Affinage

ATP2B3

Plasma membrane calcium-transporting ATPase 3 · UniProt Q16720

Length
1220 aa
Mass
134.2 kDa
Annotated
2026-06-09
19 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2B3 (PMCA3) is a plasma membrane Ca2+-ATPase that actively extrudes cytosolic Ca2+ to maintain Ca2+ homeostasis, with prominent roles in neuronal and adrenal cells (PMID:27035656, PMID:7770003). In neurons it is expressed primarily in cell processes, where it shapes Ca2+ handling: its loss accelerates differentiation and triggers compensatory upregulation of other Ca2+ transporters (PMCA1, PMCA4, SERCA), and it regulates Ca2+ specifically in sub-plasma membrane microdomains (PMID:7770003, PMID:22921123, PMID:36207321). Pump activity is negatively regulated by 14-3-3epsilon (and 14-3-3zeta) through phosphorylation-independent binding that blunts the cell's ability to restore basal Ca2+ after a transient (PMID:18029012). Loss-of-function somatic mutations clustered in the transmembrane domain — including in-frame deletions/indels such as Leu425_Val426del and K416_F418delinsN — impair Ca2+ export, elevate basal intracellular Ca2+, and produce a Na+-dependent depolarizing current; this drives upregulation of aldosterone synthase (CYP11B2) and its regulator NR4A2, accounting for autonomous aldosterone secretion in aldosterone-producing adenomas (PMID:23416519, PMID:24082052, PMID:27035656, PMID:34572956). Germline mutations in the catalytic P-domain (G733R) and adjacent to the calmodulin-binding region (E1081Q) impair Ca2+ handling, with the E1081Q effect dependent on the b splice variant, linking PMCA3 dysfunction to cerebellar ataxia (PMID:28807751, PMID:36207321). Knockdown of ATP2B3 also confers resistance to erastin-induced ferroptosis through the P62-KEAP1-NRF2-HO-1 axis (PMID:37298147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 Medium

    Establishing the genomic locus of ATP2B3 placed the gene on the X chromosome, a prerequisite for later linkage of germline mutations to X-linked phenotypes.

    Evidence FISH, somatic cell hybrid analysis, and genetic linkage mapping to Xq28

    PMID:8187550

    Open questions at the time
    • Does not address protein function or tissue expression
    • No mechanistic data
  2. 1995 Medium

    Determining where PMCA3 protein resides answered whether it is positioned to control local neuronal Ca2+, showing enrichment in neuronal cell processes.

    Evidence In situ hybridization, immunoblot, and immunohistochemistry with co-localization to neuronal processes in rat brain

    PMID:7770003

    Open questions at the time
    • Subcellular microdomain resolution not addressed
    • Functional consequence of process localization not tested
  3. 2007 High

    Identifying a regulator of PMCA3 activity revealed that 14-3-3epsilon/zeta bind the pump phosphorylation-independently and inhibit Ca2+ clearance, defining a post-translational brake on the pump.

    Evidence Two-hybrid, co-IP, GST pull-down, and aequorin Ca2+ measurements in CHO cells

    PMID:18029012

    Open questions at the time
    • Binding site on PMCA3 not mapped
    • Physiological context of inhibition in neurons not tested
  4. 2011 Low

    Linking PMCA3 to neurotransmitter synthesis machinery indicated its Ca2+ handling influences GABA synthesis enzymes in pituitary cells.

    Evidence Antisense knockdown in GH3 cells with GAD/GABA-T/SSADH enzyme assays and immunoblot

    PMID:21798237

    Open questions at the time
    • Single lab, single knockdown approach with limited mechanistic depth
    • Direct link between Ca2+ extrusion and GAD65 not established
    • Not confirmed in vivo
  5. 2012 Medium

    Knockdown phenotyping addressed PMCA3's role in neuronal Ca2+ machinery and differentiation, showing it shapes neurite outgrowth and is buffered by compensatory transporters.

    Evidence Antisense stable knockdown in PC12 cells with morphology, Ca2+ influx assays, and immunoblot for Ca2+ handling proteins

    PMID:22921123

    Open questions at the time
    • Compensation by PMCA1/4/SERCA complicates interpretation of direct role
    • Differentiation mechanism downstream of Ca2+ not resolved
  6. 2013 Medium

    Discovery of recurrent somatic ATP2B3 mutations in aldosterone-producing adenomas, with depolarization in mutant cells, established a loss-of-pump mechanism driving autonomous aldosterone secretion.

    Evidence Exome/Sanger sequencing of APAs, ex vivo electrophysiology, and overexpression in HAC15 cells with CYP11B2/NR4A2 readout

    PMID:23416519 PMID:24082052

    Open questions at the time
    • Detailed biophysical mechanism of depolarization not resolved in 2013
    • Causality of Ca2+ changes for CYP11B2 induction inferred
  7. 2016 High

    Mechanistic dissection of the Leu425_Val426del mutant resolved how transmembrane-domain loss-of-function causes disease: reduced Ca2+ export, elevated basal Ca2+, increased influx, and a Na+-dependent depolarizing current driving CYP11B2/aldosterone.

    Evidence Ca2+ imaging, patch-clamp, mRNA analysis, and aldosterone assay in NCI-H295R and HEK-293 cells

    PMID:27035656

    Open questions at the time
    • Molecular basis of the aberrant Na+-dependent current not structurally defined
    • In vivo validation absent
  8. 2017 Medium

    Characterizing a P-domain mutation (G733R) extended PMCA3 dysfunction to the catalytic core, showing impaired Ca2+ handling without gross structural perturbation.

    Evidence Live-cell Ca2+ assays plus homology modeling and molecular dynamics

    PMID:28807751

    Open questions at the time
    • No in vitro reconstitution of catalytic defect
    • Genotype–phenotype link to ataxia inferred from cell data
  9. 2021 Medium

    A new APA mutation (K416_F418delinsN) confirmed the recurrent functional logic of ATP2B3 loss-of-function in driving CYP11B2 and aldosterone.

    Evidence Sanger sequencing of APA tissue and transfection into HAC15 cells with CYP11B2 and aldosterone readouts

    PMID:34572956

    Open questions at the time
    • Single mutant, no electrophysiology
    • Ca2+ measurements not reported for this variant
  10. 2022 Medium

    Analysis of the ataxia-linked E1081Q mutation revealed a splice-variant-dependent effect on sub-plasma membrane Ca2+ microdomains, refining how calmodulin-region mutations alter local Ca2+ control.

    Evidence Live-cell sub-PM Ca2+ microdomain measurements with variant-specific PMCA3 constructs

    PMID:36207321

    Open questions at the time
    • Mechanism by which splice variant determines opposite effects unresolved
    • In vivo neuronal consequence not tested
  11. 2023 Medium

    Placing ATP2B3 in a ferroptosis pathway showed its knockdown protects neuronal cells via P62-KEAP1-NRF2-HO-1 signaling, broadening its role beyond Ca2+ pumping.

    Evidence siRNA knockdown, TMT proteomics, viability and ROS assays, and epistasis/rescue with NRF2/P62/KEAP1/HO-1 in HT-22 cells

    PMID:37298147

    Open questions at the time
    • Direct molecular connection between Ca2+ extrusion and NRF2 pathway not established
    • Single cell line

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PMCA3 Ca2+ extrusion is mechanistically coupled to its downstream regulatory outputs — CYP11B2 induction in adrenal cells, ataxia in neurons, and the ferroptosis pathway — remains unresolved at the molecular level.
  • No high-resolution structure of human PMCA3 or its mutants
  • 14-3-3 binding site and integration with mutation effects unmapped
  • Mechanism linking Ca2+ handling to NRF2/ferroptosis signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0016787 hydrolase activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3
Partners
YWHAEYWHAZ

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Somatic hotspot mutations in ATP2B3 (encoding plasma membrane Ca2+-ATPase 3) were identified in aldosterone-producing adenomas (APAs). Electrophysiological ex vivo studies on primary adrenal adenoma cells provided evidence for inappropriate depolarization of cells with ATP2B3 alterations, consistent with loss of normal Ca2+ pump function driving autonomous aldosterone secretion. Exome sequencing of APAs, electrophysiological ex vivo studies on primary adrenal adenoma cells Nature genetics Medium 23416519
2013 Somatic ATP2B3 mutations in APAs lead to upregulation of CYP11B2 (aldosterone synthase) gene expression. Overexpression of ATP2B3 mutants in HAC15 adrenal cells resulted in increased CYP11B2 and its transcriptional regulator NR4A2 expression. Sanger sequencing, overexpression in HAC15 adrenal cells, gene expression analysis (CYP11B2, NR4A2) Hypertension (Dallas, Tex. : 1979) Medium 24082052
2016 The APA-associated ATP2B3 Leu425_Val426del mutation causes: (1) reduced Ca2+ export due to loss of physiological pump function; (2) elevated basal intracellular Ca2+ and increased Ca2+ influx; (3) a Na+-dependent inward current that strongly depolarizes the plasma membrane. These effects collectively increase aldosterone synthase (CYP11B2) mRNA expression and enhance aldosterone production. Ca2+ measurements (live-cell imaging), electrophysiology (patch-clamp), mRNA expression analysis, aldosterone assay in NCI-H295R and HEK-293 cells overexpressing mutant ATP2B3 Endocrinology High 27035656
2007 The 14-3-3epsilon protein interacts with PMCA3 (ATP2B3) in a phosphorylation-independent manner, and this interaction inhibits PMCA3 pump activity. Co-expression of 14-3-3epsilon with PMCA3 in CHO cells substantially decreased the ability of cells to restore basal Ca2+ concentration following an InsP3-induced Ca2+ transient. The 14-3-3zeta isoform also interacted with PMCA3. Two-hybrid assay, co-immunoprecipitation, GST pull-down, aequorin-based Ca2+ measurements in CHO cells Cell calcium High 18029012
1995 PMCA3 protein is expressed in rat brain neurons and is localized primarily in cell processes (granule cell processes in cerebellum, dendritic fields in hippocampus CA1), with the translated protein having an observed molecular mass of ~135 kDa as predicted from molecular cloning. In situ hybridization, immunoblot analysis with anti-peptide antibodies, immunohistochemistry, co-localization with GAP-43 marker Brain research. Molecular brain research Medium 7770003
1994 ATP2B3 (PMCA isoform 3) was mapped to human chromosome Xq28 by fluorescence in situ hybridization (FISH), somatic cell hybrid analysis, and genetic linkage analysis. FISH, somatic cell hybrid analysis, genetic linkage analysis Cytogenetics and cell genetics Medium 8187550
2017 A novel PMCA3 G733R substitution in the catalytic P-domain impairs the pump's ability to control cellular Ca2+ handling under both basal and stimulated conditions. Homology modeling and molecular dynamics revealed that the mutated residue maintains the correct 3D configuration of the local pump structure. Biochemical Ca2+ handling assays (live-cell), homology modeling, molecular dynamics simulation Biochimica et biophysica acta. Molecular basis of disease Medium 28807751
2022 The ataxia-linked PMCA3 E1081Q mutation (immediately upstream of the calmodulin-binding domain) shows a splicing variant-dependent effect: in the full-length b variant it abolishes the pump's capacity to reduce sub-plasma membrane [Ca2+], while in the truncated a variant it selectively increases Ca2+ extrusion activity in sub-plasma membrane microdomains. Live-cell Ca2+ microdomain measurements, expression of variant-specific PMCA3 constructs, biochemical/molecular characterization Cell death & disease Medium 36207321
2012 Downregulation of PMCA3 in PC12 cells accelerates dibutyryl-cAMP-induced neuronal differentiation and results in longer neurites, altered expression of voltage-dependent Ca2+ channels (VDCCs), and compensatory upregulation of PMCA1, PMCA4, and SERCA, indicating that PMCA3 participates in the control of neuronal Ca2+ handling machinery and differentiation. Antisense-mediated stable knockdown in PC12 cells, morphological analysis, Ca2+ influx assays, immunoblot for Ca2+ handling proteins Cell calcium Medium 22921123
2023 ATP2B3 knockdown in HT-22 cells alleviates erastin-induced ferroptosis by acting through the P62-KEAP1-NRF2-HO-1 pathway: knockdown reversed upregulation of P62, NRF2, HO-1, NQO1 and downregulation of KEAP1 induced by erastin, and reduced ROS production. HO-1 overexpression reversed the protective effect of ATP2B3 inhibition, confirming pathway placement. siRNA knockdown, TMT-based proteomics, cell viability assay, ROS measurement, epistasis by NRF2 KD/P62 inhibition/KEAP1 OE, HO-1 overexpression rescue International journal of molecular sciences Medium 37298147
2021 A novel ATP2B3 K416_F418delinsN somatic mutation causes a functional defect: HAC15 adrenal cells transfected with this mutant showed increased CYP11B2 expression and increased aldosterone production. Sanger sequencing of APA tissue, transfection of mutant gene into HAC15 cells, CYP11B2 expression analysis, aldosterone production assay Cancers Medium 34572956
2011 Suppression of PMCA3 in GH3 cells increased GAD65 expression, indicating that PMCA3 activity modulates GABA synthesis machinery in pituitary cells. Antisense-mediated knockdown of PMCA3 in GH3 cells, enzyme activity assays (GAD, GABA-T, SSADH), immunoblot Biochemical and biophysical research communications Low 21798237

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nature genetics 448 23416519
2013 Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension (Dallas, Tex. : 1979) 135 24082052
2006 CLA-1 and its splicing variant CLA-2 mediate bacterial adhesion and cytosolic bacterial invasion in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 57 17071747
2016 Cellular Pathophysiology of an Adrenal Adenoma-Associated Mutant of the Plasma Membrane Ca(2+)-ATPase ATP2B3. Endocrinology 52 27035656
1995 Localization of the plasma membrane Ca(2+)-ATPase isoform PMCA3 in rat cerebellum, choroid plexus and hippocampus. Brain research. Molecular brain research 45 7770003
1994 Localization of two genes encoding plasma membrane Ca2+ ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes 3p26-->p25 and Xq28, respectively. Cytogenetics and cell genetics 32 8187550
2007 Inhibitory interaction of the 14-3-3 proteins with ubiquitous (PMCA1) and tissue-specific (PMCA3) isoforms of the plasma membrane Ca2+ pump. Cell calcium 26 18029012
2012 Downregulation of PMCA2 or PMCA3 reorganizes Ca(2+) handling systems in differentiating PC12 cells. Cell calcium 25 22921123
2004 Characterization and expression of plasma membrane Ca2+ ATPase (PMCA3) in the crayfish Procambarus clarkii antennal gland during molting. The Journal of experimental biology 24 15277554
2013 Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Human molecular genetics 18 23773993
1989 Analysis of a novel VHS107 haplotype in CLA-2 and WSA mice. Evidence for gene conversion among IgVH genes in outbred populations. The Journal of experimental medicine 14 2584925
2017 A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect. Biochimica et biophysica acta. Molecular basis of disease 12 28807751
2023 ATP2B3 Inhibition Alleviates Erastin-Induced Ferroptosis in HT-22 Cells through the P62-KEAP1-NRF2-HO-1 Pathway. International journal of molecular sciences 6 37298147
2022 The ataxia-linked E1081Q mutation affects the sub-plasma membrane Ca2+-microdomains by tuning PMCA3 activity. Cell death & disease 5 36207321
2015 A Novel Somatic Deletion Mutation of ATP2B3 in Aldosterone-Producing Adenoma. Endocrine pathology 5 26481629
2012 Ectopic expression of a maize calreticulin mitigates calcium deficiency-like disorders in sCAX1-expressing tobacco and tomato. Plant molecular biology 5 23007728
2011 GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform. Biochemical and biophysical research communications 4 21798237
2021 Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma. Cancers 1 34572956
2022 Expression, purification and structure determination of the chlorinase ClA2. Biochemical and biophysical research communications 0 36081280

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