (55). An efficient scar-forming process will allow faster recovery of neurons at risk. Here, the Sig-1R may play an important role by virtue of its regulation of molecular trafficking.
The activated Sig-1R, immersed in lipid rafts, is a vehicle for transport of proteins or lipids to the plasma membrane (8), (14), (56), (57). In neurons this could either involve transport of de novo synthesized proteins from the cell body or promote trafficking in synapses as part of the externalization/internalization process of receptors/channels (58). The translocation of lipid rafts formed in the ER of glia and neurons, also allows the transport of cholesterol and ceramides essential for neuronal function, (10), (14). The intracellular trafficking and extracellular release of lipids supported by Sig-1R, may serve to replenish lipids in areas of high turnover such as synapses and/or support growth and proliferation of cells. In this context, it is noteworthy that the Sig-1R also activates gene expression of specific protein mRNAs such as that of the NMDA receptor (58), and processing of various growth factors particularly BDNF (52), (59).
The Sig-1R in lipid rafts is upregulated after a hypoxic episode. Trafficking is enhanced in cells activated by a Sig-1R agonist and is depressed by an antagonist (14). After experimental stroke, the Sig-1R is strongly expressed in reactive astrocytes surrounding the infarct and can also be found in the extracellular space. This suggests that Sig-1R may promote the release of exosomes that support the scar-forming and/or plasticity-promoting processes in recuperating neurons (Fig. 1).
Also, Sig-1R agonists could stimulate cell proliferation and migration of progenitor cells. Within hours after stroke, GFAP is expressed in the subventricular zone (60), an important site for cell genesis. Indeed, the Sig-1R is involved in the proliferation of oligodendrocytes (10). Furthermore, in Sig-1R KO animals, neurogenesis in the subventricular zone of the hippocampus is depressed (61).
