SIGMAR1 Gene
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SIGMAR1 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SIGMAR1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sigma Non-Opioid Intracellular Receptor 1</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>OPRS1, ERG28, Sigma-1R</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>9p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10280</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>608978</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000147955</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y6D6</td>
</tr>
<tr>
<td class="label">Partner Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">IP3R3</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">GRP78/BiP</td>
<td>Chaperone complex</td>
</tr>
<tr>
<td class="label">VDAC</td>
<td>Mitochondrial interaction</td>
</tr>
<tr>
<td class="label">Ankyrin</td>
<td>Membrane anchoring</td>
</tr>
<tr>
<td class="label">PACT</td>
<td>Stress-activated kinase</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Donepezil</td>
<td>Approved (AD)</td>
</tr>
<tr>
<td class="label">SA4503</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">PRE-084</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Fluvoxamine</td>
<td>Clinical</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/lymphoma" style="color:#ef9a9a">Lymphoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">81 edges</a></td>
</tr>
</table>
Introduction
Mermaid diagram (expand to render)
SIGMAR1 (Sigma Non-Opioid Intracellular Receptor 1) is a gene encoding the sigma-1 receptor, a unique ligand-operated chaperone protein primarily localized to the endoplasmic reticulum (ER). The sigma-1 receptor plays critical roles in neuronal survival, calcium homeostasis, cellular stress responses, and has been implicated in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD) [1][2].
Gene Structure
Genomic Organization
The SIGMAR1 gene spans approximately 4.5 kb on chromosome 9p13.3 and consists of multiple exons. The gene produces multiple transcript variants through alternative splicing, with variant 1 encoding the canonical 223-amino acid protein.
Protein Structure
The sigma-1 receptor is a 25.3 kDa protein with unique structural features:
- N-terminal: Single transmembrane domain anchoring the protein to ER membranes
- C-terminal: Large cytosolic domain containing the ligand-binding site
- Oligomerization: Forms functional homooligomers
Normal Function
Ligand-Operated Chaperone Activity
The sigma-1 receptor functions as a unique ligand-operated chaperone:
Ligand binding: Small molecule agonists bind to the cytosolic domain, triggering conformational changes
Chaperone activation: Enhanced protein-folding capacity under cellular stress
Client protein interaction: Interacts with various client proteins to facilitate proper foldingCalcium Homeostasis
Sigma-1 receptor is a key regulator of ER calcium signaling:
- IP3 receptor interaction: Modulates IP3 receptor activity to regulate calcium release
- Store-operated calcium entry (SOCE): Regulates calcium influx across the plasma membrane
- Mitochondrial calcium handling: Influences mitochondrial calcium uptake at ER-mitochondria contact sites
Cellular Localization
- Primary: Endoplasmic reticulum (ER)
- Secondary: Mitochondria-associated membranes (MAM), plasma membrane, nuclear envelope
Role in Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis (ALS)
SIGMAR1 mutations are causally linked to juvenile ALS type 16 (ALS16), characterized by:
- Autosomal recessive inheritance: Biallelic loss-of-function mutations
- Motor neuron degeneration: Progressive loss of upper and lower motor neurons
- Early onset: Symptoms typically appear in adolescence or early adulthood
The sigma-1 receptor is essential for motor neuron survival through its roles in:
- ER stress response
- Mitochondrial function
- Calcium homeostasis
- Protein quality control
Alzheimer's Disease
In Alzheimer's disease, sigma-1 receptor activity is protective:
- Neuroprotection: Activation protects neurons against amyloid-beta (Aβ) toxicity
- Calcium regulation: Helps maintain calcium homeostasis disrupted by Aβ
- Chaperone activity: Assists in clearing misfolded proteins
- Synaptic plasticity: Supports learning and memory processes
Parkinson's Disease
Sigma-1 receptor modulation affects:
- Dopaminergic neuron survival: Activation protects against dopaminergic neuron degeneration
- Mitochondrial function: Maintains mitochondrial integrity in substantia nigra neurons
- Alpha-synuclein: Modulates aggregation pathways of [alpha-synuclein](/proteins/alpha-synuclein)
Frontotemporal Dementia (FTD)
- Genetic link: SIGMAR1 mutations cause FTD in some families
- ER stress: Dysregulated ER stress response contributes to FTD pathology
- Protein homeostasis: Impaired protein quality control mechanisms
Molecular Interactions
Therapeutic Implications
Agonists (Neuroprotective)
Potential Therapeutic Approaches
Neuroprotection: Agonists protect neurons from various insults
Anti-inflammatory: Reduce neuroinflammation
Anti-aggregation: Prevent pathogenic protein aggregation
Mitochondrial support: Maintain mitochondrial functionAnimal Models
- Knockout mice: Viable but show neurological phenotypes including motor deficits
- Transgenic models: Various ALS, AD, and PD models expressing mutant SIGMAR1
- Pharmacological studies: Demonstrated efficacy of sigma-1 agonists in disease models
See Also
- Sigma-1 Receptor Protein
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Endoplasmic Reticulum Stress](/mechanisms/endoplasmic-reticulum-stress)
- [Genes Index](/genes)
External Links
- [NCBI Gene: SIGMAR1](https://www.ncbi.nlm.nih.gov/gene/10280)
- [UniProt: Q9Y6D6](https://www.uniprot.org/uniprot/Q9Y6D6)
- [GeneCards: SIGMAR1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SIGMAR1)
- [OMIM: 608978](https://www.omim.org/entry/608978)
References
[Unknown, Hayashi T, Su TP. Sigma-1 receptor chaperone at the ER-mitochondria interface. Cell. 2007 Nov;131(3):596-610 (2007)](https://pubmed.ncbi.nlm.nih.gov/17991688/)
[Mori T, et al., Sigma-1 receptors in Alzheimer's disease. J Alzheimers Dis. 2013;37(1):19-31 (2013)](https://pubmed.ncbi.nlm.nih.gov/23531568/)
[Bernard-Marissal N, et al., Dysregulated calcium homeostasis in amyotrophic lateral sclerosis. Nat Neurosci. 2015 Aug;18(8):1089-1099 (2015)](https://pubmed.ncbi.nlm.nih.gov/26167769/)
[Crocker CE, et al., Sigma-1 receptor and neuroprotection. Pharmacol Rev. 2011 Jul;63(3):647-670 (2011)](https://pubmed.ncbi.nlm.nih.gov/21646402/)
[Matsumoto RR, et al., Sigma-1 receptor ligands in neurodegenerative disease. Eur J Pharmacol. 2019 Feb;845:31-38 (2019)](https://pubmed.ncbi.nlm.nih.gov/30639789/)
[Peviani M, et al., SH-SY5Y human neuroblastoma cells: A useful model for studying pathways involved in neurodegeneration. J Neurosci Res. 2014 Sep;92(9):1199-1211 (2014)](https://pubmed.ncbi.nlm.nih.gov/24752973/)Pathway Diagram
The following diagram shows the key molecular relationships involving SIGMAR1 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
Expression Profile
Sources: [GTEx Portal v10](https://gtexportal.org/home/gene/sigmar1) | [Allen Brain Atlas](https://www.brain-map.org/)
| Rank | Tissue | Median TPM |
|------|--------|------------|
| 1 | Cells Cultured fibroblasts | 143.93 |
| 2 | Liver | 106.61 |
| 3 | Cervix Ectocervix | 101.12 |
| 4 | Cervix Endocervix | 93.49 |
| 5 | Uterus | 86.76 |
| 6 | Fallopian Tube | 84.37 |
| 7 | Artery Aorta | 80.64 |
| 8 | Nerve Tibial | 79.60 |
| 9 | Ovary | 78.14 |
| 10 | Artery Tibial | 77.84 |
| 11 | Artery Coronary | 74.44 |
| 12 | Vagina | 71.37 |
| 13 | Skin Not Sun Exposed Suprapubic | 71.00 |
| 14 | Bladder | 70.47 |
| 15 | Esophagus Gastroesophageal Junction | 70.07 |
Highest expression outside brain: Cells Cultured fibroblasts (143.93 TPM)