Sigma Receptor Redux

First described in the 1960s as types of opioid receptors based on in vivo studies, sigma receptors are not opioid receptors at all.  The two subtypes, SR-1 and SR-2, were cloned in 1996 and 2017, respectively; the crystal structures were published in 2016 and 2021, respectively.  In humans, SR-1 is more characterized than is SR-2.  It is not a receptor in the conventional sense; rather, it is a chaperone protein.  But unlike most other chaperones, it is responsive to agonist or antagonist activity of endogenous or synthetic ligands, making it a special type of receptor, and target for standard drug discovery.  Functionally, SRs are versatile – they are involved in multiple physiological processes, including lipid metabolism, lipid transport, gene transcription, modulation of voltage-gated ion channels (Na⁺, K⁺, and Ca²⁺), regulation of ion channels, intracellular calcium homeostasis, control of oxidative stress, and the regulation of cellular electrical activity, as well as others.  

Purpose/Objectives:

The objective of this presentation is to present the results of a literature and internet search of the history and development of the concepts related to the erstwhile, and still, enigmatic sigma ‘receptors’.  The purpose was the creation of a short summary and narrative review of the current understanding of sigma receptors and how the evolving elucidation of these protein chaperone-receptors may offer important pharmacotherapeutic targets for drug discovery and development.  

Method: PubMed and Google Scholar were searched using the keywords “sigma receptor”, “sigma-1 receptor”, and “sigma-2 receptor” for publications in the English language related to the development of the concept of chaperone activity.  The references therein of some of the articles were also searched for additional relevant publications. The goal was to create the basis for a succinct summary and narrative review of the complex and rapidly evolving topic of ligand-sensitive chaperones-receptors.

Results:

A chaperone protein guides other proteins during their synthesis, folding, translocation and/or function.  Nascent proteins enter the endoplasmic reticulum (ER) as linear peptide chains via translocons (complex aqueous pores). In the ER, proteins are folded into the proper three-dimensional configuration, then transported to their final destination. Post-translational modification can occur. Chaperone proteins such as sigma receptors assist with the fidelity of these processes.  Chaperones also have a quality-control function, searching out misfolded polypeptide chains, so that they can be removed.  Such an accumulation of misfolded proteins has been implicated in the pathogenesis of cancer, neurodegenerative diseases, diabetes, and other conditions.

Conclusions: Sigma-1 and sigma-2 receptors were once thought to be opioid receptor subtypes, a notion no longer supported. Today, they are understood to be protein chaperones that can be modulated by selective ligands (agonists and antagonists). These unique receptor-chaperones are not fully
understood, but as the basic science becomes elucidated, a wide range of potential therapeutic applications from cancer to Alzheimer’s disease have emerged. SR-1 and SR-2 agonists and antagonists – selective or cojoined with other pharmacologic activity – are being developed,
and the results have been promising, suggesting new therapeutic alternatives paralleling the elucidation of previously enigmatic pathophysiological processes. These successes encourage further research and drug development efforts, as these agents may offer new breakthrough treatments for a range of diseases. There are scarcely any topics in medicine for which sigma receptors are not at least potentially of interest. Additional research is needed for the full potential to emerge. Importantly, education is needed that this is a new type of receptor – a ligand-sensitive chaperone-receptor.

References: 1. Pergolizzi et al. (2023) Cureus 15(3): e35756
2. Scmidt et al. (2019) Trends Pharmacol Sci 40:636-54