The role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases

Correspondence: Kenji Hashimoto Division of Clinical Neuroscience, Chiba University for Forensic Mental Health, Chiba 260-8670, Japan Tel +81 43 226 2149 Fax +81 43 226 2150 email [email protected] Abstract: The endoplasmic reticulum protein sigma-1 receptors, first regarded as opioid receptors and later confused as the phencyclidine (PCP) binding sites of the N-methyl-D-aspartate (NMDA) receptor, are now confirmed to be independent receptors. They are involved in the modulation of various neurotransmitter systems and have a high affinity for diverse classes of psychotropic drugs. Accumulating evidence suggests that the sigma-1 receptors are implicated in higher-ordered brain functions and play important roles in the pathophysiology of neuropsychiatric diseases such as schizophrenia, depression, anxiety disorders, and dementia. Recently, sigma-1 receptors have been shown to function at the molecular level as “receptor chaperones.” This mechanism may unify the explanation of the role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases. With the development of the positron emission tomography (PET) ligand [C]SA4503, it has become possible to visualize sigma-1 receptors and estimate the sigma-1 receptor occupancy of drugs in the human brain. This approach may provide additional information on the function of sigma-1 receptors. This article reviews the function of sigma-1 receptors and attempts to reinterpret their role in the pathophysiology of neuropsychiatric diseases based on their new description as “receptor chaperones.”