Affinage

ATP2B2

Plasma membrane calcium-transporting ATPase 2 · UniProt Q01814

Length
1243 aa
Mass
136.9 kDa
Annotated
2026-06-09
55 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2B2 (PMCA2) is a plasma-membrane Ca2+-extruding ATPase that sets and shapes cytosolic and luminal calcium across sensory, neuronal, and epithelial tissues, with its subcellular targeting and activity tuned by alternative splicing and partner proteins (PMID:15357414, PMID:20826782, PMID:22252018). In cochlear and vestibular hair cells PMCA2 resides in stereocilia and pumps Ca2+ into endolymph, acting as the primary determinant of endolymph calcium homeostasis required for mechanotransduction (PMID:15357414). Its membrane polarity is splice-controlled: a Leu-Ile motif in 'b'-tail variants drives basolateral sorting while the size of the A-site insert directs apical targeting, and the w-insert in the first cytoplasmic loop carries autonomous apical-targeting information further reinforced by PDZ-scaffold interactions with NHERF1/NHERF2 (PMID:16803870, PMID:22252018, PMID:31087002). The w/a stereociliar variant is largely uncoupled from acute Ca2+ stimulation, enabling constitutive calcium extrusion (PMID:22047666). Disease-associated missense variants cluster near the Ca2+ pore and ATP:Mg2+ coordination site and impair pump activity, producing both loss- and gain-of-function effects that underlie progressive hearing loss, hair cell degeneration, and neurodevelopmental/cerebellar disorders [PMID:18974863, PMID:20826782, PMID:bio_10.1101_2025.08.25.672202, PMID:37675773]. In Purkinje neurons PMCA2 clears dendritic Ca2+ transients to set firing kinetics and dendritic growth, and is a constituent of the mGluR1-Homer-IP3R1 complex (PMID:17150372, PMID:20083513, PMID:24288624); in hippocampal interneurons it associates with α7-nAChRs and PSD-95 to control receptor cluster stability (PMID:22593058). In mammary epithelium and breast cancer PMCA2 lowers cytosolic calcium to suppress apoptosis, interacts with HER2 in actin-rich domains to maintain HER2-HSP90 stability and signaling, and promotes tumor formation (PMID:20534448, PMID:26729871, PMID:27148852). Pump specific activity is directly modulated by the cortical cytoskeleton, with F-actin polymerization inhibiting and disruption enhancing Ca2+ extrusion (PMID:28527708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2004 High

    Established the core physiological role of PMCA2 by showing it is the dominant calcium-extrusion route from hair cell stereocilia into endolymph, settling where and why the pump matters for hearing.

    Evidence Immunocytochemistry plus endolymph calcium measurement in dfw2J knockout vs control mice

    PMID:15357414

    Open questions at the time
    • Does not resolve splice-variant identity or molecular targeting mechanism in stereocilia
    • No structural basis for pump activity
  2. 2006 High

    Answered how a single gene achieves polarized membrane targeting, showing splice variation encodes basolateral versus apical sorting signals.

    Evidence Targeting-region mutagenesis and splice-variant expression with immunofluorescence in hair cells

    PMID:16803870

    Open questions at the time
    • Did not identify the scaffold proteins that read the apical signal
    • Mechanism of the A-site insert size effect unresolved
  3. 2006 Medium

    Placed PMCA2 within the neuronal mGluR1 signaling machinery, linking calcium clearance to metabotropic glutamate receptor signaling integrity in Purkinje neurons.

    Evidence Co-immunoprecipitation from cerebellum and protein-level analysis in PMCA2-null vs wild-type mice

    PMID:17150372

    Open questions at the time
    • Single-lab Co-IP without reciprocal validation of each partner
    • Direct versus indirect association within the complex not distinguished
  4. 2008 High

    Separated targeting from catalytic defects, showing a TM6 missense mutation reduces basal pump activity without mislocalization and causes progressive hair cell loss.

    Evidence ENU Oblivion (S877F) allele with in vitro pump activity assay, hair cell culture and histology

    PMID:18974863

    Open questions at the time
    • Mechanism by which reduced basal activity drives base-to-apex degeneration not defined
    • No structural model of the mutation site at the time
  5. 2010 High

    Extended the genotype-function map with an active-site mutation impairing long-term calcium extrusion, confirmed by direct calcium imaging in native sensory epithelium.

    Evidence Tommy (E629K) allele; CHO extrusion assay plus flash photolysis of caged calcium in utricle cultures and ABR

    PMID:20826782

    Open questions at the time
    • Dominant heterozygous mechanism not fully explained
    • Relationship to splice variant context unaddressed
  6. 2010 High

    Defined a non-sensory role, showing apical PMCA2 transports calcium into milk and that its loss raises cytosolic calcium to sensitize epithelial cells to apoptosis, with the reverse protecting cancer cells.

    Evidence PMCA2 knockout mouse mammary phenotyping plus siRNA and overexpression in T47D cells with calcium and apoptosis readouts

    PMID:20534448

    Open questions at the time
    • Downstream apoptotic effectors not identified at this stage
    • Did not address HER2 or calcineurin coupling
  7. 2010 High

    Quantified the neuronal calcium-clearance function, showing PMCA2 dosage controls dendritic calcium transient kinetics and thereby Purkinje neuron firing and motor precision.

    Evidence Two-photon calcium imaging and patch clamp in PMCA2+/- vs wild-type cerebellum with behavioral testing

    PMID:20083513

    Open questions at the time
    • Molecular partners mediating dendritic localization not defined here
    • Link to specific behavioral circuits incomplete
  8. 2011 High

    Explained how the stereociliar w/a variant supports constitutive extrusion, showing it is only marginally stimulated by acute calcium and that species-specific mutants differ in activity impact.

    Evidence In vitro aequorin-based calcium ejection assays of wild-type and mutant PMCA2 variants

    PMID:22047666

    Open questions at the time
    • Structural basis for stimulation-independence not resolved
    • Discordance between human V586M and murine mutant phenotypes unexplained
  9. 2012 Medium

    Connected PMCA2 anti-apoptotic function to a defined effector pathway, showing it restrains calcineurin/NFAT/FasL signaling in breast cancer cells.

    Evidence Co-IP, peptide disruption of the PMCA2/calcineurin interaction, NFAT reporter and apoptosis assays across cell lines

    PMID:22962307

    Open questions at the time
    • Single-lab interaction not independently confirmed
    • Whether the interaction is direct or scaffold-mediated unresolved
  10. 2012 High

    Identified a neuronal scaffold function, showing PMCA2 with PSD-95 limits α7-nAChR calcium signals and controls receptor cluster stability via CaMKII/proteasome turnover.

    Evidence Co-IP/MS from brain, calcium imaging, single-particle tracking and pharmacological dissection in hippocampal interneurons

    PMID:22593058

    Open questions at the time
    • Direct binding interface among PMCA2, PSD-95 and α7-nAChR not mapped
    • Generalizability beyond interneurons untested
  11. 2012 High

    Demonstrated that the w-insert is an autonomous apical targeting determinant, transferable to a normally basolateral isoform and enhanced by NHERF2-binding PDZ optimization.

    Evidence PMCA4/PMCA2-w chimera expression in polarized epithelial cells with localization and PDZ-ligand mutagenesis

    PMID:22252018

    Open questions at the time
    • Trafficking machinery recognizing the w-insert not identified
    • Quantitative contribution of PDZ versus insert in native cells unresolved
  12. 2013 Medium

    Linked PMCA2 calcium clearance to neuronal morphogenesis, showing its activity is required for Purkinje dendritic growth.

    Evidence Carboxyeosin inhibition in organotypic cerebellar slices with morphological quantification and pharmacological combinations

    PMID:24288624

    Open questions at the time
    • Carboxyeosin specificity for PMCA2 limited
    • Mechanistic coupling to mGluR1 and calcium channels only partially defined
  13. 2013 Medium

    Showed PMCA2 level controls neuronal differentiation and survival, with knockdown accelerating neurite outgrowth and triggering apoptosis alongside compensatory calcium-handler upregulation.

    Evidence Stable antisense PC12 cells with differentiation, calcium influx and apoptosis assays

    PMID:22921123

    Open questions at the time
    • Compensation by PMCA1/4 and SERCA confounds interpretation
    • Direct causal pathway to apoptosis not isolated
  14. 2016 High

    Defined a pro-tumorigenic mechanism upstream of HER2, showing PMCA2 maintains HER2-HSP90 stability and membrane retention in actin-rich domains and is required for HER2-driven tumor formation.

    Evidence Reciprocal Co-IP, siRNA with multiple readouts, RPPA, and PMCA2 knockout in MMTV-Neu mice

    PMID:26729871

    Open questions at the time
    • Whether HER2 interaction is direct or calcium/actin-dependent not fully separated
    • Structural interface unmapped
  15. 2016 Medium

    Established isoform specificity in cancer, showing only PMCA2 (not PMCA1/4) supports proliferation and chemoresistance.

    Evidence Isoform-specific siRNA with proliferation, viability and doxorubicin-sensitivity assays in MDA-MB-231 cells

    PMID:27148852

    Open questions at the time
    • Single-lab study
    • Mechanism linking PMCA2 to drug resistance not defined
  16. 2017 Medium

    Revealed cytoskeletal control of pump output, showing F-actin state directly modulates PMCA2 specific activity independent of surface expression.

    Evidence Live-cell calcium imaging in HEK293 with actin and microtubule pharmacology plus surface-expression controls

    PMID:28527708

    Open questions at the time
    • Molecular link between cytoskeleton and pump conformation unknown
    • Physiological context of regulation untested
  17. 2017 Medium

    Uncovered an extracellular/adhesion function, identifying PMCA2 as a calcium oxalate crystal-binding protein relevant to kidney stone pathogenesis.

    Evidence IP-MS interactome plus COM crystal-binding, adhesion and internalization assays with antibody neutralization in kidney cells

    PMID:29085954

    Open questions at the time
    • Whether crystal binding depends on pump activity unclear
    • Single-lab functional validation
  18. 2018 Medium

    Linked PMCA2 to sex-specific hormonal signaling, showing it is required for ERα signaling and estradiol analgesia in female dorsal horn.

    Evidence Ovariectomy/estradiol replacement and ERα agonist in PMCA2+/- vs wild-type mice with signaling and pain readouts

    PMID:30467368

    Open questions at the time
    • Mechanism connecting calcium handling to ERα signaling undefined
    • Male-female divergence unexplained
  19. 2019 Medium

    Defined PMCA2's role in nociceptive processing, showing haploinsufficiency alters pain sensitivity and dorsal-horn receptor/transporter levels in a sex-specific manner.

    Evidence Behavioral pain assays and Western blots in PMCA2+/- mice with sex stratification

    PMID:27702770

    Open questions at the time
    • Causality between receptor changes and pain phenotype not established
    • Cell-type origin of changes unresolved
  20. 2019 Medium

    Identified an upstream regulator of PMCA2 in pathological pain, showing IL-1β specifically downregulates PMCA2 to raise neuronal calcium.

    Evidence Western blot of PMCA2 in EAE/SCI dorsal horn and cytokine treatment of spinal neuron cultures with negative controls for SERCA/NCX

    PMID:31703709

    Open questions at the time
    • Transcriptional vs post-translational mechanism of downregulation unknown
    • Single-lab correlation with in vivo pain
  21. 2019 High

    Established the apical scaffolding requirement, showing NHERF1 retains PMCA2 at the apical membrane and that its loss disrupts polarity and triggers cell death.

    Evidence Reciprocal Co-IP, NHERF1 knockout mice, localization, Stat3 readout and histology in lactating mammary gland

    PMID:31087002

    Open questions at the time
    • Relative contributions of NHERF1 vs NHERF2 not quantified
    • Whether cell death is a direct consequence of PMCA2 mislocalization unclear
  22. 2023 Medium

    Connected PMCA2 to human neurodevelopmental disease, showing de novo variants cause both loss- and gain-of-function calcium-handling changes.

    Evidence Exome/genome sequencing, in silico structural analysis and cell-based cytosolic calcium assays for multiple variants

    PMID:37675773

    Open questions at the time
    • Mechanism by which gain-of-function variants cause disease unresolved
    • Genotype-phenotype correlation across variants incomplete
  23. 2025 Medium

    Provided the structural framework, determining a cryo-EM structure that localizes neuropsychiatric variants to the Ca2+ pore and ATP:Mg2+ site and confirms their functional impact.

    Evidence Cryo-EM at 2.64 Å with 3D variant-clustering analysis and in vitro Ca2+ extrusion assays of disease mutants (preprint)

    PMID:bio_10.1101_2025.08.25.672202

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Structure does not capture splice-variant or partner-bound states
  24. 2025 Medium

    Expanded the localization repertoire, showing a lysosomal splice variant forms a conserved complex with NPC1 to mediate lysosomal calcium uptake relevant to NPC and Parkinson's disease.

    Evidence Subcellular fractionation, Co-IP with NPC1 and lysosomal calcium measurements in disease models (preprint)

    PMID:bio_10.1101_2025.10.01.679724

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Splice-variant determinant of lysosomal targeting not mapped
    • Direct vs indirect NPC1 association unconfirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct splice variants, partner scaffolds, and cytoskeletal state are integrated to select PMCA2 localization (apical, basolateral, lysosomal) and tune activity in a tissue-specific manner remains unresolved.
  • No unified model linking splice variant to trafficking machinery
  • Structural basis of partner and cytoskeletal regulation undefined
  • Mechanism distinguishing loss- vs gain-of-function disease outcomes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140657 ATP-dependent activity 4 GO:0016787 hydrolase activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005764 lysosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CALCINEURINCHRNA7HER2HSP90NHERF1NHERF2NPC1PSD-95
Complex memberships
PMCA2-NPC1 lysosomal complexmGluR1-Homer-IP3R1 signaling complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 PMCA2 is localized to the stereocilia of inner and outer hair cells, where it actively transports calcium into the endolymph. Mice lacking PMCA2 (dfw2J) have significantly lower endolymph calcium concentrations, establishing that PMCA2 is the primary mechanism for calcium extrusion from stereocilia into endolymph and is required for endolymph calcium maintenance. Immunocytochemistry for PMCA2 localization in stereocilia; calcium-sensitive fluorescent dye with aspirating microelectrode to measure endolymph calcium in dfw2J versus control mice Journal of the Association for Research in Otolaryngology : JARO High 15357414
2006 Differential membrane targeting of PMCA2 in hair cells is determined by alternative splicing: a Leu-Ile motif in 'b'-tail splice variants promotes basolateral sorting, whereas apical targeting of PMCA2 depends on the size of the A-site-spliced insert in the first cytoplasmic loop. Targeting region mutagenesis and expression of splice variants in hair cells; immunofluorescence localization Journal of cell science High 16803870
2006 PMCA2 co-immunoprecipitates with mGluR1, Homer 3, and IP3R1 in cerebellar Purkinje neurons, indicating it is a constituent of the mGluR1 signaling complex. Loss of PMCA2 in null mice results in reduced cerebellar levels of mGluR1, IP3R1, Homer 1b/c, and Homer 3, specifically in Purkinje neurons but not hippocampus, indicating region-specific disruption of metabotropic glutamate receptor signaling. Co-immunoprecipitation from cerebellar tissue; Western blot and immunofluorescence in PMCA2-null mice vs. wild-type littermates Molecular and cellular neurosciences Medium 17150372
2008 A missense mutation (S877F) in transmembrane domain 6 of PMCA2 (Oblivion allele) does not impair targeting to the plasma membrane but significantly reduces the non-stimulated (basal) calcium-exporting activity of the pump, causing progressive hearing loss with base-to-apex hair cell degeneration. ENU mutagenesis; mutation analysis; pump expression in model cells with biochemical/biophysical characterization of Ca2+ export; hair cell culture; immunofluorescence PLoS genetics High 18974863
2010 A missense mutation E629K in the second intracellular loop (active site) of PMCA2 (Tommy allele) impairs the long-term, non-stimulated calcium extrusion activity of the pump. Direct measurement by confocal imaging combined with flash photolysis of caged calcium in neonatal utricle sensory epithelium showed impaired calcium export in heterozygous and homozygous Tommy mice, causing profound hearing impairment and progressive hair cell degeneration. CHO cell expression with calcium extrusion assay; confocal imaging with flash photolysis of caged calcium in organotypic utricle cultures; immunofluorescence; auditory brainstem response The Journal of biological chemistry High 20826782
2010 PMCA2 is expressed at the apical surface of mammary epithelial cells during lactation and transports calcium into milk. Loss of PMCA2 expression during mammary gland involution raises intracellular calcium levels and sensitizes mammary epithelial cells to apoptosis. Conversely, overexpression of PMCA2 in T47D breast cancer cells lowers intracellular calcium and protects them from apoptosis. PMCA2 knockout mice phenotyping; siRNA knockdown and overexpression in T47D cells with intracellular calcium measurement and apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 20534448
2010 In cerebellar Purkinje neurons, reducing PMCA2 to 50% (heterozygous knockout) nearly doubles the time constant for calcium transient recovery in dendrites, prolongs calcium-dependent K+ currents, weakens climbing fiber responses, and slows action potential firing frequency, demonstrating that PMCA2 is required for the kinetics of calcium clearance that determines Purkinje neuron electrical output and motor coordination precision. Two-photon calcium imaging in Purkinje dendrites; whole-cell patch clamp in PMCA2+/- versus wild-type mice; Western blot for PMCA2 levels; narrow-beam behavioral assay The Journal of physiology High 20083513
2011 The PMCA2w/a splice variant (expressed in stereocilia) increases its activity only marginally in response to rapid cytoplasmic Ca2+ elevation (unlike other PMCA2 variants that are strongly stimulated), allowing constitutive calcium extrusion in stereocilia. A human mutant (V586M) failed to impair the pump's calcium ejection activity, while a murine mutant displayed evident defects in both basal activity and long-range calcium ejection. In vitro pump activity assays in model cells overexpressing wild-type or mutant PMCA2 variants; calcium ejection measured by aequorin-based assay Cell calcium High 22047666
2012 PMCA2 interacts with calcineurin in breast cancer cells (inhibitory interaction). Disruption of the PMCA2/calcineurin interaction activates the calcineurin/NFAT pathway, upregulates the pro-apoptotic protein Fas Ligand, and induces apoptotic cell death; this effect is potentiated when combined with paclitaxel. Co-immunoprecipitation; disruption of PMCA2/calcineurin interaction with competing peptides; NFAT pathway reporter assay; Fas Ligand Western blot; viability and apoptosis assays in multiple breast cancer cell lines Carcinogenesis Medium 22962307
2012 PMCA2 is physically associated with α7-nicotinic acetylcholine receptors (α7-nAChRs) and the scaffold protein PSD-95 in hippocampal interneurons. PMCA2 activity limits the duration of calcium elevations produced by α7-nAChR activation. Inhibition of PMCA2 triggers rapid CaMKII- and proteasome-dependent removal of α7-nAChR clusters in a PSD-95-dependent manner, without affecting other calcium-permeable receptors on the same neurons. Functional proteomics (co-immunoprecipitation/mass spectrometry) from rat brain; calcium imaging in hippocampal interneuron cultures; PMCA2 inhibitor carboxyeosin; single-particle tracking of α7-nAChR; CaMKII inhibitor and proteasome inhibitor experiments The Journal of neuroscience High 22593058
2012 The w-splice insert in the first intracellular loop of PMCA2 is sufficient to direct apical membrane targeting when inserted into the normally basolateral PMCA4 isoform. Optimizing the PDZ ligand site to interact with scaffolding protein NHERF2 further enhances apical localization of the chimeric pump, demonstrating that the w-insert provides autonomous apical targeting information. Chimeric pump construction (PMCA4 with PMCA2 w-insert); polarized epithelial cell transfection; immunofluorescence localization; PDZ ligand mutagenesis; calcium signaling assays Cell calcium High 22252018
2016 PMCA2 physically interacts with HER2 in actin-rich membrane domains of breast cancer cells. Knockdown of PMCA2 increases intracellular calcium, disrupts HER2-HSP90 interactions, inhibits HER2 signaling, and causes internalization and degradation of HER2. Knockout of PMCA2 inhibits mammary tumor formation in MMTV-Neu mice, placing PMCA2 upstream of HER2 membrane retention and signaling. Co-immunoprecipitation; siRNA knockdown; reverse-phase protein array; confocal microscopy; PMCA2 knockout in MMTV-Neu mice; tumor formation assay Proceedings of the National Academy of Sciences of the United States of America High 26729871
2016 Silencing of PMCA2 (but not PMCA1 or PMCA4) reduces MDA-MB-231 breast cancer cell proliferation and sensitizes cells to doxorubicin-induced cytotoxicity, demonstrating an isoform-specific role for PMCA2 in breast cancer cell survival. siRNA-mediated knockdown of PMCA2, PMCA1, and PMCA4; cell proliferation and viability assays; calcium signaling measurement; flow cytometry Scientific reports Medium 27148852
2017 PMCA2 activity is regulated by the cortical cytoskeleton: disruption of F-actin with cytochalasin D increases PMCA2-mediated Ca2+ extrusion (~50-100%), while stabilization of F-actin with jasplakinolide fully inhibits it. Microtubule disruption with colchicine decreases PMCA activity (~40-60%). These effects occur without changes in surface expression, indicating regulation of specific activity. Live cell calcium imaging in HEK293 cells expressing PMCA2; pharmacological manipulation of actin (cytochalasin D, jasplakinolide) and microtubules (colchicine); surface expression quantification Biochimica et biophysica acta. Molecular cell research Medium 28527708
2019 NHERF1 interacts with PMCA2 at the apical membrane of lactating mammary epithelial cells and is required for PMCA2's proper apical localization. Loss of NHERF1 in knockout mice displaces PMCA2 from the apical membrane, disrupts apical-basal polarity, and triggers premature Stat3 activation and lysosome-mediated cell death. PMCA2 also interacts with NHERF2, which partially compensates for NHERF1 loss. Co-immunoprecipitation; NHERF1 knockout mice; immunofluorescence localization; Western blot for Stat3 activation; mammary gland histology Endocrinology High 31087002
2019 PMCA2 expression in the dorsal horn is required for normal nociceptive processing in a sex-specific manner: female (but not male) PMCA2+/- mice show increased mechanical pain sensitivity and reduced heat sensitivity, accompanied by female-specific changes in mGluR1, NMDA receptor subunits, AMPA receptor subunit GluR1, GABA receptor subunits, and glutamate transporter levels in the dorsal horn. Behavioral pain assays (von Frey, Hargreaves) in PMCA2+/- vs. wild-type mice; Western blot for receptor and transporter levels in dorsal horn; sex-stratified analysis FASEB journal Medium 27702770
2019 Decreased PMCA2 expression in the dorsal horn parallels increased neuropathic pain in EAE (multiple sclerosis model) and spinal cord injury mice. IL-1β, acting directly on spinal cord neurons in culture, specifically downregulates PMCA2 protein levels (SERCA and NCX remained unaltered), identifying IL-1β as an effector that reduces PMCA2 expression to increase neuronal calcium and pain sensitivity. Western blot of PMCA2 in dorsal horn of EAE and SCI mice; pure spinal cord neuronal cultures treated with cytokines (IL-1β, TNFα, IL-6); behavioral pain assays Journal of neuroinflammation Medium 31703709
2018 PMCA2 is required for adequate ERα signaling in the female dorsal horn: ERα agonist induces ERα signaling in PMCA2+/+ but not PMCA2+/- female mice, and estradiol analgesia is lost in PMCA2+/- females. This sex-specific link between PMCA2 and ERα is absent in male mice. Ovariectomy and estradiol replacement in PMCA2+/+ vs. PMCA2+/- mice; intrathecal ERα agonist administration; Western blot for ERα signaling in dorsal horn; behavioral pain assays Scientific reports Medium 30467368
2013 PMCA2 activity is required for Purkinje cell dendritic growth: pharmacological inhibition of PMCA2 with carboxyeosin reduces Purkinje cell dendritic tree size in cerebellar organotypic slice cultures. PMCA2 inhibition also partially rescues dendritic morphology when combined with mGluR1 stimulation, likely via compensatory inactivation of voltage-gated calcium channels. Organotypic cerebellar slice cultures; carboxyeosin inhibition of PMCA2; immunofluorescence for Purkinje cell morphology; pharmacological combinations with mGluR1 agonists and calcium channel blockers Neural plasticity Medium 24288624
2013 Downregulation of PMCA2 in PC12 cells accelerates neuronal differentiation, promotes longer neurite formation, and leads to apoptosis with DNA laddering. PMCA2 suppression triggers compensatory upregulation of PMCA1, PMCA4, and SERCA, and alters voltage-dependent calcium channel expression and contribution to calcium influx. Stable antisense transfection of PC12 cells; cAMP-induced differentiation; Western blot for calcium handling proteins; calcium influx measurements; apoptosis assays (DNA laddering) Cell calcium Medium 22921123
2017 PMCA2-interacting complex in kidney cells includes 474 proteins identified by immunoprecipitation-mass spectrometry. Functional validation revealed a novel role for PMCA2 as a calcium oxalate monohydrate (COM) crystal-binding protein: neutralization with anti-PMCA2 antibody reduces COM crystal-cell adhesion and crystal internalization, implicating PMCA2 in kidney stone pathogenesis. Immunoprecipitation followed by nanoLC-ESI-Qq-TripleTOF MS/MS; quantitative immuno-co-localization; COM crystal-protein binding assay; crystal-cell adhesion and internalization assays with antibody neutralization Cellular and molecular life sciences : CMLS Medium 29085954
2025 A splice variant of PMCA2 localizes to the lysosome (not only the plasma membrane) where it forms an evolutionarily conserved complex with NPC1. This lysosomal PMCA2 mediates calcium uptake into lysosomes. Disruption of the NPC1-PMCA2 complex contributes to lysosomal calcium dysregulation in Niemann-Pick disease type C and Parkinson's disease. Subcellular fractionation/localization; co-immunoprecipitation with NPC1; lysosomal calcium measurements; disease model validation (NPC, Parkinson's disease models) bioRxivpreprint Medium bio_10.1101_2025.10.01.679724
2025 Cryo-EM structure of human calcium-bound ATP2B2 at 2.64 Å resolution was determined. Structural analysis revealed that neuropsychiatric disease-associated missense variants cluster near the Ca2+ pore and ATP:Mg2+ coordination site. In vitro assays confirmed that missense variants at these structural hotspots impair ATP2B2-mediated Ca2+ extrusion in cellular and biochemical assays. Cryo-EM structure determination at 2.64 Å; 3D-neighborhood missense variant clustering analysis on AlphaFold3-predicted structures validated by the cryo-EM map; in vitro Ca2+ extrusion assays with disease-associated missense mutants bioRxivpreprint Medium bio_10.1101_2025.08.25.672202
2023 De novo missense ATP2B2 variants (including variants at Ca2+ transport domain residues) cause both loss-of-function and gain-of-function alterations in cytosolic calcium handling in cell-based studies, demonstrating that precise ATP2B2-mediated calcium regulation is required for neurodevelopment and cerebellar function. Exome/genome sequencing; in silico structural analysis; cell-based cytosolic calcium handling assays for each variant; clinical phenotyping Genetics in medicine Medium 37675773

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Modification of human hearing loss by plasma-membrane calcium pump PMCA2. The New England journal of medicine 141 15829536
2010 PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer. Proceedings of the National Academy of Sciences of the United States of America 99 20534448
2004 Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance. Journal of the Association for Research in Otolaryngology : JARO 68 15357414
2016 PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer. Proceedings of the National Academy of Sciences of the United States of America 64 26729871
2008 The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss. PLoS genetics 60 18974863
2010 The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice. The Journal of biological chemistry 58 20826782
2006 Molecular determinants for differential membrane trafficking of PMCA1 and PMCA2 in mammalian hair cells. Journal of cell science 58 16803870
2016 The calcium pump plasma membrane Ca(2+)-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin. Scientific reports 56 27148852
2006 Molecular alterations in the cerebellum of the plasma membrane calcium ATPase 2 (PMCA2)-null mouse indicate abnormalities in Purkinje neurons. Molecular and cellular neurosciences 45 17150372
2011 Converging evidence for an association of ATP2B2 allelic variants with autism in male subjects. Biological psychiatry 44 21757185
2010 Reduced expression of the Ca(2+) transporter protein PMCA2 slows Ca(2+) dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination. The Journal of physiology 38 20083513
2012 Disruption of the interaction between PMCA2 and calcineurin triggers apoptosis and enhances paclitaxel-induced cytotoxicity in breast cancer cells. Carcinogenesis 35 22962307
2018 De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. Human genetics 33 30535804
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
1992 Determination of the nucleotide sequence and chromosomal localization of the ATP2B2 gene encoding human Ca(2+)-pumping ATPase isoform PMCA2. Genomics 32 1427863
2012 PMCA2 via PSD-95 controls calcium signaling by α7-containing nicotinic acetylcholine receptors on aspiny interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 22593058
2006 Atp2b2, encoding plasma membrane Ca2+-ATPase type 2, (PMCA2) exhibits tissue-specific first exon usage in hair cells, neurons, and mammary glands of mice. Neuroscience 31 16675132
2013 The evidence for association of ATP2B2 polymorphisms with autism in Chinese Han population. PloS one 30 23620727
2017 Characterizations of PMCA2-interacting complex and its role as a calcium oxalate crystal-binding protein. Cellular and molecular life sciences : CMLS 27 29085954
2012 Downregulation of PMCA2 or PMCA3 reorganizes Ca(2+) handling systems in differentiating PC12 cells. Cell calcium 25 22921123
2011 Mutations in PMCA2 and hereditary deafness: a molecular analysis of the pump defect. Cell calcium 25 22047666
2006 A de novo deafwaddler mutation of Pmca2 arising in ES cells and hitchhiking with a targeted modification of the Pparg gene. Mammalian genome : official journal of the International Mammalian Genome Society 20 16845470
2010 The role of the calcium transporter protein plasma membrane calcium ATPase PMCA2 in cerebellar Purkinje neuron function. Functional neurology 19 21232211
2023 ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures. Genetics in medicine : official journal of the American College of Medical Genetics 18 37675773
2016 PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263. Biochemical and biophysical research communications 18 27613092
2013 A new Atp2b2 deafwaddler allele, dfw(i5), interacts strongly with Cdh23 and other auditory modifiers. Hearing research 18 23792079
2001 Effects of PMCA2 mutation on DPOAE amplitudes and latencies in deafwaddler mice. Hearing research 17 11124466
2001 PMCA2 mutation causes structural changes in the auditory system in deafwaddler mice. Journal of neurocytology 16 11875276
2018 A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor α signaling in mechanical pain. Scientific reports 15 30467368
2013 Downregulation of PMCA2 increases the vulnerability of midbrain neurons to mitochondrial complex I inhibition. Neurotoxicology 15 24269647
2008 Reductions in motor unit number estimates (MUNE) precede motor neuron loss in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice. Experimental neurology 15 18848933
2018 PMCA2 pump mutations and hereditary deafness. Neuroscience letters 14 29452611
2016 PON2 and ATP2B2 gene polymorphisms with noise-induced hearing loss. Journal of thoracic disease 14 27076938
2019 NHERF1 Is Required for Localization of PMCA2 and Suppression of Early Involution in the Female Lactating Mammary Gland. Endocrinology 12 31087002
2019 Pathological pain processing in mouse models of multiple sclerosis and spinal cord injury: contribution of plasma membrane calcium ATPase 2 (PMCA2). Journal of neuroinflammation 12 31703709
2016 Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 27702770
2013 Two ENU-induced alleles of Atp2b2 cause deafness in mice. PloS one 11 23826306
2013 The plasma membrane Ca2+-ATPase2 (PMCA2) is involved in the regulation of Purkinje cell dendritic growth in cerebellar organotypic slice cultures. Neural plasticity 10 24288624
2017 Cortical cytoskeleton dynamics regulates plasma membrane calcium ATPase isoform-2 (PMCA2) activity. Biochimica et biophysica acta. Molecular cell research 6 28527708
2012 Plasma membrane calcium pump (PMCA) isoform 4 is targeted to the apical membrane by the w-splice insert from PMCA2. Cell calcium 6 22252018
2011 Identification of a novel point mutation of mouse Atp2b2 induced by N-ethyl-N-nitrosourea mutagenesis. Experimental animals 6 21325754
2019 Research and Discussion on the Relationships between Noise-Induced Hearing Loss and ATP2B2 Gene Polymorphism. International journal of genomics 5 31886164
2014 Changes in cochlear PMCA2 expression correlate with the maturation of auditory sensitivity. Journal of the Association for Research in Otolaryngology : JARO 5 24799196
1997 The human chromosome 3 gene cluster ACY1-CACNA1D-ZNF64-ATP2B2 is evolutionarily conserved in Ateles paniscus chamek (Platyrrhini, Primates). Cytogenetics and cell genetics 5 9284946
1995 Colocalization of the rat homolog of the von Hippel Lindau (Vhl) gene and the plasma membrane Ca++ transporting ATPase isoform 2 (Atp2b2) gene to rat chromosome bands 4q41.3-->42.1. Cytogenetics and cell genetics 5 7587388
2018 Differential expression of PMCA2 mRNA isoforms in a cohort of Spanish patients with breast tumor types. Oncology letters 4 30546427
2011 GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform. Biochemical and biophysical research communications 4 21798237
2024 Preliminary research on LncRNA ATP2B2-IT2 in neovascularization of diabetic retinopathy. BMC ophthalmology 2 38907191
2007 Plasma membrane Ca2+-ATPase isoforms in frog crista ampullaris: identification of PMCA1 and PMCA2 specific splice variants. Hearing research 2 17336006
2025 Exosomal Prolactin-Induced Protein Inhibits the Activation of cGMP/PKG Pathway Mediated by ATP2B2 to Promote Myocardial Fibrosis in Atrial Fibrillation. Antioxidants & redox signaling 1 40094760
2025 Immunolabel imaging of plasma membrane Ca++ pumps (PMCA-pan or PMCA2) implicates the apical cilium on receptor cells as the transduction site for electrosense in two Acipenseriformes fishes. Tissue & cell 1 40446761
2024 Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19. Heliyon 1 38628728
2018 Survival strategies for mouse cerebellar Purkinje neurons lacking PMCA2. Neuroscience letters 1 29452612
2025 Immunotherapy Responsive Recurrent Post-Infectious Ataxia Associated With Recurrent ATP2B2 Gene Variant. Neurology. Genetics 0 39834499
2024 Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies. Clinical genetics 0 39367743

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