Identification of the gene that codes for the σ ₂ receptor

Abstract

The σ receptor is an enigmatic protein that has attracted significant attention because of its involvement in diseases as diverse as cancer and neurological disorders. Unlike virtually all other receptors of medical interest, it has eluded molecular cloning since its discovery, and the gene that codes for the receptor remains unknown, precluding the use of modern biological methods to study its function. Using a chemical biology approach, we purified the σ receptor from tissue, revealing its identity as TMEM97, an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter NPC1. We show that TMEM97 possesses the full suite of molecular properties that define the σ receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the σ receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target.

Structure–Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma

“…Recently, the progesterone receptor membrane component 1 (PGRMC1) has been proposed as the σ 2 R binding site, although this was questioned by other evidence supporting that the two targets are two different proteins . More recently TMEM97, an endoplasmic reticulum (ER)‐resident membrane protein, was shown to possess the full suite of molecular properties that define the σ 2 R …”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…These experiments led to identifying σ2R as being transmembrane protein 97 (TMEM97). 227 Notably, cloning σ2R resolves a longstanding mystery that will greatly facilitate biological studies to discover the molecular mechanisms that are associated with small molecule modulation of σ2R/TMEM97.…”

Structure–Affinity Relationships of Fluorinated Spirocyclic σ2 Receptor Ligands with an Exocyclic Benzylamino Moiety

“…Its structure shows four transmembrane helices with both the C and N termini located on the cytosolic side. Mutagenesis experiments revealed the importance of Asp29 and Asp56 for the binding of basic σ 2 receptor ligands …”