In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor (Sig-1R) in 1982, many preclinical studies have shown that Sig-1Rs and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and psychostimulant addiction. However, the basic biological action of Sig-1R has been elusive and the mechanism via which Sig-1Rs and ligands may act to counteract those diseases remains unknown. Nevertheless in the past year, which represents a landmark period in the Sig-1R research, we have identified the basic biological action of Sig-1Rs. We have now identified the Sig-1R as a new class of molecular chaperone, namely as a receptor chaperone that performs in biological systems the chaperone activity in a ligand-operated manner and in an agonist/antagonist fashion. Specifically, Sig-1Rs chaperone the mature, functional IP3 receptors at the endoplasmic reticulum(ER)-mitochondrion interface (known as mitochondrion-associated membrane or MAM) and regulate the calcium influx from ER into mitochondrion. Sig-1Rs do so by sensing the drop of the ER Ca2+ level and then freeing themselves from another chaperone Bip so as to target and stabilize IP3 receptors which would otherwise be rapidly degraded by proteosomes. Sig-1R agonists promote the dissociation of Sig-1Rs fom Bip whereas the Sig-1R antagonists block this action of the agonists. Moreover, upon chronic ER stress, Sig-1Rs translocate from the MAM to the entire ER network to combat apoptosis. These results shed light on several previous unexplained observations and provide a new paradigm for regulation of IP3R signalling as well as mitochondrial signalling and calcium signalling in general. Further, inasmuch as (1) Sig-1Rs exist in many organs including the brain, liver, lungs, retina, heart, spleen, pancreas, and adrenal gland, and are highly expressed in almost all types of cancer cells; and (2) the secretory proteins from those organs, including BDNF, insulin, and apolipoprotein, are chaperoned by Sig-1Rs, results of our studies potentially link the chaperone nature of Sig-1Rs to diseases of those organs and suggest that the Sig-1R chaperone may represent a new therapeutic target for many human diseases. Our results also constitute the first report showing that chaperone activity in biological systems can be activated or deactivated at will by pharmacological agents. Future plans include the elucidation and establishment of the molecular pathways wherein Sig-1R chaperones are related to human diseases including neurodegeneration and addiction.
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