SERCA2

SERCA2 is a Ca²⁺-ATPase that pumps calcium ions (Ca²⁺) from the cytoplasm into the sarcoplasmic/endoplasmic reticulum using energy (ATP). The enzyme is encoded by the ATP2A2 gene, which is localized on chromosome 12q24.11. SERCA2 has two main isoforms:

• SERCA2a: mainly in the heart muscle (cardiomyocytes) and in slow skeletal muscle fibers - important for relaxation after contraction.
• SERCA2b: ubiquitously expressed, constitutively active - higher affinity for Ca²⁺, but lower transport speed.

Calcium-pumping ATPases have the task of maintaining a low cytoplasmic concentration of Ca2+ ions. They are transporters with high affinity and low capacity. The enzyme is also involved in the following biological processes:

• Autophagy in response to starvation
• Controls ER isolation membrane contacts for autophagosome formation after interaction with VMP1 and activation
• Also modulates ER contacts with lipid droplets, mitochondria and endosomes
• SERCA2 is involved in the regulation of the contraction/relaxation cycle of the muscle cell
• Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64, which is responsible for TNFSF11-induced CREB1 activation and mitochondrial ROS formation required for proper osteoclast formation.

AtPase activity is modulated by phospholamban (PLN) in cardiac muscle. Non-phosphorylated PLN inhibits SERCA2a. Phosphorylated PLN (e.g. by β-adrenaline stimulation) removes the inhibition. The activity can also be regulated by post-translational modifications (e.g. oxidation, phosphorylation).

Heart failure: reduced SERCA2a activity leads to impaired Ca²⁺ recycling and contraction weakness.

Dyskeratosis follicularis: mutations in the ATP2A2 gene lead to impaired cell adhesion

1. Korosec B et al. (2006) Alterations in the ATP2A2 gene in correlation with colon and lung cancer. Cancer Genet Cytogenet 171:105-111
2. Ren YQ et al. (2006) Five mutations of ATP2A2 gene in Chinese patients with Darier's disease and a literature review of 86 cases reported in China. Arch Dermatol Res 298:58-63.
3. Zhao YG et al. (2018) The ER-localized autophagy protein EPG-3/VMP1 regulates ER contacts with other organelles by modulating ATP2A/SERCA activity. Autophagy 14:362-363.