The Molecular Function of σ Receptors: Past, Present, and Future

Abstract

The σ₁ and σ₂ receptors are enigmatic proteins that have attracted attention for decades due to the chemical diversity and therapeutic potential of their ligands. However, despite ongoing clinical trials with σ receptor ligands for multiple conditions, relatively little is known regarding the molecular function of these receptors. In this review, we revisit past research on σ receptors and discuss the interpretation of these data in light of recent developments. We provide a synthesis of emerging structural and genetic data on the σ₁ receptor and discuss the recent cloning of the σ₂ receptor. Finally, we discuss the major questions that remain in the study of σ receptors.

Keywords: molecular pharmacology; structural pharmacology; σ(1) receptor; σ(2) receptor/TMEM97.

Figure 1:. Representative σ receptor ligands and the central pharmacophore.

A depiction of some high-affinity σ receptor ligands, as well as the central σ₁ receptor pharmacophore. Adapted from Glennon et al., 2005 [19].

Figure 2:. A summary of the chaperone model for σ₁ receptor function.

The σ₁ receptor has been proposed to act as a ligand-regulated chaperone to modulate multiple signaling pathways. Based on the text from Weng et al. [5]. Interaction partners are taken from the references in Table 1, and the localization of each partner was based on both the references in Table 1 and the Uniprot localization annotations for those proteins.

Figure 3:. The structure of the σ₁ receptor.

(A) the σ₁ receptor’s amino acid sequence annotated by secondary structure, with α helices in blue and β sheets in orange. Histidine 116 is in red. (B) the structure of the human σ₁ receptor (PDB ID: 5HK1). Each σ₁ monomer is colored separately, and the membrane is represented by gray shading. The ligand PD 144418 is depicted in grey spheres. (C), (D), a σ₁ receptor monomer, with amino acids 1–116 colored in orange (C) or hidden completely (D), to show parts of the protein that would remain if these residues were deleted. (E) a view of the ligand binding pocket (PDB ID: 5HK1). The red dashed line shows electrostatic interaction between the Glu172 and the basic nitrogen in the ligand. (F) Overlays of the structures of the σ₁ receptor bound to the antagonist PD 144418 (PDB ID: 5HK1, blue) and the agonist (+)-pentazocine (PDB ID: 6DK1, orange). The red arrow shows the shift in helix α4 between the two structures. Waters unique to the (+)-pentazocine bound structure are depicted as red spheres. (G) The same overlay as in (F), but only helix α4 is colored and the rest of the receptor is shown in gray. Red arrows indicate the direction of the α4 shift induced by (+)-pentazocine.

Figure 4:. Structural locations of σ₁ receptor disease mutations.

The crystal structure of the σ₁ receptor with amino acids L65, E102, E138, and E150 of chain A shown in orange, while the rest of chain A is shown in grey. Chains B and C are shown in blue and green, respectively. Dashed red lines represent hydrogen bonds. PD 144418 is shown in cyan. Waters are depicted as red spheres. (A), L65 is located on helix α4 and is surrounded by hydrophobic amino acids. Mutation to Q would likely be energetically unfavorable. (B), E102 makes two hydrogen bonds with backbone amide nitrogen atoms. Mutation to Q would replace one of these attractive bonds with a repulsive interaction, presumably destabilizing the protein. (C), E138 coordinates a complex network of water molecules and amino acids at the oligomeric interface. Mutation to Q would disrupt this network. (D), E150 makes a hydrogen bond with a backbone amide nitrogen to stabilize the β hairpin at the base of the ligand binding pocket’s “lid”. Mutation to K would prevent this interaction.