Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis

Abstract

Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.

Keywords: cancer; cytochrome P450; ferrochelatase; ferroptosis; heme chaperone; hemochromatosis; hepcidin; labile iron pool; progesterone receptor membrane components; sigma receptors.

Figure 1

(A) Amino acid sequence and structure of human S1R. The predicted transmembrane domains (shaded in yellow), α-helices (indicated in red below the amino acid sequence), and β-strands (indicated in green below the amino acid sequence) according to the analysis of the amino acid sequence of human S1R [23]. (B) The homotrimeric structure of human S1R (PDB: 5HK1), each monomer with a membrane-spanning transmembrane domain at the N-terminus, and a second predicted transmembrane domain at the C-terminus on the membrane interface with the cytosolic side.

Figure 2

(A) Amino acid sequence and structure of human S2R. The predicted transmembrane domains (shaded in yellow) and β-strands (indicated in green below the amino acid sequence) according to the analysis of the amino acid sequence of human S2R using the POLYVIEW program [65]. (B) The AlphaFold model of human S2R is a monomer, but this structure was superimposed onto the recently described homodimeric structure of bovine S2R to generate the model for human S2R.

Figure 3

Amino acid sequence and structure for PGRMC1 and PGRMC2. (A) Transmembrane and secondary structure prediction of PGRMC1 and PGRMC2. The region highlighted in yellow in each protein represents the membrane-spanning transmembrane domain. Predicted α-helices are identified in red below the amino acid sequence, and β-strands are identified in green below the amino acid sequence. The POLYVIEW program [65] was used for these predictions. (B) Robetta model for PGRMC1 homodimer based on the crystal structure (PDB: 4X8Y). The heme ligand bound to each monomer is shown in yellow. (C) Robetta model for PGRMC2 monomer. Membrane boundaries were predicted with OPM (Orientations of Proteins in Membranes) server [67].