Sigma receptors were first identified as a subtype of opioid receptors. The different members of the family are differentially distributed in various parts of the CNS and are responsible for a vast range of functions and behaviors¹. Today, sigma receptors are mostly considered to be a separate receptor family with two main subtypes characterized.

The sigma-1 receptor is encoded by a gene baring the same name and is a protein of 223 amino acids with two transmembrane domains and a typical endoplasmic reticulum localized signal near its short N terminus. Sigma receptors are mostly detected in the central nervous system with a high density in the spinal cord, pons, medulla oblongata, red nucleus, cerebellum and hippocampus.

Sigma-1 is mainly localized on the mitochondrial associated endoplasmic reticulum membrane (MAM), forming a BiP chaperone structure with high sensitivity to the calcium ion. When activated by agonists such as cocaine or analgesics, sigma-1 receptors separate from BiP and translocate from MAM to other parts of the cell. Through regulation of inositol triphosphate (IP₃) receptors, NMDA receptors, dopamine receptors and voltage-gated Ca²⁺ channels, sigma-1 receptors can influence TCA cycle, oxidative stress, mitochondrial function, neuron plasticity and the release of various neurotransmitters.

The exact etiology and pathophysiology of Alzheimer’s disease is not fully understood. A few hypotheses suggest the involvement of Sigma-1 in the progression of Alzheimer’s disease. The suggested mechanisms include protection from Aβ toxicity, prevention of Tau protein hyperphosphorylation and the upregulation of acetylcholine release².