THE SIGMA-1 (σ1) RECEPTOR AND ITS ROLE IN THE TREATMENT OF MOOD DISORDERS

Sigma (sigma) receptors have long been implicated in a variety of neuronal and brain functions, although their precise biochemical and physiological role, and potential involvement in neurological and psychiatric disorders, remains elusive. However, nearly 30 years after their characterization, evidence arising from various research fields has begun to unveil the biological function and clinical implications of sigma receptors. These receptors ore intracellular molecules consisting of at least two subtypes - sigma(1) ond sigma(2). The sigma(1) receptor, an integral membrane protein with two transmembrane domains, mainly localizes at the endoplasmic reticulum (ER). A recent study identified the sigma(1) receptor as possessing innate biological activity as a molecular chaperone, activity that can be activated/inactivated by synthetic compounds that bind to sigma(1) receptors. The sigma(1) receptor regulates Ca2+ signaling, ion channel activity, trophic factor signaling, cell Survival, myelination and synaptogenesis. Certain clinically used antidepressants and steroids bind to the sigma(1) receptor, and selective sigma(1) agonists have demonstrated relatively rapid antidepressant-like actions in preclinical studies; such agents have been introduced into clinical trials. The recent discoveries regarding the hitherto enigmatic sigma receptor have fueled expectation that this receptor class may provide novel opportunities for pharmacological interventions. In this review, we present current data supporting the notion that this novel ligand-operated molecular chaperone may provide a new intracellular target for future therapeutic agents.