Sigma receptors

Sigma receptors (σ1R and σ2R) are widely distributed in the central and peripheral nervous system and in peripheral organs (Quirion et al., 1992).

Sigma receptors are mainly located intracellularly in the membranes of mitochondria-associated endoplasmic reticulum (ER), but can translocate along the ER network to nuclear envelope and plasma membrane (Banister et al., 2012). High densities of both σ1- and σ2-receptors have been found in many human tumour cell lines.

Sigma receptors are implicated in the pathophysiology of many CNS disorders, including affective disorders, psychosis, schizophrenia, drug addiction, and Parkinson’s disease. Therefore several σ receptor ligands for drug use and radioligands for PET imaging have been developed (Banister et al., 2012). In the brain the density of σ1Rs is higher than that of σ2Rs, and therefore σ1R radioligands are mainly developed for brain imaging, and σ2R radioligands for oncological imaging applications, including brain tumours (Banister et al., 2012; van Waarde et al., 2015). Many steroid hormones, including testosterone and progesterone, and opioids can bind to sigma receptors. These, and sphingolipid-derived amines may be some of the endogenous ligands of sigma receptors.

Sigma-1 receptor

Sigma-1 receptor is an integral protein consisting of 223 amino acids. In the mitochondria-associated ER σ1Rs act as chaperones for type 3 inositol-1,4,5-triphosphate receptors (IP3Rs), regulating ER-mitochondria Ca2+ signalling, and in the cell membrane can modulate the function of membrane-bound Ca2+, K+, and Cl- channels. Choline is an endogenous activator of σ1 receptors, potentiating the Ca2+-releasing actions of IP3R (Brailoiu et al., 2019). In the CNS, σ1Rs modulate the function of cholinergic, dopaminergic, glutamatergic, and serotonergic systems (Banister et al., 2012).

For PET imaging of σ1Rs, [11C]SA4503 (Toyohara et al., 2012) and [18F]FTC-146 (Shen et al., 2015) are promising radioligands.

[11C]Donepezil is a reversible antagonist radioligand of AChE, which also binds to σ1-receptors with comparable affinity to that of AChE (Horsager et al., 2019).

Sigma-2 receptor

Sigma-1 receptor is an integral protein, slightly smaller than σ1R. The gene TMEM97 that codes σ2R is involved in cholesterol homeostasis. The σ2Rs have been implicated in apoptotic and non-apoptotic cell death. Tumour cells overexpress σ2Rs, suggesting a role in cell proliferation or survival. Sigma-2 receptor expression is higher in malignant than dormant tumours. Normally, σ1R densities are high in the lungs, liver, and kidneys. In the brain the highest densities are found in the cerebellum, motor cortex, hippocampus, and substantia nigra.

Synthesized σ2R agonists and antagonists are internalized by endocytosis after binding to receptor on the cell membranes. Agonists can inhibit tumour cell proliferation and induce apoptosis.

For PET imaging of σ2Rs, [18F]ISO-1 (Dehdashti et al., 2013; Shoghi et al., 2013) and [18F]RHM-4 (Tu et al., 2010) are promising radioligands.

See also:


Smith SB, Su T-P (eds.): Sigma Receptors: Their Role in Disease and as Therapeutic Targets. Springer, 2017. doi: 10.1007/978-3-319-50174-1.

Tesei A, Cortesi M, Zamagni A, Arienti C, Pignatta S, Zanoni M, Paolillo M, Curti D, Rui M, Rossi D, Collina S. Sigma receptors as endoplasmic reticulum stress “gatekeepers” and their modulators as emerging new weapons in the fight against cancer. Front Pharmacol. 2018; 9:711. doi: 10.3389/fphar.2018.00711.

van Waarde A, Rybczynska AA, Ramakrishnan NK, Ishiwata K, Elsinga PH, Dierckx RAJO. Potential applications for sigma receptor ligands in cancer diagnosis and therapy. Biochim Biphys Acta 2015; 1848: 2703-2714. doi: 10.1016/j.bbamem.2014.08.022.

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Updated at: 2019-04-30
Created at: 2019-04-30
Written by: Vesa Oikonen