Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

Abstract

Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer’s (AD) and Huntington’s diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.

The role of sigma-1 receptor in organization of endoplasmic reticulum signaling microdomains

“…Sigma 1 receptor (S1R) is a 223 amino acid-long single-pass transmembrane ER protein (Hayashi, 2019;D. A. Ryskamp, Korban, Zhemkov, Kraskovskaya, & Bezprozvanny, 2019;Schmidt & Kruse, 2019) that has a short cytoplasmic tail and a large luminal ligand binding domain (Mavylutov, Chen, Guo, & Yang, 2018;Schmidt et al, 2016).…”

Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function

“…Sigma-1 receptor (Sigmar1) is a widely expressed intraorganelle signaling modulator that interacts physically with client proteins to regulate cellular calcium homeostasis 23 , endoplasmic reticulum (ER) stress, cell survival 24 , and to regulate gene transcription 25 . Extensive Sigmar1 ligand-based studies indicate that activation (expression) of Sigmar1 confers neuroprotection in neurodegenerative diseases 26,27 . Interestingly, Sigmar1 has been found to be a direct target of METH as METH binds to Sigmar1 at physiological concentrations (K i value of~2 µM) 28 .…”

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

“…As mentioned above, σ 1Rs also found their place in the context of neurodegenerative disorders [ 90 ]. These receptors are mainly situated in the endoplasmic reticulum where they normally exert prosurvival and antiapoptotic effects, but they can be found in other organelles influencing lipid, protein, and ion trafficking [ 91 ]. Changes in the function or expression of this multifunctional protein have been linked to various diseases, including AD [ 92 ] and HD.…”