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Tclin Sigma non-opioid intracellular receptor 1

Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration (PubMed:16472803, PubMed:9341151). Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria (By similarity).

This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2013]

 Comments

Property Summary

NCBI Gene PubMed Count 81
Grant Count 34
R01 Count 9
Funding $10,957,807.34
PubMed Score 177.50
PubTator Score 84.16

Knowledge Summary

Patent

No data available

TINX Plot

  Disease Relevance (23)

Disease Z-score Confidence
Amyotrophic Lateral Sclerosis 431 3.554 1.8
Lateral sclerosis 13 3.189 1.6
Schizophrenia 501 3.059 1.5
AMYOTROPHIC LATERAL SCLEROSIS 16, JUVENI... 1 
Amnesia 17
Cocaine-Related Disorders 88
Frontotemporal Lobar Degeneration 5
General anesthesia 53
HIV Infections 100
Labor pain 4
Learning Disorders 27
Local anesthesia 40
Memory Disorders 36
Neurodegenerative disease 383 4.0
Pain 70
Prenatal Exposure Delayed Effects 9
Seizures 95
Spinal muscular atrophy, Jerash type 1
colon cancer 1,475
lung cancer 4,466
medulloblastoma, large-cell 6,234
ovarian cancer 8,484
pancreatic ductal adenocarcinoma liver m... 1,795 

Expression

  Differential Expression (5)

Disease log2 FC p
medulloblastoma, large-cell 1.300 0.002
pancreatic ductal adenocarcinoma liver m... -2.013 0.000
lung cancer 2.200 0.000
colon cancer 1.600 0.003
ovarian cancer 1.400 0.000

Synonym

Accession Q99720 D3DRM7 O00673 O00725 Q0Z9W6 Q153Z1 Q2TSD1 Q53GN2 Q7Z653 Q8N7H3 Q9NYX0
Symbols SRBP
ALS16
DSMA2
OPRS1
SR-BP
SIG-1R
SR-BP1
sigma1R
hSigmaR1

Gene

SIGMAR1

 Grant Application (34)

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PDB

5HK1   5HK2  

 GO Function (2)

 GO Component (13)

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 GO Process (4)

 Compartment GO Term (64)

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 MGI Term (1)

Pathway (3)

 UniProt Keyword (24)

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Drug (53)

Structure of pentazocine

pentazocine
pEC50 8.76

Structure of cisapride

cisapride
pIC50 6.00

Structure of spiperone

spiperone
pIC50 6.02

Structure of quetiapine

quetiapine
pKi 6.02

Structure of astemizole

astemizole
pKi 6.03

Structure of trazodone

trazodone
pKi 6.03

Structure of methysergide

methysergide
pIC50 6.04

Structure of buflomedil

buflomedil
pKi 6.04

Structure of levobunolol

levobunolol
pIC50 6.11

Structure of labetalol

labetalol
pKi 6.12

Structure of tetracaine

tetracaine
pKi 6.15

Structure of dexchlorpheniramine

dexchlorpheniramine
pKi 6.16

Structure of raloxifene

raloxifene
pIC50 6.17

Structure of mepyramine

mepyramine
pKi 6.18

Structure of loperamide

loperamide
pIC50 6.20

Structure of doxepin

doxepin
pIC50 6.20

Structure of clomipramine

clomipramine
pKi 6.24

Structure of terbinafine

terbinafine
pIC50 6.25

Structure of phentolamine

phentolamine
pIC50 6.26

Structure of buspirone

buspirone
pIC50 6.30

Ligand (1,795)

Structure of CHEMBL6224

CHEMBL6224
pIC50 6.00

Structure of CHEMBL275528

CHEMBL275528
pIC50 6.00

Structure of CHEMBL328986

CHEMBL328986
pIC50 6.00

Structure of CHEMBL1089752

CHEMBL1089752
pIC50 6.00

Structure of CHEMBL557002

CHEMBL557002
pIC50 6.01

Structure of CHEMBL285203

CHEMBL285203
pIC50 6.01

Structure of CHEMBL336706

CHEMBL336706
pIC50 6.02

Structure of CHEMBL320435

CHEMBL320435
pIC50 6.02

Structure of CHEMBL2374421

CHEMBL2374421
pIC50 6.02

Structure of CHEMBL78356

CHEMBL78356
pIC50 6.02

Structure of CHEMBL553745

CHEMBL553745
pIC50 6.02

Structure of CHEMBL142617

CHEMBL142617
pIC50 6.02

Structure of CHEMBL435046

CHEMBL435046
pKi 6.03

Structure of CHEMBL419161

CHEMBL419161
pKi 6.03

Structure of CHEMBL607156

CHEMBL607156
pIC50 6.03

Structure of CHEMBL2391379

CHEMBL2391379
pIC50 6.03

Structure of CHEMBL2105667

CHEMBL2105667
pKi 6.03

Structure of CHEMBL154446

CHEMBL154446
pKi 6.03

Structure of CHEMBL82246

CHEMBL82246
pIC50 6.03

Structure of CHEMBL37468

CHEMBL37468
pIC50 6.03

MLP Assay (2)

AID Type Active / Inconclusive / Inactive Description
1788 other 0 / 0 / 0 Discovery of novel allosteric modulators of the M1 muscarinic receptor: Agonist Ancillary Activity
1921 other 2 / 0 / 0 Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator: Ancillary Activity

Gene RIF (72)

PMID Text
27042935 crystal structures of the human sigma1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP
26792723 Collectively, these studies define Sig1R as a key mediator of TRAIL induction of cancer-specific killing.
26078401 Homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive distal hereditary motor neuropathy (dHMN) in a Chinese consanguineous family; endoplasmic reticulum stress may have a role in the pathogenesis of dHMN
25902777 Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain--{REVIEW}
25704016 Expression of mutant Sig-1R protein reduces mitochondrial ATP production, inhibits proteasome activity and causes mitochondrial injury, aggravating ER stress-induced neuronal death.
25704015 mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease.
25704014 overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function.
25704013 Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity.
25704011 Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation.
25569182 Inhibition of sigma receptor or VEGFR causes a significant decrease in HIV-1 Tat- and cocaine-induced H2O2 generation in human pulmonary arterial smooth muscle cells
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AA Sequence 

MQWAVGRRWAWAALLLAVAAVLTQVVWLWLGTQSFVFQREEIAQLARQYAGLDHELAFSRLIVELRRLHP      1 - 70
GHVLPDEELQWVFVNAGGWMGAMCLLHASLSEYVLLFGTALGSRGHSGRYWAEISDTIISGTFHQWREGT     71 - 140
TKSEVFYPGETVVHGPGEATAVEWGPNTWMVEYGRGVIPSTLAFALADTVFSTQDFLTLFYTLRSYARGL    141 - 210
RLELTTYLFGQDP                                                             211 - 223
//

Text Mined References (85)

PMID Year Title
27042935 2016 Crystal structure of the human ?1 receptor.
26792723 2016 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates caspases in human prostate cancer cells through sigma 1 receptor.
26078401 2015 A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.
25944712 2015 N-terminome analysis of the human mitochondrial proteome.
25902777 2015 Sigma-1 receptor and inflammatory pain.
25704016 2015 The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.
25704015 2015 The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration.
25704014 2015 Role of sigma-1 receptors in neurodegenerative diseases.
25704013 2015 Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS).
25704011 2015 Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs.
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