ATP1A1 Protein

ATP1A1 Protein

Na+/K+ ATPase Alpha-1 Subunit

<div class="infobox infobox-protein"> [@cardiac]
<div class="infobox-header">ATP1A1 Protein</div>

Overview

ATP1A1 Protein

Na+/K+ ATPase Alpha-1 Subunit

<div class="infobox infobox-protein"> [@cardiac]
<div class="infobox-header">ATP1A1 Protein</div>

Overview

ATP1A1 Protein is a protein encoded by the [ATP1A1](/genes/atp1a1) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
[@nak2020]
<table> [@nakatpase2019]
<tr><th>Protein Name</th><td>Na+/K+ ATPase Alpha-1 Subunit</td></tr> [@fxyd2019]
<tr><th>Gene</th><td>[ATP1A1](/genes/atp1a1)</td></tr> [@nak]
<tr><th>UniProt ID</th><td>[P05023](https://www.uniprot.org/uniprot/P05023)</td></tr> [@alphasynuclein2021]
<tr><th>PDB Structures</th><td>[3WGU](https://www.rcsb.org/structure/3WGU), [5KUG](https://www.rcsb.org/structure/5KUG), [6MRB](https://www.rcsb.org/structure/6MRB)</td></tr>
<tr><th>Molecular Weight</th><td>~112 kDa</td></tr>
<tr><th>Subcellular Localization</th><td>Plasma membrane</td></tr>
<tr><th>Protein Family</th><td>P-type ATPase (E1-E2 ATPase family)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</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">25 edges</a></td>
</tr>
</table>
</div>

Structure

The Na+/K+ ATPase is a heteromeric protein consisting of an alpha (catalytic), beta, and gamma (or FXYD) subunit. The alpha-1 subunit is the largest component (~1000 amino acids) and contains:

• 10 transmembrane helices (M1-M10) that form the ion channel
• ATP-binding domain (N/P domains) in the cytoplasmic region
• Pump specificity determinants for Na+ and K+ ion binding
• Ouabain-binding site on the extracellular face

Normal Function in the Nervous System

In [neurons](/entities/neurons) and glial cells, the Na+/K+ ATPase maintains:

The alpha-1 subunit is the ubiquitous isoform, expressed in most cell types including neurons, [astrocytes](/entities/astrocytes), and oligodendrocytes.

Role in Neurodegeneration

Alzheimer's Disease (AD)

• [Amyloid-beta](/proteins/amyloid-beta) toxicity: Aβ oligomers directly inhibit Na+/K+ ATPase activity in hippocampal neurons [1]
• Energy failure: Reduced ATPase activity contributes to neuronal hyperexcitability and vulnerability
• Calcium dysregulation: Impaired Na+ gradient affects NCX function, leading to calcium overload
• Therapeutic relevance: Cardiac glycosides (digoxin, ouabain) that inhibit Na+/K+ ATPase show complex effects in AD models [2]

Parkinson's Disease (PD)

• [Alpha-synuclein](/proteins/alpha-synuclein) interaction:研究发现α-突触核蛋白聚集体可以抑制Na+/K+ ATPase活性
• Mitochondrial dysfunction: Energy deficits compound complex I deficiency in PD
• Neuronal vulnerability: Dopaminergic neurons show particular sensitivity to ATPase inhibition

Amyotrophic Lateral Sclerosis (ALS)

• Motor neuron vulnerability: Motor neurons rely heavily on precise ion homeostasis
• Excitotoxicity: Impaired glutamate uptake due to gradient disruption contributes to excitotoxic cell death
• Energy metabolism: ALS motor neurons show metabolic vulnerabilities that ATPase dysfunction compounds

Stroke and Ischemia

• Ischemic injury: Na+/K+ ATPase failure is an early event in ischemic neuronal death
• Reperfusion damage: Restoring ATPase function is crucial for neuronal recovery
• Therapeutic target: Na+/K+ ATPase modulators are being investigated for neuroprotection [3]

Therapeutic Targeting

Drug Development

• Cardiac glycosides: Digoxin, ouabain - show neuroprotective effects in some studies but narrow therapeutic window
• Novel inhibitors: Safer analogs being developed for specific neuroprotective applications
• FXYD proteins: Regulatory subunits (FXYD1-10) offer targeting opportunities for isoform-specific modulation

Research Applications

• Stroke therapy: Na+/K+ ATPase activation/protection strategies in development
• Neurodegeneration: Understanding ATPase dysfunction provides insights into energy failure mechanisms

Protein Interactions

| Interactor | Function | Reference |
|------------|----------|-----------|
| ATP1B1 | Beta-1 subunit - required for proper folding and membrane localization | [4](https://doi.org/10.1016/j.bbamcr.2019.06.008) |
| FXYD proteins | Regulatory subunits modulating pump kinetics | [5](https://doi.org/10.1016/j.tibs.2019.01.001) |
| Src kinase | Na+/K+ ATPase activates Src signaling cascades | [6](https://doi.org/10.1074/jbc.M109.068460) |
| Alpha-synuclein | PD-linked protein inhibits ATPase function | [7](https://doi.org/10.1016/j.jbc.2021.100280) |
| Amyloid-beta | Aβ oligomers inhibit ATPase activity | [1](https://doi.org/10.1016/j.neurobiolaging.2019.04.012) |

See Also

• [ATP1A1 Gene](/genes/atp1a1)

External Links

• [UniProt: P05023](https://www.uniprot.org/uniprot/P05023)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:P05023)
• [GeneCards: ATP1A1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ATP1A1)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ATP1A1 Protein discovered through SciDEX knowledge graph analysis: