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.
Highlights
Sigma-1 receptor (S1R) is a ligand-operated protein that modulates activity of several client proteins from its position within the membrane of the endoplasmic reticulum (ER)
Autosomal recessive loss-of-function mutations in S1R are primarily associated with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) (Luty et al, 2010; Al-Saif et al, 2011; Kim et al, 2014; Li et al, 2015; Ullah et al, 2015; Gregianin et al, 2016; Horga et al, 2016; Watanabe et al, 2016), but polymorphisms in S1R affect risk of developing Alzheimer’s disease (AD) (Uchida et al, 2005; Maruszak et al, 2007; Huang et al, 2011; Fehér et al, 2012)
The CAG expansion compromises normal functions of Htt and disrupts cellular functioning through gain of mutant Huntingtin (mHtt) function mechanisms (Imarisio et al, 2008; Kim et al, 2009), with possible toxic contributions from repeat-associated nonAUG translation (Banez-Coronel et al, 2015). This results in oxidative damage, glial reactivity, altered intracellular signaling, metabolism and energy levels, impaired axonal transport, transcriptional dysregulation, aberrant calcium regulation associated with ER stress, synapse loss and excitotoxicity (Zhai et al, 2005; Mochel and Haller, 2011; Leitman et al, 2013; Ryskamp et al, 2017)
Summary
Sigma-1 receptor (S1R) is a ligand-operated protein that modulates activity of several client proteins from its position within the membrane of the endoplasmic reticulum (ER). S1R expression and activity regulates the cardiac Kv channel hERG through control of maturation and trafficking (Crottes et al, 2011) and this function appears to be dependent on cholesterol and not S1R ligands, possibly suggesting a role for lipid rafts in S1R client protein assembly and trafficking (Balasuriya et al, 2014).
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