Identification of the gene that codes for the σ2 receptor

Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7160-7165. doi: 10.1073/pnas.1705154114. Epub 2017 May 30.


The σ2 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 σ2 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 σ2 receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the σ2 receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target.

Keywords: NPC1; TMEM97; cholesterol regulation; sigma receptors; sigma-2 receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Aspartic Acid / chemistry
  • Carrier Proteins / metabolism
  • Cattle
  • Cholesterol / chemistry
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Regulation*
  • Humans
  • Insecta
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Liver / metabolism
  • MCF-7 Cells
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Niemann-Pick C1 Protein
  • PC12 Cells
  • Protein Binding
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, sigma / genetics*
  • Receptors, sigma / metabolism
  • Recombinant Proteins / metabolism
  • Schizophrenia / metabolism


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • RNA, Small Interfering
  • Receptors, sigma
  • Recombinant Proteins
  • TMEM97 protein, human
  • Aspartic Acid
  • Cholesterol