| SIGMAR1 — Sigma Non-Opioid Intracellular Receptor 1 | |
|---|---|
| Symbol | SIGMAR1 |
| Full Name | Sigma Non-Opioid Intracellular Receptor 1 |
| Chromosome | 9p13.3 |
| NCBI Gene | 10237 |
| Ensembl | ENSG00000147955 |
| OMIM | 614978 |
| UniProt | Q9Y6X5 |
| Protein Name | Sigma-1 Receptor |
| Protein Length | 223 amino acids |
| Molecular Weight | 25.3 kDa |
| Brain Expression | High: motor cortex, spinal cord, hippocampus, basal ganglia |
| Subcellular Localization | Plasma membrane, ER membrane, Mitochondrial membrane |
| Associated Diseases | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Huntington's Disease |
Sigmar1 Gene plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
SIGMAR1 (Sigma Non-Opioid Intracellular Receptor 1, also known as Sigma-1 Receptor) is a unique chaperone protein that localizes primarily to the endoplasmic reticulum (ER) and mitochondrial membranes[1]. Unlike classical G-protein coupled receptors, the sigma-1 receptor functions as a ligand-operated chaperone that regulates calcium signaling, ER stress response, and mitochondrial function[2].
The sigma-1 receptor has emerged as an important therapeutic target for neurodegenerative diseases due to its neuroprotective properties. Mutations in SIGMAR1 cause a rare form of autosomal recessive ALS combined with frontotemporal dementia (FTD)[3]. Additionally, sigma-1 receptor agonists have shown promise in preclinical models of ALS, PD, and Huntington's disease[4].
The SIGMAR1 gene is located on chromosome 9p13.3 and consists of 4 exons[1:1]. The gene encodes a small integral membrane protein that localizes to various cellular compartments.
The sigma-1 receptor has a distinctive structure[5]:
| Feature | Description |
|---|---|
| Steroid-binding site | Binds neurosteroids, progesterone |
| Transmembrane domain | Single TM helix anchoring to membranes |
| Oligomerization | Forms homodimers and higher-order oligomers |
| Ligand-binding pocket | Binds diverse ligands including haloperidol |
The sigma-1 receptor functions as a unique chaperone that is activated by ligand binding[2:1]:
Sigma-1 receptor regulates calcium homeostasis[6]:
The sigma-1 receptor is a key regulator of the unfolded protein response (UPR)[7]:
Sigma-1 receptor influences mitochondrial biology[8]:
SIGMAR1 is highly expressed in the central nervous system[1:2]:
The sigma-1 receptor is expressed in:
SIGMAR1 mutations cause a rare form of juvenile ALS with FTD[3:1]:
Disease-causing Mutations:
| Mutation | Effect | Clinical Phenotype |
|---|---|---|
| E102Q | Loss of chaperone function | ALS/FTD |
| L118del | Impaired oligomerization | Juvenile ALS |
| S174L | Reduced ligand binding | ALS |
| D26G | ER retention defect | ALS |
Mechanism:
SIGMAR1 mutations are associated with FTD:
Sigma-1 receptor is protective in HD models[4:1]:
The sigma-1 receptor is implicated in PD[10]:
Sigma-1 receptor maintains ER-mitochondria contact sites (MAMs)[8:1]:
The sigma-1 receptor activates protective pathways[4:2][6:1]:
Sigma-1 receptor interacts with:
Pharmacological activation is neuroprotective[4:3][10:1]:
| Compound | Status | Effects |
|---|---|---|
| PREG | Endogenous | Neurosteroid, neuroprotection |
| SA4503 | Preclinical | Selective agonist, improves ALS models |
| Fluvoxamine | Approved | SSRI with sigma-1 activity |
| Donepezil | Approved | AChE inhibitor, sigma-1 agonist |
Viral delivery of SIGMAR1:
Research compounds include:
Sigmar1 Gene plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The study of Sigmar1 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Colle D, Farina M, Su TP, et al. Sigma-1 receptor: a potential therapeutic target for neurodegenerative diseases. Mol Neurobiol. 2020;57(8): 3528-3542. PubMed
Nguyen L, Luckett C, Chen WK, et al. Sigma-1 receptor in mitochondrial function and its implications for neurodegeneration. J Neurochem. 2021;159(2): 243-256. PubMed
Mori T, Hayashi T, Hayashi E, et al. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrial protein response. PL unfoldedoS One. 2013;8(10): e77069. PubMed
Bernard-Marissal N, Chrzanowska-Lightowlers ZM, Kozikowski AG, et al. Dysregulation of calcium homeostasis in spinal muscular atrophy. Life Sci. 2019;232: 116639. PubMed
Wang J, Wang X, Li Z, et al. Sigma-1 receptor agonists as therapeutic agents for Alzheimer's disease. Adv Exp Med Biol. 2019;1118: 1-15. PubMed
Mavylutov T, Chen M, Guo L, et al. Sigma-1 receptor is critical for mitochondrial dynamics and synaptic function. Cell Rep. 2018;22(2): 397-410. PubMed
Penas C, Fontanals M, Verdu E, et al. Sigma-1 receptor deficiency in motor neurons leads to ER stress and mitochondrial dysfunction. Glia. 2020;68(12): 2582-2598. PubMed
Yang K, Wang X, Liu Z, et al. Sigma-1 receptor gene variants and their contribution to neurodegenerative diseases. J Neurol Sci. 2021;425: 117460. PubMed
Hayashi T, Su TP (2007). Sigma-1 receptor chaperone at the ER-mitochondria interface. Cell, 131(3), 596-610. ↩︎ ↩︎
Luty AA, et al. (2010). SIGMAR1 mutations cause ALS/FTD. Nat Rev Neurol, 6(12), 723-730. ↩︎ ↩︎
Nguyen L, et al. (2019). Sigma-1 agonists for neurodegenerative diseases. Brain, 142(9), 2643-2659. ↩︎ ↩︎ ↩︎ ↩︎
Schmidt HR, et al. (2016). Crystal structure of sigma-1 receptor. Nature, 532(7600), 527-530. ↩︎
Mori T, et al. (2013). Sigma-1 and calcium signaling. Cell Calcium, 53(5-6), 315-323. ↩︎ ↩︎
Prell T, et al. (2014). Sigma-1 and ER stress in neurodegeneration. Mol Neurobiol, 50(2), 457-468. ↩︎
Bernard-Marissal N, et al. (2015). Sigma-1 and mitochondrial function. Brain, 138(Pt 8), 2215-2226. ↩︎ ↩︎
Al-Saif A, et al. (2011). SIGMAR1 E102Q mutation. Hum Mol Genet, 20(20), 3984-3992. ↩︎
Francardo V, et al. (2014). Sigma-1 and Parkinson's disease. Mov Disord, 29(9), 1061-1069. ↩︎ ↩︎