Sarco/endoplasmic reticulum Ca2+-ATPase 2 - calcium pump critical for neuronal calcium homeostasis
The ATP2A2 protein (SERCA2) is a calcium ATPase pump localized to the endoplasmic reticulum. [1]
| Gene | [ATP2A2](/genes/atp2a2) |
| UniProt | [UniProt:P16615](https://www.uniprot.org/uniprot/P16615) |
| PDB IDs | [PDB:5K7P](https://www.rcsb.org/structure/5K7P), [PDB:6O79](https://www.rcsb.org/structure/6O79), [PDB:3W5C](https://www.rcsb.org/structure/3W5C), [PDB:2E25](https://www.rcsb.org/structure/2E25) |
| Molecular Weight | 110 kDa |
| Localization | Endoplasmic reticulum (ER) membrane |
| Protein Family | P-type ATPase, SERCA family |
The SERCA2 protein contains 10 transmembrane helices forming the ion channel, three cytosolic domains (A, P, and N domains) that undergo conformational changes during the transport cycle, and regulatory domains. The P-domain contains the critical aspartate residue that is phosphorylated during the transport cycle.
SERCA2 undergoes phosphorylation, glycosylation, and palmitoylation. Phosphorylation at specific residues modulates activity, and palmitoylation affects ER membrane association.
The sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) is a calcium pump that transports calcium from the cytoplasm into the endoplasmic reticulum lumen. This pump is critical for maintaining low cytosolic calcium concentrations and high ER calcium stores. In neurons, SERCA2 regulates calcium homeostasis essential for synaptic transmission, neuronal plasticity, and cellular signaling. The protein uses ATP hydrolysis to transport calcium ions against a concentration gradient, with two calcium ions transported per ATP molecule hydrolyzed. SERCA2 is expressed in all neuronal subtypes and is particularly important in regions with high synaptic activity.
Dysregulation of SERCA2 contributes to calcium homeostasis defects observed in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Reduced SERCA activity leads to elevated cytosolic calcium, mitochondrial dysfunction, and activation of calcium-dependent apoptotic pathways [1]. In AD, amyloid-beta oligomers directly inhibit SERCA function, leading to ER stress and neuronal death [2]. SERCA dysfunction also contributes to synaptic loss and cognitive decline. Additionally, SERCA2 mutations cause Darier disease, characterized by neurological symptoms including seizures and intellectual disability.
Small molecule SERCA activators such as CDn2PEt and istirslumab are being developed for neurodegenerative diseases [3]. Gene therapy approaches using AAV vectors to deliver SERCA2 are in preclinical development. Natural compounds including resveratrol and curcumin show SERCA-modulating activity. Calcium stabilizers targeting SERCA function represent a therapeutic strategy for AD and PD.
Ferrao et al. Amyloid-beta impairs SERCA function in hippocampal neurons (2022). 2022. ↩︎