Knocking Out Sigma-1 Receptors Reveals Diverse Health Problems

Couly, Simon; Goguadze, Nino; Yasui, Yuko; Kimura, Yukitaka; Wang, Shao-Ming; Sharikadze, Nino; Wu, Hsiang‐En; Su, Tsung‐Ping

doi:10.1007/s10571-020-00983-3

Cited by 33 publications

(36 citation statements)

References 140 publications

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“…Increased local cholesterol concentration and membrane thickness can modulate activity of ER proteins recruited to these microdomains. Our hypothesis may explain how a small protein such as S1R is able to modulate activity of almost a hundred effector proteins ( Couly et al, 2020 ; Delprat et al, 2020 ; Kourrich et al, 2012 ; Ryskamp et al, 2019 ; Schmidt and Kruse, 2019 ). We reason that activity of these proteins could be affected by changes in local lipid microenvironment and not only via protein-protein interactions with the S1R.…”

Section: Discussionmentioning

confidence: 93%

“…S1R modulates many physiological processes, such as cell excitability, transcriptional activity, Ca 2+ homeostasis, stress response, and autophagy ( Christ et al, 2019 ; Couly et al, 2020 ; Hayashi, 2019 ; Kourrich, 2017 ; Maurice and Goguadze, 2017 ; Ryskamp et al, 2019 ). However, S1R-mediated signal transduction differs from a canonical second messenger-coupled transmembrane receptor signaling, and S1R is often referred to as a ‘ligand-gated molecular chaperone’ ( Hayashi, 2019 ; Nguyen et al, 2017 ; Su et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…S1R is highly enriched in the liver and expressed in the nervous system. Analysis of S1R knockout (KO) mice revealed a number of nervous system abnormalities ( Couly et al, 2020 ), suggesting that S1R plays an important role in neurons. In humans, mutations in S1R lead to a juvenile form of amyotrophic lateral sclerosis (ALS) ( Al-Saif et al, 2011 ) and distal hereditary motor neuropathies (dHMNs) ( Almendra et al, 2018 ; Gregianin et al, 2016 ; Horga et al, 2016 ; Li et al, 2015 ; Ververis et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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

Zhemkov

Ditlev

Lee

et al. 2021

eLife

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Sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins and is a well-established drug target. However, signaling functions of S1R in cells are poorly understood. Here, we test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER membrane. By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness and that increased local cholesterol concentration and/or membrane thickness in these microdomains can modulate signaling of inositol-requiring enzyme 1α in the ER. Further, S1R agonists cause disruption of S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains. Our results provide novel insights into S1R-mediated signaling mechanisms in cells.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhemkov

Ditlev

Lee

et al. 2021

eLife

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“…The most-reported neurological dysfunction in Sigmar1 null mice were locomotor defects [26], signi cant nerve denervation [25], loss of motor neurons [25], age-dependent motor phenotype [27], and showed a depressive-like behavior [24,28]. Additionally, the lack of Sigmar1 in the liver showed increased oxidative and metabolic stress with increased anaerobic metabolism [45,46]. Extensive studies on cardiac muscles of Sigmar1 null mice showed mitochondrial dysfunction, abnormal mitochondrial architecture, adverse cardiac pathological remodeling, and development of cardiac contractile dysfunction [47].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle fiber-type switching, myopathy, and exercise intolerance in Sigmar1 null mice

Aishwarya¹,

Abdullah²,

Remex³

et al. 2021

Preprint

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Sigmar1 is a widely expressed, multitasking molecular chaperone protein playing functional roles in several cellular processes. Mutations in the Sigmar1 gene have been reported to associate with several motor neuropathies, including amyotrophic lateral sclerosis, distal hereditary motor neuropathy, silver-like syndrome, and frontotemporal lobar degeneration. All these human mutations associated with motor neuropathies show strong manifestation in skeletal muscle with phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle remains unexplored. Here, we determined the physiological role of Sigmar1 in skeletal muscle structure and function in five different skeletal muscles: gastrocnemius (Gastro), quadriceps (Quad), soleus (Sol), extensor digitorum longus (EDL), and tibialis anterior (TA). Quantification of myofiber cross-sectional area (CSA) showed altered muscle mass and a slow-to-fast fiber-type switch in the skeletal muscle fibers of the Sigmar1−/− mice. Interestingly, ultrastructural analysis by transmission electron microscopy showed the presence of tubular aggregates in the type I myofibers (Gastro, Quad, and TA) of Sigmar1−/− mice. Immunostaining also showed derangements in dystrophin localization in skeletal muscles from Sigmar1−/− mice. Additionally, skeletal muscle myopathy in Sigmar1−/− mice was associated with an increased number of central nuclei, increased collagen deposition, and fibrosis. Functional studies also showed reduced endurance and exercise capacity in the Sigmar1−/− mice. Overall, our studies demonstrated, for the first time, a potential physiological function of Sigmar1 in the skeletal muscle in maintaining healthy muscle structure and function.

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“…Since the discovery of Sigmar1, most studies have focused on elucidating the role of Sigmar1 under physiological and pathological conditions in the brain. Studies have demonstrated that the absence of Sigmar1 in Sigmar1 –/– mice affected a wide range of brain functions ( Couly et al, 2020a ), including regulation of cognition and memory ( Chevallier et al, 2011 ), motor activity ( Bernard-Marissal et al, 2015 ), psychiatry-related behaviors ( Chevallier et al, 2011 ; Di et al, 2017 ), sensory system and pain ( Cendan et al, 2005 ). However, studies carried out to demonstrate the role of Sigmar1 in memory regulation using the Sigmar1 null mice resulted in inconsistent data.…”

Section: Physiological and Pathological Role Of Sigmar1mentioning

confidence: 99%

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

et al. 2021

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The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1’s subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1’s molecular, cellular, pathophysiological, and biological functions.

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Knocking Out Sigma-1 Receptors Reveals Diverse Health Problems

Cited by 33 publications

References 140 publications

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

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

Skeletal muscle fiber-type switching, myopathy, and exercise intolerance in Sigmar1 null mice

Sigmar1’s Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

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