The controversial identity of the sigma-2 receptor with PGRMC1: is the PGRMC1/sigma-2 protein, that binds Abeta oligomer, made of two independent molecular entities?

Sigma-2 receptors are intriguing targets under study for their involvement in tumors and neurodegenerative diseases. However, the ‘sigma enigma’ is not over yet, with controversies about sigma-2 receptor identity. In one of the last attempts for the characterization, the identification of the sigma-2 protein with the progesterone receptor membrane component 1 (PGRMC1) was proposed and generally accepted. Recently, the so-called PGRMC1/sigma-2 protein was identified as a neuronal receptor for Abeta oligomers binding, with Abeta oligomers behaving as ‘regular’ ligands at such proteins. Very importantly, a few sigma-2 receptor antagonists were able to displace in a dose-dependent manner synthetic Abeta oligomers from synaptic puncta, as well as human Abeta oligomers from brain sections of Alzheimer’s disease (AD) patients. In vivo, these compounds showed to reverse cognitive deficits restoring memory and sustaining long-term improvement in AD mice models. The PGRMC1/sigma-2 protein involvement in these activities was demonstrated by radioactive sigma-2 ligand binding together with PGRMC1 silencing, starting from the consideration that PGRMC1 and sigma-2 are the same molecular entity. Nevertheless, we feel that the clear identification of the proteins involved in the described effects is crucial for future development of AD disease-modifying therapies. With this perspective, we verified how the expression of sigma-2 receptor is independent of PGRMC1 expression by western blotting and scatchard analyses on cell lines where sigma-2 receptors were constitutively present, and where PGRMC1 was alternatively silenced or overexpressed (human breast adencarcinoma MCF7 cells). In addition, the sigma-2 mediated activity, which was studied through sigma-2 agonists, was independent of the presence and amount of PGRMC1. In order to further investigate the connection between sigma-2 and PGRMC1, the profiling of these proteins in a number of cell lines is in progress. Confocal microscopy and flow-cytometry studies employing sigma-2 fluorescent tracers are undergoing in cell lines where PGRMC1 is silenced, overexpressed and/or constitutively present. Results from this work will contribute to clarify the controversial relationship between sigma-2 and PGRMC1, so that unbiased research focused on these targets for the development of AD-modifying agents may be conducted.