Society for Neuroscience Annual Meeting; Nanosymposium: Sigma-2/PGRMC1 Receptor Function in Disease and Therapeutics

Shedding light on the controversial identity of the sigma-2 receptor with PGRMC1 M. L. Pati, C. Abate, M. Niso, F. Berardi, N.A. Colabufo Dipartimento di Farmacia-Scienze del Farmaco, Via Orabona, 4 70125 Bari, Italy After four decades from their discovery, the enigma about sigma receptors is still unsolved. Despite the emerging controversies about the identification of the sigma-2 protein with the progesterone receptor membrane component 1 (PGRMC1), several literatures still refer to the PGRMC1/sigma-2 protein, and a misidentification of these proteins would seriously hamper their future therapeutic or diagnostic exploitation. A recent study highlighted the AD disease-modifying potentials of PGRMC1/sigma-2 proteins, demonstrating that a few sigma-2 receptor antagonists displace Abeta oligomers (which behave as ‘regular’ ligands at the PGRMC1/sigma-2 protein) in vitro, and reverse cognitive deficits in AD mice models in vivo. At the same time, both PGRMC1 and sigma-2 proteins represent promising targets for the therapy and diagnosis of tumors, because of their overexpression and proliferative effects in a wide variety of cancers. Therefore, it goes without saying that a clear identification of these proteins is mandatory. Our previous contribution towards this direction showed how the expression of sigma-2 receptor is independent of PGRMC1, and that the sigma-2 mediated activity is independent of the presence and amount of PGRMC1. Herein, we give further support to these findings by flow-cytometry studies in three cell lines (human breast adencarcinoma MCF7 cells) where sigma-2 receptors are constitutively present, and PGRMC1 is constitutively present or alternatively silenced or overexpressed. Three sigma-2 fluorescent tracers with different structures were used in the three cell lines, and were dose-dependently displaced by diverse sigma-2 ligands but not by AG205 - the putative PGRMC1 inhibitor. Additionally, localization experiments in the three cell lines were conducted by confocal microscopy in order to define the intracellular localization of both sigma-2 and PGRMC1 and their eventual co-localization. We feel that these results together with the very recent crystallographic characterization of the PGRMC1 and the delineation of its mechanism of action will be helpful for the clarification of the controversial relationship between sigma-2 and PGRMC1, prompting future unbiased research for the development of AD-modifying agents. Within this context, sigma-2 antagonists with metal (copper or iron) chelating moiety may find place. These compounds, would preclude the Abeta oligomer binding to the neuronal sigma-2 receptor, while removing from the media copper and iron, whose impaired homeostasis is associated with AD. These combined actions would reinforce the AD-modifying properties of the sigma-2 antagonist.