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Sigma receptors were discovered by Martin et al. 1976 and were first classified as a subtype of opioid receptors. Later the availability of newer and more selective ligands established sigma receptors as distinct from opiate receptors or the phencyclidine (PCP) binding site. Based on the specific pharmacological characteristics of the sigma ligands, sigma receptors were further divided into two subtypes denoted sigma-1 and sigma-2. The sigma receptors and its agonists have been implicated in many cellular functions, biological processes and diseases. Although the exact molecular functions of sigma receptors are not fully defined and the endogenous ligand(s) still not known, there is evidence for a role of sigma receptors in regulation of neurotransmitter release, modulation of neurotransmitter receptor function, endocrine and immune system functions or apoptosis and, therefore, in movement and posture, in psychosis, in learning and memory or in cancer.
Sigma Receptors’ Interactions with Ion Channels
The most prominent action of sigma receptors in biological systems including cell
lines, primary cultures, and animals is the regulation and modulation of voltage-regulated
and ligand-gated ion channels, including Ca2+-, K+-, Na+,
Cl-, and SK channels, and NMDA and IP3 receptors. The final output of
the action of sigma receptor agonists is to inhibit all above-mentioned voltage-gated
ion channels, while they potentiate ligand-gated channels.
Originally considered an enigmatic protein, the sigma-1 receptor has recently been
identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum
of cells. This discovery causes to look back at the many proposed roles of this
receptor, even before its molecular function was identified, in many
neurological diseases such as
Alzheimer's disease, amnesia, pain, depression, schizophrenia, and retinal
The Role of Sigma-1 and Sigma-2 Receptors in Cancer
The discovery of the presence of sigma-1 and sigma-2 receptors in many human and
rodent cell lines opens up this new area of cancer
research, which is the most attractive for sigma-2 receptors. The most prominent
fact is the involvement of these receptors in the death signalling of cancer cells.
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