Structural Perspectives on Sigma-1 Receptor Function

Alon, Assaf; Schmidt, Hayden R.; Zheng, Sanduo; Kruse, Andrew C.

doi:10.1007/978-3-319-50174-1_2

Cited by 16 publications

(13 citation statements)

References 41 publications

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“…This topology was consistent with evidence that BiP, an ER luminal chaperone protein, binds to the C-terminal domain of Sig-1R ( Hayashi and Su, 2007 ). However, a crystal structure of Sig-1R challenges these observations because it identified only a single TMD within each subunit of a trimeric complex, and it placed the C-terminal region on the cytosolic side of the ER membrane ( Alon et al., 2017 , Schmidt et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors

et al. 2019

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SummarySigma-1 receptors (Sig-1Rs) are integral ER membrane proteins. They bind diverse ligands, including psychoactive drugs, and regulate many signaling proteins, including the inositol 1,4,5-trisphosphate receptors (IP3Rs) that release Ca2+ from the ER. The endogenous ligands of Sig-1Rs are unknown. Phospholipase D (PLD) cleaves phosphatidylcholine to choline and phosphatidic acid (PA), with PA assumed to mediate all downstream signaling. We show that choline is also an intracellular messenger. Choline binds to Sig-1Rs, it mimics other Sig-1R agonists by potentiating Ca2+ signals evoked by IP3Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and PLD, deliver two signals to IP3Rs: IP3 activates IP3Rs, and choline potentiates their activity through Sig-1Rs. Choline is also produced at synapses by degradation of acetylcholine. Choline uptake by transporters activates Sig-1Rs and potentiates Ca2+ signals. We conclude that choline is an endogenous agonist of Sig-1Rs linking extracellular stimuli, and perhaps synaptic activity, to Ca2+ signals.

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Section: Introductionmentioning

confidence: 99%

Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors

et al. 2019

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“…TMEM97 is located in the ER and has the ability to regulate the sterol transporter Niemann-Pick disease, type C1 Protein (NPC1) (Alon et al., 2017b). In that study, the authors found that its pharmacologic profile is the same as that of Sigma-2 receptor; moreover, TMEM97 ligands bind Sigma-2 receptors (Alon et al., 2017a). A new study has also shown that Sigma-2 receptor/TMEM97 is involved in alcohol withdrawal behaviors, indicating that this receptor can be targeted to treat alcohol use disorder (Scott et al., 2018).…”

Section: The Introduction Of Sigma Receptorsmentioning

confidence: 90%

The Roles of Intracellular Chaperone Proteins, Sigma Receptors, in Parkinson’s Disease (PD) and Major Depressive Disorder (MDD)

2019

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Sigma receptors, including Sigma-1 receptors and Sigma-2 receptors, are highly expressed in the CNS. They are intracellular chaperone proteins. Sigma-1 receptors localize mainly at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM). Upon stimulation, they translocate from MAM to plasma membrane (PM) and nucleus, where they interact with many proteins and ion channels. Sigma-1 receptor could interact with itself to form oligomers, its oligomerization states affect its ability to interact with client proteins including ion channels and BiP. Sigma-1 receptor shows high affinity for many unrelated and structurally diverse ligands, but the mechanism for this diverse drug receptor interaction remains unknown. Sigma-1 receptors also directly bind many proteins including G protein-coupled receptors (GPCRs) and ion channels. In recent years, significant progress has been made in our understanding of roles of the Sigma-1 receptors in normal and pathological conditions, but more studies are still required for the Sigma-2 receptors. The physiological roles of Sigma-1 receptors in the CNS are discussed. They can modulate the activity of many ion channels including voltage-dependent ion channels including Ca 2+ , Na + , K + channels and NMDAR, thus affecting neuronal excitability and synaptic activity. They are also involved in synaptic plasticity and learning and memory. Moreover, the activation of Sigma receptors protects neurons from death via the modulation of ER stress, neuroinflammation, and Ca 2+ homeostasis. Evidences about the involvement of Sigma-1 receptors in Parkinson’s disease (PD) and Major Depressive Disorder (MDD) are also presented, indicating Sigma-1 receptors might be promising targets for pharmacologically treating PD and MDD.

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“…Sigma1R has a unique amino acid sequence and has no homology with known mammalian proteins [43,44]. In 2016 the crystal structure of a protein with one transmembrane domain for each monomer was determined under the general supervision of Andrew C. Kruse [45,46]. Sigma1R oligomerization affects the chaperone functional activity and depends on the interaction with ligands [41,[47][48][49][50].…”

Section: Structure and Functional Activity Of The Chaperone Sigma1rmentioning

confidence: 99%

Chaperone Sigma1R and Antidepressant Effect

Voronin

Vakhitova

Seredenin

2020

IJMS

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This review analyzes the current scientific literature on the role of the Sigma1R chaperone in the pathogenesis of depressive disorders and pharmacodynamics of antidepressants. As a result of ligand activation, Sigma1R is capable of intracellular translocation from the endoplasmic reticulum (ER) into the region of nuclear and cellular membranes, where it interacts with resident proteins. This unique property of Sigma1R provides regulation of various receptors, ion channels, enzymes, and transcriptional factors. The current review demonstrates the contribution of the Sigma1R chaperone to the regulation of molecular mechanisms involved in the antidepressant effect.

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Structural Perspectives on Sigma-1 Receptor Function

Cited by 16 publications

References 41 publications

Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors

Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors

The Roles of Intracellular Chaperone Proteins, Sigma Receptors, in Parkinson’s Disease (PD) and Major Depressive Disorder (MDD)

Chaperone Sigma1R and Antidepressant Effect

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