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Sigma-1 Receptor: Neuronal Functions, Disorders of the Nervous System, and Therapeutic Potential

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The sigma-1 receptor (σ1) is an enigmatic and still poorly characterized protein discovered in 1976 and originally mistaken for a subtype of opioid receptors. It was later discovered that σ1 is a 24-kDa chaperone protein that is enriched in intracellular organelles, and especially at the interface between ...

The sigma-1 receptor (σ1) is an enigmatic and still poorly characterized protein discovered in 1976 and originally mistaken for a subtype of opioid receptors. It was later discovered that σ1 is a 24-kDa chaperone protein that is enriched in intracellular organelles, and especially at the interface between the endoplasmic reticulum (ER) and the mitochondrion (mitochondrion-associated ER membrane [MAM]). There, it regulates ER-mitochondrial inter-organelle Ca2+ signaling and cell survival. σ1 was cloned in 1996 and crystallized in 2016; and its 223 amino acid sequence does not resemble that of any other mammalian proteins. So far, no other members have been found in this class of protein except for a short variant of the σ1 that is expressed in the mitochondria.

Unique to this chaperone protein, the activity of σ1 is regulated by endogenous and synthetic compounds in a clear agonist-antagonist manner. Upon ligand activation, σ1 dissociates from the Binding Immunoglobulin Protein (BiP), another ER chaperone protein, and translocates from the MAM to other subcellular compartments, including the ER and the nucleus, where it exerts several distinct functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription. However, its most intriguing feature is the ability to regulate a variety of functional proteins either directly via protein-protein associations or indirectly through G protein-dependent, as well as protein kinase C (PKC)-dependent and protein kinase A (PKA)-dependent signaling pathways. In particular, σ1 regulates membrane transporter proteins, G-protein coupled receptors (GPCRs), and the trafficking and functions of voltage-gated ion channels (VGICs) and NMDAR glutamate receptors to the plasma membrane. While this diversity of client proteins makes σ1 difficult to study, it endows σ1 with a powerful capability to regulate several survival and metabolic functions, fine tune neuronal excitability, and regulate the transmission of information within brain circuits. This versatility may also explain why σ1 is associated to numerous chronic diseases.

Thus, this Research Topic will discuss the current state of knowledge on the role of σ1 in the regulation of neuronal activity, how dysregulation of σ1’s activity by internal or external stimuli lead to cellular pathology, and thereby leading to chronic diseases of the nervous system, including Alzheimer’s’ disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, neuropathic pain, cancer, and drug addiction. As such, this Research Topic will also discuss therapeutic potential of σ1 ligands.


Keywords: Sigma-1 receptor, chaperone protein, neuronal excitability, synaptic transmission, psychiatric disorders


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