Affinage

SIGMAR1

Sigma non-opioid intracellular receptor 1 · UniProt Q99720

Length
223 aa
Mass
25.1 kDa
Annotated
2026-06-10
64 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIGMAR1 (sigma-1 receptor) is a type II integral ER membrane protein enriched at ER sheets that couples ER membrane architecture, lipid and protein homeostasis, and inter-organelle calcium signaling (PMID:41476177, PMID:38971154). Its oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing curvature and stabilizing rough ER sheets, with cellular SIGMAR1 levels setting the amount of rough ER sheets (PMID:38971154); a C-terminal β-barrel binds phosphatidylcholine, and this lipid binding strengthens association with the translocon components TRAPα and Nicalin, such that SIGMAR1 loss disrupts cellular protein and lipid homeostasis (PMID:41476177). At mitochondria-associated ER membranes (MAM), SIGMAR1 acts as a chaperone that binds and stabilizes IP3R3 to maintain ER–mitochondria contacts and calcium transfer; ALS-linked variants are unstable, fail to bind IP3R3, mislocalize from the MAM, and trigger calpain activation, impaired mitochondrial ATP production, and ER stress, driving motor neuron degeneration (PMID:27821430, PMID:25678561, PMID:27402882, PMID:25175561). SIGMAR1 promotes autophagy at several steps: it stabilizes LC3B and GABARAP mRNAs for localized ER-proximal translation (PMID:39369298), interacts with the fusion machinery ATG14, STX17, and VAMP8 to enable autophagosome–lysosome fusion (PMID:30871407), and chaperones the nucleoporin POM121 to support KPNB1-dependent nuclear import of TFEB (PMID:35507432). It also controls SIRT3-mediated, parkin-dependent mitophagy that limits endothelial ferroptosis (PMID:41655128). Beyond these core roles, SIGMAR1 regulates ion-channel signaling complexes (SK3/Orai1; hERG/β1-integrin/PI3K–AKT) (PMID:28114279, PMID:26645564), supports retinal and motor neuron survival through ERK1/2 MAPK signaling (PMID:26868747, PMID:21862648), promotes AMPAR trafficking via ubiquitin-dependent degradation of NPTX1 in nociceptive neurons (PMID:41457187), and suppresses vascular fibrosis through the TGF-β/Smad2/3 pathway (PMID:38851304). SIGMAR1 protein abundance is controlled by ubiquitin-dependent turnover, including STUB1-mediated ubiquitination (PMID:40567075) and SEL1L/HRD1-mediated ERAD at lysine 142 (PMID:38718507).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2011 Medium

    Established that sigma-1 receptor is required for survival of inner retinal neurons in vivo, moving the protein from a pharmacological binding site to a cell-survival factor.

    Evidence σR1 knockout mice analyzed by electroretinography, morphometry, TUNEL/caspase-3, and electron microscopy

    PMID:21862648

    Open questions at the time
    • Molecular pathway linking σR1 loss to neuronal death not defined here
    • Does not address whether the role is cell-autonomous in ganglion cells
  2. 2014 Medium

    Linked an ALS-associated SIGMAR1 variant to mitochondrial Ca2+ handling, showing that aberrant Ca2+ transport, not just protein aggregation, drives TDP-43 mislocalization.

    Evidence Overexpression of p.E102Q vs wild-type in Neuro2A, ATP/proteasome assays, TDP-43 imaging, Ru360 pharmacological mimicry

    PMID:25175561

    Open questions at the time
    • Overexpression system may not reflect endogenous stoichiometry
    • Direct molecular target of Ca2+ transport not identified in this study
  3. 2015 High

    Demonstrated that SIGMAR1 maintains ER–mitochondria contacts and mitochondrial dynamics in motor neurons, defining a contact-site mechanism for axonal degeneration.

    Evidence Primary motor neuron cultures, pharmacological/siRNA inactivation, Sigmar1-/- mice, mitochondrial and calcium live imaging, epistasis rescue

    PMID:25678561

    Open questions at the time
    • Molecular tether partner at the contact site not resolved in this work
    • Relative contribution of fission defect vs Ca2+ defect not fully separated
  4. 2016 High

    Identified IP3R3 as the SIGMAR1 client at the MAM and showed ALS variants fail to bind and stabilize it, unifying chaperone activity with the degenerative phenotype.

    Evidence Co-IP of Sig1R–IP3R3, Sig1R KO × SOD1 mutant mouse epistasis, immunofluorescence, fractionation; plus mutagenesis of p.E138Q/p.E150K with Ca2+ and viability readouts

    PMID:27402882 PMID:27821430

    Open questions at the time
    • Structural basis of IP3R3 binding not defined
    • Whether IP3R3 is the sole relevant MAM client unaddressed
  5. 2019 High

    Placed SIGMAR1 at the autophagosome–lysosome fusion step, distinguishing its role from autophagosome biogenesis.

    Evidence CRISPR Sigmar1 KO, reciprocal Co-IP with ATG14/STX17/VAMP8, GFP-RFP-LC3 flux assay, rescue

    PMID:30871407

    Open questions at the time
    • How an ER-resident protein engages the fusion SNARE complex spatially unclear
    • Direct vs indirect nature of SNARE interactions not dissected
  6. 2022 Medium

    Extended SIGMAR1's autophagy role to nuclear import of TFEB via POM121 chaperoning, connecting it to nucleocytoplasmic transport in C9orf72-ALS.

    Evidence Co-IP of SIGMAR1–POM121, nuclear fractionation, pridopidine agonism, LC3-II readouts in NSC34 C9orf72 HRE cells

    PMID:35507432

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Generality beyond C9orf72 context not established
  7. 2024 High

    Resolved the structural mechanism of SIGMAR1 as an ER-sheet morphogen, showing amphipathic-helix oligomers flatten the membrane lumenal leaflet.

    Evidence Proteomics, live imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on GUVs

    PMID:38971154

    Open questions at the time
    • Link between sheet-shaping and downstream homeostasis phenotypes not directly demonstrated
    • Regulation of oligomerization in vivo unknown
  8. 2024 High

    Defined SIGMAR1 as a translocon-associated, phosphatidylcholine-binding factor governing protein and lipid homeostasis at ER sheets.

    Evidence Endogenous tagging, fractionation, Co-IP with TRAPα/Nicalin, lipid-binding assays, knockout phenotype (hepatocyte lipid droplets)

    PMID:41476177

    Open questions at the time
    • Mechanistic link from PC binding to translocon function not fully traced
    • Substrate proteins affected at the translocon not enumerated
  9. 2024 Medium

    Added an RNA-level function: SIGMAR1 stabilizes Atg8-family mRNAs for ER-proximal localized translation, coupling autophagy to membrane biology.

    Evidence smFISH, Co-IP of SIGMAR1 with LC3B mRNA (3'UTR), KO cells, mRNA stability and lipidation assays

    PMID:39369298

    Open questions at the time
    • Direct vs indirect mRNA binding mechanism for an ER membrane protein unclear
    • Breadth of mRNA targets beyond LC3B/GABARAP not mapped
  10. 2024 Medium

    Identified SEL1L/HRD1 ERAD as a regulator of SIGMAR1 abundance via K142 ubiquitination, linking SIGMAR1 turnover to Ca2+ homeostasis and senescence.

    Evidence Neuron cultures, mouse model, site-specific (K142) ubiquitination assay, Co-IP of SEL1L/HRD1–SigmaR1, senescence markers

    PMID:38718507

    Open questions at the time
    • Physiological triggers of SIGMAR1 ERAD beyond CdCl2 unknown
    • Single lab
  11. 2025 Medium

    Defined a second degradation route (STUB1) and a substrate-level signaling output (NPTX1 ubiquitination driving AMPAR trafficking).

    Evidence Co-IP/ubiquitination of STUB1–Sigmar1 with ER-stress epistasis in cardiomyocytes; HPLC-MS/MS, Co-IP, m6A MeRIP, intrathecal manipulation, AMPAR trafficking assay for NPTX1

    PMID:40567075 PMID:41457187

    Open questions at the time
    • Whether STUB1 and SEL1L/HRD1 act on overlapping pools of SIGMAR1 unknown
    • Both single-lab studies
  12. 2026 Medium

    Connected SIGMAR1 to a mitophagy program (SIRT3/ATP5F1A K498 deacetylation, parkin-dependent) that restrains ferroptosis, broadening its mitochondrial quality-control role.

    Evidence Sigmar1 KO mice, PRE-084 agonism, SIRT3 modulation, ATP5F1A acetylation assay, GFP-LC3 mitophagy readouts in pulmonary microvascular endothelial cells

    PMID:41655128

    Open questions at the time
    • Mechanism by which SIGMAR1 controls SIRT3 activity not defined
    • Single lab and disease-model specific

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIGMAR1's structural ER-sheet/translocon role mechanistically gives rise to its diverse downstream activities (MAM Ca2+ chaperone, autophagy regulator, ion-channel modulator) remains unresolved.
  • No unified model linking membrane-shaping to chaperone and signaling outputs
  • Endogenous ligand and conformational regulation not established in the corpus
  • Direct structural data on client/partner complexes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0098772 molecular function regulator activity 2 GO:0003723 RNA binding 1 GO:0008289 lipid binding 1
Localization
GO:0005635 nuclear envelope 3 GO:0005783 endoplasmic reticulum 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 1 R-HSA-8953854 Metabolism of RNA 1
Partners
ATG14IP3R3NPTX1POM121STUB1STX17TRAPALPHAVAMP8

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 SigmaR1 is a type II integral ER membrane protein specifically enriched at ER sheets. A short N-terminal region promotes its ER-sheet localization. SigmaR1 directly interacts with components of the translocon complex including TRAPα and Nicalin. A β-barrel at the C-terminus of SigmaR1 binds phosphatidylcholine (PC), and PC binding strengthens the association of SigmaR1 with the translocon complex. SigmaR1 knockout systematically impaired cellular protein and lipid homeostasis, resulting in accumulation of lipid droplets in hepatocytes. Endogenous tagging, cell fractionation, Co-IP, biochemical interaction studies, lipid-binding assays, knockout cells Nature communications High 41476177
2024 SigmaR1 oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing membrane curvature and stabilizing rough ER sheets. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles supported this mechanism. SigmaR1 levels determine the amount of rough ER sheets in cells. Proteomics screen, high-resolution live cell imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on giant unilamellar vesicles Developmental cell High 38971154
2016 ALS-linked SIGMAR1 variants (including p.L95fs) are unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP3R3). Loss of Sig1R function causes mislocalization of IP3R3 from the mitochondria-associated membrane (MAM), calpain activation, and mitochondrial dysfunction. Sig1R deficiency accelerated disease onset in mutant SOD1 ALS mice, indicating MAM collapse is a shared pathomechanism. Co-IP (Sig1R–IP3R3 interaction), mouse genetic model (Sig1R KO × SOD1 mutant), immunofluorescence, biochemical fractionation EMBO molecular medicine High 27821430
2015 Pharmacological or genetic inactivation of SIGMAR1 in motor neurons disrupts ER–mitochondria contacts, impairs intracellular calcium signaling, activates ER stress, and causes defects in mitochondrial dynamics and axonal transport, leading to axonal degeneration and cell death. Inhibition of mitochondrial fission alone recapitulated axonal transport defects and degeneration. Intracellular calcium scavenging and ER stress inhibition restored mitochondrial function and prevented motor neuron degeneration. Primary motor neuron cultures, pharmacological inhibition, siRNA knockdown, Sigmar1−/− mice, live imaging of mitochondrial dynamics, calcium imaging, epistasis experiments Brain : a journal of neurology High 25678561
2019 SIGMAR1 knockout impairs autophagosome–lysosome fusion without affecting autophagosome biogenesis markers (BECN1, ATG7) or lysosomal pH/protease activity. SIGMAR1 co-immunoprecipitates with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome–lysosome membrane fusion. Re-expressing SIGMAR1 in null background rescued clearance of mitochondria and autophagosomes. Sigmar1 knockout (CRISPR), Co-IP (SIGMAR1 with ATG14/STX17/VAMP8), GFP-RFP-LC3 fusion assay, lysosome colocalization, rescue experiments Autophagy High 30871407
2022 SIGMAR1 facilitates TFEB transport into the nucleus by chaperoning the nuclear pore protein POM121, which recruits importin-β1 (KPNB1). In C9orf72-ALS cells, hexanucleotide repeat expansion reduces SIGMAR1–POM121 association, lowering nuclear TFEB, KPNB1, and LC3-II. SIGMAR1 overexpression or agonist treatment (pridopidine) rescued these deficits. Co-IP (SIGMAR1–POM121), overexpression, pharmacological agonism with pridopidine, nuclear fractionation, LC3-II western blot in NSC34 cells with C9orf72 HRE Autophagy Medium 35507432
2024 SIGMAR1 stabilizes MAP1LC3B/LC3B and GABARAP mRNAs, promoting their localized translation proximal to the ER for efficient lipidation and autophagosome formation. SIGMAR1 directly binds a conserved region in the 3' UTR of LC3B mRNA. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux. smFISH, Co-IP (SIGMAR1–LC3B mRNA), SIGMAR1 knockout cells, mRNA stability assays, lipidation assays Autophagy Medium 39369298
2016 Two novel SIGMAR1 mutations (p.E138Q and p.E150K) reduce cell viability, cause formation of abnormal protein aggregates, prevent correct targeting of sigma-1R to the MAM, and impair global Ca2+ signaling and ER–mitochondria tethering in neuronal cell lines, demonstrating the chaperone activity of sigma-1R at the MAM as critical for motor neuron survival. Site-directed mutagenesis, cell viability assays, immunofluorescence for MAM localization, Ca2+ imaging, ER–mitochondria contact quantification in neuronal cell lines Human molecular genetics Medium 27402882
2014 The ALS-linked SIGMAR1 variant p.E102Q promotes dissociation of sigma-1R from the ER membrane and cytoplasmic aggregation, impairs mitochondrial ATP production and proteasome activity, and causes aberrant extra-nuclear localization of TDP-43. Treatment with the mitochondrial Ca2+ transporter inhibitor Ru360 mimicked these effects, indicating that aberrant sigma-1R-mediated mitochondrial Ca2+ transport underlies TDP-43 mislocalization. Neuro2A overexpression of mutant vs. wild-type sigma-1R, mitochondrial function assays (ATP production), proteasome activity assay, TDP-43 immunofluorescence, pharmacological inhibition of mitochondrial Ca2+ transport Biochimica et biophysica acta Medium 25175561
2017 SigmaR1 physically binds SK3 (KCNN3, a Ca2+-activated K+ channel) in breast cancer cells. SigmaR1 triggers coupling between SK3 and the Ca2+ channel Orai1, increasing Ca2+ influx. Inhibition of SigmaR1 decreased SK3 current and Ca2+ entry, and diminished SK3 and/or Orai1 levels in lipid nanodomains, reducing cancer cell invasiveness. Co-IP (SigmaR1–SK3), lipid nanodomain fractionation, patch-clamp electrophysiology, siRNA silencing, sigma ligand (igmesine) treatment Oncogene Medium 28114279
2015 Sig1R dynamically controls the membrane expression of the hERG voltage-gated K+ channel in myeloid leukemia and colorectal cancer cells. Sig1R promotes formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering PI3K/AKT pathway activation, increasing cell motility and VEGF secretion. Co-IP (hERG–Sig1R–β1-integrin complex), siRNA knockdown, PI3K/AKT pathway western blot, cell motility assay, in vivo xenograft model Cancer research Medium 26645564
2021 In cardiomyocytes, Sigmar1 localizes to mitochondrial membranes (confirmed by quantum dot electron microscopy, subcellular fractionation, and MitoTracker colocalization) and functions as an integral mitochondrial membrane protein (shown by alkaline extraction and proteinase K protection assays). The N-terminal region is required for mitochondrial localization. Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes. Quantum dot transmission electron microscopy, subcellular fractionation, immunocytochemistry, alkaline extraction, proteinase K treatment, FLAG-tagged truncation constructs, extracellular flux analysis, high-resolution respirometry Mitochondrion Medium 34902622
2020 Methamphetamine inhibits Sigmar1, resulting in inactivation of CREB, decreased expression of mitochondrial fission 1 protein (FIS1), and alteration of mitochondrial dynamics and function, leading to cardiomyopathy. Mouse 'binge and crash' methamphetamine model, human autopsy cardiac samples, western blot for CREB/FIS1, mitochondrial function assays, Sigmar1 KO mice Communications biology Medium 33203971
2025 SIGMAR1 directly binds neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Downregulation of NPTX1 promotes AMPAR (GluA1 subunit) membrane trafficking and central sensitization, driving neuropathic pain. SIGMAR1 is upregulated in the spinal dorsal horn by mRNA m6A modification during neuropathic pain development. HPLC-MS/MS, Co-IP (SIGMAR1–NPTX1), methylated RNA immunoprecipitation (m6A), intrathecal SIGMAR1 siRNA/antagonist, AAV-mediated NPTX1 overexpression, AMPAR membrane trafficking assay Neuroscience bulletin Medium 41457187
2024 CdCl2 exposure activates SEL1L/HRD1-mediated ERAD, which promotes ubiquitinated degradation of SigmaR1 specifically at its K142 site, resulting in Ca2+ dyshomeostasis and mitochondrial dysfunction that activates the p53/p21/Rb neuronal senescence pathway. In vitro neuron culture, in vivo mouse model, ubiquitination assay with site-specific mutagenesis (K142), Co-IP (SEL1L/HRD1–SigmaR1), western blot for senescence markers, Ca2+ imaging Journal of hazardous materials Medium 38718507
2025 STUB1 (an E3 ubiquitin ligase) interacts with Sigmar1 and degrades it via ubiquitination in cardiomyocytes exposed to CVB3. STUB1-mediated Sigmar1 degradation promotes ER stress (upregulation of GRP78, Caspase-12, CHOP). Sigmar1 overexpression reversed CVB3-induced ER stress and cardiomyocyte apoptosis, while STUB1 overexpression counteracted Sigmar1 overexpression effects. Co-IP (STUB1–Sigmar1), ubiquitination assay, overexpression constructs in neonatal mouse cardiomyocytes, LDH assay, TUNEL apoptosis assay, western blot General physiology and biophysics Medium 40567075
2024 Sigmar1 suppresses COL1A1 expression and vascular fibrosis by blocking the TGF-β/Smad2/3 signaling pathway in vascular smooth muscle cells exposed to methamphetamine. Sigmar1 KO mice showed higher blood pressure and collagen deposition, while Sigmar1 agonist (PRE-084) prevented these effects. Sigmar1 KO mice, Sigmar1 antagonist (BD1047) and agonist (PRE-084), western blot for TGF-β/Smad2/3, collagen staining, blood pressure measurement Biochimica et biophysica acta. Molecular basis of disease Medium 38851304
2022 Veratramine inhibited the expression of SIGMAR1 and the phosphorylation of NMDAR at Ser896 in spinal cord tissue, and inhibited formation of SIGMAR1–NMDAR and NMDAR–CaMKII protein complexes, thereby reducing neuropathic pain in diabetic rats. Co-IP (SIGMAR1–NMDAR, NMDAR–CaMKII complexes), western blot, in vivo rat diabetic neuropathy model with veratramine treatment Pharmaceutical biology Low 36373991
2017 Alternatively spliced variants of sigma1 receptor all fail to bind sigma ligands when expressed in HEK293 cells, indicating that each truncated region is important for ligand binding. However, all splice variants retain the ability to physically associate with mu opioid receptor (mMOR-1) by Co-IP, and can disrupt sigma1 receptor dimerization with mMOR-1 in a dominant-negative manner. Ligand binding assay, Co-IP (splice variants with mMOR-1), competition Co-IP for dimerization, expression in HEK293 cells PloS one Medium 28350844
2019 Cocaine enhances Sigma1R association with nuclear lamina proteins emerin, lamin A/C, and BANF1, causing Sigma1R-dependent and emerin-dependent transcriptional repression of MAOB1. Novel missense variants (p.Q2P and p.R208W) were identified as tools to study the molecular basis of this association. Co-IP (Sigma1R with emerin/lamin A/C/BANF1 in cocaine-treated cells), transcriptional repression assay, population genetics (ExAC database for variant identification) Experimental biology and medicine (Maywood, N.J.) Low 31324122
2024 CLCC1 co-localizes with SigmaR1 not only at the ER but also at mitochondria-associated ER membranes (MAMs), and SigmaR1 was identified as a CLCC1-interacting protein by LC-MS proteomics, validated by co-immunoprecipitation and microscopy. LC-MS proteomics, Co-IP (CLCC1–SigmaR1), immunofluorescence co-localization microscopy Neuroscience letters Low 38621504
2026 SIGMAR1 activates SIRT3-mediated mitophagy, which alleviates endothelial ferroptosis and microvascular hyperpermeability in LPS-induced acute lung injury. SIRT3 deacetylates ATP5F1A at lysine 498; this deacetylation is essential for SIGMAR1-mediated PRKN/parkin-dependent mitophagy. Sigmar1 KO worsened ferroptosis and hyperpermeability, effects reversed by SIRT3 activation. Sigmar1 KO mice, pharmacological agonism (PRE-084), SIRT3 inhibition/activation, acetylation assay (ATP5F1A K498), mitophagy markers, GFP-LC3 puncta, mouse pulmonary microvascular endothelial cells Autophagy Medium 41655128
2015 A splice-site mutation in SIGMAR1 (c.151+1G>T) generates a truncated protein σ1R(31_50del) that is degraded by the proteasome and forms nuclear aggregates upon proteasome inhibition. Stable expression of σ1R(31_50del) induces ER stress and enhances apoptosis in cell lines. RNA analysis of patient peripheral blood, stable cell line expression of mutant σ1R, proteasome inhibitor treatment, immunofluorescence, western blot, apoptosis assay Neurology Low 26078401
2016 Sigma-1 receptor agonist (+)-pentazocine promotes retinal ganglion cell survival after NMDA-induced excitotoxicity through a σR1-dependent mechanism and enhances activation of ERK1/2 (MAPK) at 6 hours post-NMDA. In σR1 knockout mice, (+)-pentazocine failed to protect RGCs and failed to activate ERK, placing σR1 upstream of ERK in the neuroprotective pathway. Intravitreal NMDA injection in WT and σR1 KO mice, intraperitoneal (+)-pentazocine treatment, retinal flat-mount RGC counting, TUNEL assay, western blot for ERK1/2 phosphorylation Investigative ophthalmology & visual science Medium 26868747
2011 Absence of σR1 in knockout mice leads to late-onset inner retinal dysfunction (decreased ERG b-wave amplitudes, loss of ganglion cell layer cells, increased apoptosis by TUNEL/caspase-3), preceded by ultrastructural axonal disruption in the optic nerve head, establishing a direct role for σR1 in maintaining inner retinal neuron survival. σR1 knockout mice, electroretinography, morphometric analysis, TUNEL assay, active caspase-3 immunostaining, electron microscopy Investigative ophthalmology & visual science Medium 21862648
2008 Gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate methamphetamine-induced depression- and anxiety-like behaviors through a SIGMAR1-dependent mechanism: Sigmar1 knockout (Sigmar1−/−) repressed the BDNF/TRKB pathway and produced behavioral phenotypes similar to methamphetamine exposure, and eliminated the anti-anxiety and anti-depression effects of SCFAs. Fluvoxamine-mediated SIGMAR1 activation attenuated methamphetamine-induced behaviors. Sigmar1 KO mice, fecal microbiota transplant, SCFA supplementation, fluvoxamine pharmacological activation, behavioral assays, western blot for SIGMAR1/BDNF/TRKB pathway Acta pharmaceutica Sinica. B Low 38045052

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO molecular medicine 204 27821430
2015 Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain : a journal of neurology 192 25678561
2017 The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis. Oncogene 103 28114279
2021 Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology. Frontiers in physiology 81 34305655
2016 Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling. Human molecular genetics 80 27402882
2019 SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance. Autophagy 74 30871407
2015 A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy. Neurology 71 26078401
2023 Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression- and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner. Acta pharmaceutica Sinica. B 69 38045052
2015 SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness. Cancer research 56 26645564
2022 Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine. Autophagy 55 35507432
2011 Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1). Investigative ophthalmology & visual science 52 21862648
2020 Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function. Communications biology 49 33203971
2014 Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis. Biochimica et biophysica acta 49 25175561
2014 The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis. Journal of pharmacological sciences 49 25704016
2002 Analysis of sigma receptor (sigmaR1) expression in retinal ganglion cells cultured under hyperglycemic conditions and in diabetic mice. Brain research. Molecular brain research 44 12425939
2015 In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia. Neurogenetics 38 26205306
2010 Association analysis of SIGMAR1 with major depressive disorder and SSRI response. Neuropharmacology 34 20178807
2016 SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology 32 27629094
2016 (+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism. Investigative ophthalmology & visual science 28 26868747
2012 Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia. European journal of human genetics : EJHG 28 22739338
2011 The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex. Progress in neuro-psychopharmacology & biological psychiatry 26 21549171
2014 Mutations in UBQLN2 and SIGMAR1 genes are rare in Korean patients with amyotrophic lateral sclerosis. Neurobiology of aging 25 24684794
2023 Autophagy-mediated circHIPK2 promotes lipopolysaccharide-induced astrocytic inflammation via SIGMAR1. International immunopharmacology 22 36827915
2017 The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder. Advances in therapy 19 28144920
2019 Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation. Journal of medical genetics 17 31511340
2018 SIGMAR1 gene mutation causing Distal Hereditary Motor Neuropathy in a Portuguese family. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 17 30079398
2020 Mutations in the SIGMAR1 gene cause a distal hereditary motor neuropathy phenotype mimicking ALS: Report of two novel variants. Neuromuscular disorders : NMD 16 32600828
2021 The molecular role of Sigmar1 in regulating mitochondrial function through mitochondrial localization in cardiomyocytes. Mitochondrion 15 34902622
2016 Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy. Child neurology open 15 28503617
2023 SIGMAR1 Confers Innate Resilience against Neurodegeneration. International journal of molecular sciences 14 37175473
2021 Molecular Characterization of Skeletal Muscle Dysfunction in Sigma 1 Receptor (Sigmar1) Knockout Mice. The American journal of pathology 14 34710383
2017 Recessive distal motor neuropathy with pyramidal signs in an Omani kindred: underlying novel mutation in the SIGMAR1 gene. European journal of neurology 14 29115704
2017 Isolation and characterization of alternatively spliced variants of the mouse sigma1 receptor gene, Sigmar1. PloS one 13 28350844
2024 SigmaR1 shapes rough endoplasmic reticulum membrane sheets. Developmental cell 11 38971154
2024 The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure. Journal of hazardous materials 10 38718507
2023 Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels. Frontiers in physiology 6 37051024
2022 Generation of Sigmar1 conditional knockout mouse using CRISPR-Cas9 gene targeting. Genesis (New York, N.Y. : 2000) 6 35633570
2025 SigmaR1 is an auxiliary translocon factor with lipid-binding activity that regulates protein and lipid droplet homeostasis. Nature communications 5 41476177
2022 Veratramine ameliorates pain symptoms in rats with diabetic peripheral neuropathy by inhibiting activation of the SIGMAR1-NMDAR pathway. Pharmaceutical biology 5 36373991
2025 SIGMAR1 screened by a GPCR-related classifier regulates endoplasmic reticulum stress in bladder cancer. Journal of translational medicine 4 40211230
2024 SIGMAR1 targets AMPK/ULK1 pathway to inhibit SH-SY5Y cell apoptosis by regulating endoplasmic reticulum stress and autophagy. Functional & integrative genomics 4 39107544
2022 Conduction block and temporal dispersion in a SIGMAR1-related neuropathy. Journal of the peripheral nervous system : JPNS 4 36222432
2019 Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine. Experimental biology and medicine (Maywood, N.J.) 4 31324122
2024 Blocking Sigmar1 exacerbates methamphetamine-induced hypertension. Biochimica et biophysica acta. Molecular basis of disease 3 38851304
2024 SIGMAR1 Knockdown Enhances Oral Cancer Cell Chemosensitivity to Cisplatin via Decreased PD-L1 Expression. International journal of molecular sciences 3 39595926
2023 Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia. Journal of Alzheimer's disease : JAD 3 37545231
2024 Unraveling the CLCC1 interactome: Impact of the Asp25Glu variant and its interaction with SigmaR1 at the Mitochondrial-Associated ER Membrane (MAM). Neuroscience letters 2 38621504
2024 SIGMAR1/Sigma-1 receptor: a key regulator in stabilizing and translating LC3B mRNA for autophagosome formation. Autophagy 2 39369298
2023 SIGMAR1 variants in ALS-PD complex cases: a case report of a novel mutation and literature review. Frontiers in neurology 2 37780700
2025 Suppression of SIGMAR1 hinders oral cancer cell growth via modulation of mitochondrial Ca2+ dynamics. Molecular biology reports 1 39934454
2025 A novel SIGMAR1 missense mutation leads to distal hereditary motor neuropathy phenotype mimicking juvenile ALS: a case report of China. Frontiers in genetics 1 40309037
2025 SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice. Neuroscience bulletin 1 41457187
2024 Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction. Frontiers in physiology 1 38742156
2024 Anti-tumor activity of butorphanol in colorectal cancer via targeting SIGMAR1. Discover oncology 1 39589602
2026 A Novel YTHDF2/SIGMAR1 Axis in Astrocytes Regulates Neuroinflammation and Cognitive Impairment in Diabetic Encephalopathy. Inflammation 0 41543792
2026 SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury. Autophagy 0 41655128
2026 Linking intestinal distribution to pharmacological mechanism: Berberine prevents and treats colorectal cancer by targeting SIGMAR1. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 42172984
2026 The Role of Sigmar1 in Autophagy Regulation and Disease Therapy. International journal of molecular sciences 0 42196470
2025 Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels. Current molecular medicine 0 38204277
2025 Genomic Insights into Oral Cancer Highlight Mutant SIGMAR1 as a Critical Target to Overcome Chemoresistance. Biochemical genetics 0 40257692
2025 In silico-based analysis and in vitro experiments identify SIGMAR1 as a potential marker of putative lung cancer stem cells. Discover oncology 0 40285994
2025 The regulatory role of Sigmar1 in CVB3-induced myocarditis. General physiology and biophysics 0 40567075
2025 Letter to editor: SIGMAR1 screened by a GPCR-related classifier regulates endoplasmic reticulum stress in bladder cancer. Journal of translational medicine 0 40770335
2025 SIGMAR1 gene-related neuromuscular disorders - what do we know? Neurologia i neurochirurgia polska 0 41334667

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