Affinage

ATP2B2

Plasma membrane calcium-transporting ATPase 2 · UniProt Q01814

Round 2 corrected
Length
1243 aa
Mass
136.9 kDa
Annotated
2026-04-28
85 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP2B2 encodes PMCA2, a P-type Ca²⁺-ATPase that actively extrudes cytosolic calcium across the plasma membrane, functioning as the dominant calcium clearance mechanism in inner ear hair cell stereocilia and cerebellar Purkinje neuron dendrites (PMID:5357414, PMID:20083513). Alternative splicing at the first intracellular loop (site A) and C-terminal tail (site C) generates isoforms with distinct calmodulin sensitivity, apical versus basolateral membrane targeting, and PDZ-domain scaffold interactions (NHERF1/2, PSD-95), with the w/a splice variant providing calmodulin-independent sustained Ca²⁺ extrusion in stereocilia (PMID:8245032, PMID:22252018, PMID:29452611, PMID:31087002). PMCA2 participates in multi-protein signaling complexes—including mGluR1/Homer/IP3R1 in cerebellum, α7-nAChR/PSD-95 in hippocampus, and HER2/HSP90 in breast cancer cells—through which it couples local calcium homeostasis to synaptic function, receptor stability, calcineurin/NFAT-mediated apoptosis, and mammary gland involution (PMID:17150372, PMID:22593058, PMID:26729871, PMID:22962307, PMID:20534448). De novo ATP2B2 missense and frameshift variants cause a neurodevelopmental syndrome featuring ataxia, dystonia, intellectual disability, and seizures, while hypofunctional variants modify sensorineural hearing loss severity (PMID:37675773, PMID:15829536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1992 High

    Molecular identity of PMCA2 was established by cloning the human ATP2B2 cDNA, revealing it as a distinct plasma membrane Ca²⁺-ATPase isoform with high interspecies conservation and mapping it to chromosome 3.

    Evidence cDNA cloning, sequencing, and somatic cell hybrid Southern blot analysis

    PMID:1427863

    Open questions at the time
    • No functional characterization of pump activity at this stage
    • Tissue-specific expression pattern not yet determined
  2. 1993 High

    Alternative splicing at two regulatory sites (A and C) was shown to generate multiple PMCA2 isoforms with tissue-restricted expression (brain, skeletal muscle), establishing that splice variation is a major determinant of PMCA2 functional diversity.

    Evidence Quantitative RT-PCR with isoform-specific primers across seven human tissues

    PMID:8245032

    Open questions at the time
    • Functional consequences of individual splice variants not yet measured
    • Subcellular targeting determinants of splice variants unknown
  3. 2001 High

    PMCA2b was found to interact selectively with PDZ-domain scaffold proteins (PSD-95, PSD-93, SAP97 but not SAP102) and colocalize with PSD-95 in hippocampal dendritic spines, establishing PMCA2 as a component of organized postsynaptic signaling complexes rather than an isolated pump.

    Evidence Yeast two-hybrid, co-immunoprecipitation, confocal immunofluorescence in MDCK cells and hippocampal neurons

    PMID:11274188

    Open questions at the time
    • Functional consequence of PMCA2–scaffold interaction on local calcium dynamics not yet measured
    • Selectivity mechanism for SAP family members unclear
  4. 2004 High

    PMCA2 was localized to hair cell stereocilia and shown to be essential for endolymph calcium homeostasis: deafwaddler2J mice lacking stereociliary PMCA2 had significantly reduced endolymph Ca²⁺, directly linking pump activity to hearing and balance.

    Evidence Immunocytochemistry and Ca²⁺-sensitive fluorescent dye measurement in dfw2J versus control mouse endolymph

    PMID:15357414

    Open questions at the time
    • Contribution of PMCA2 relative to other Ca²⁺ transport mechanisms in endolymph not quantified
    • Mechanism of progressive hair cell degeneration not delineated
  5. 2005 High

    The first human genetic evidence showed that a hypofunctional PMCA2 variant (V586M) acts as a modifier of sensorineural hearing loss severity across multiple families and etiologies, establishing PMCA2 as a clinically relevant modifier locus.

    Evidence Genetic analysis of human families with SNHL, functional characterization of V586M

    PMID:15829536

    Open questions at the time
    • Precise biochemical defect of V586M debated—later studies showed it may not impair Ca²⁺ ejection directly
    • Population frequency and penetrance not fully defined
  6. 2006 High

    Splice-dependent membrane targeting was mechanistically resolved: the w-insert in the first intracellular loop drives apical targeting, while a Leu-Ile motif in the b-tail promotes basolateral sorting, explaining how the same gene achieves polarized distribution in different cell types.

    Evidence PMCA chimera mutagenesis and immunofluorescence targeting assays in hair cells and cell lines

    PMID:16803870

    Open questions at the time
    • Binding partners that read the w-insert apical signal not identified
    • Whether targeting mechanism is identical in hair cells versus epithelial cells not resolved
  7. 2006 High

    PMCA2 was identified as a constituent of the mGluR1/Homer/IP3R1 signaling complex in cerebellum: PMCA2-null mice showed reduced levels of multiple complex members specifically in Purkinje neurons, revealing that PMCA2 is structurally required for complex integrity.

    Evidence Co-immunoprecipitation and immunohistochemistry in PMCA2-null versus wild-type mouse cerebellum

    PMID:17150372

    Open questions at the time
    • Direct binding interface between PMCA2 and mGluR1 not mapped
    • Whether complex disruption is cause or consequence of Purkinje neuron dysfunction not fully dissected
  8. 2008 High

    The Oblivion (S877F) mutation demonstrated that a transmembrane domain substitution can abolish non-stimulated Ca²⁺ export while preserving correct plasma membrane targeting, dissecting pump activity from trafficking for the first time.

    Evidence ENU mutagenesis, immunofluorescence, biochemical/biophysical Ca²⁺ export assays in CHO cells expressing mutant PMCA2

    PMID:18974863

    Open questions at the time
    • Structural basis for selective loss of basal versus stimulated activity not resolved
    • Whether similar mechanism applies to human hearing loss mutations unknown
  9. 2010 High

    Haploinsufficiency studies in heterozygous PMCA2 knockout mice established that PMCA2 is the rate-limiting calcium clearance mechanism in Purkinje dendrites: half-normal levels nearly doubled Ca²⁺ transient recovery time and degraded cerebellar motor output, while complete knockout showed elevated basal Ca²⁺, hyperpolarized membranes, and aberrant firing.

    Evidence Calcium imaging and whole-cell patch clamp in brain slices from PMCA2+/− and PMCA2−/− mice, beam-walking behavioral tests

    PMID:20083513 PMID:21232211

    Open questions at the time
    • Contribution of compensatory mechanisms (SERCA, NCX) in knockout not fully quantified
    • Long-term neurodegenerative consequences not tracked
  10. 2010 High

    PMCA2 was shown to regulate apoptotic threshold in mammary epithelial cells: its downregulation during involution raises intracellular Ca²⁺ and sensitizes cells to apoptosis, while overexpression in breast cancer cells confers apoptosis resistance, revealing an oncologically relevant survival function.

    Evidence PMCA2 knockdown and overexpression in MECs and T47D breast cancer cells, calcium imaging, apoptosis assays, mammary gland involution model

    PMID:20534448

    Open questions at the time
    • Transcriptional regulation of PMCA2 during involution not identified
    • Interaction with specific apoptotic effectors not mapped
  11. 2012 High

    Two parallel studies revealed that PMCA2 couples its Ca²⁺ extrusion activity to signaling complex regulation: it directly inhibits calcineurin/NFAT to suppress Fas Ligand-mediated apoptosis in breast cancer cells, and it constrains α7-nAChR-evoked calcium transients via PSD-95 scaffolding in hippocampal interneurons, with PMCA2 inhibition triggering CaMKII/proteasome-dependent receptor cluster loss.

    Evidence Co-immunoprecipitation, NFAT pathway and apoptosis assays in breast cancer cells; functional proteomics, calcium imaging, and single-particle tracking in hippocampal interneurons

    PMID:22593058 PMID:22962307

    Open questions at the time
    • Calcineurin binding site on PMCA2 not mapped
    • Whether α7-nAChR cluster regulation occurs in vivo not tested
  12. 2012 High

    Chimeric pump experiments proved that the w-insert carries autonomous apical targeting information transferable to the normally basolateral PMCA4, and that NHERF2 PDZ-ligand optimization further enhances apical localization without altering intrinsic pump kinetics.

    Evidence Chimeric PMCA4(2w)/b constructs with mutagenesis in polarized epithelial cells, immunofluorescence, Ca²⁺ signaling assays

    PMID:22252018

    Open questions at the time
    • Whether the w-insert interacts with specific coat or motor proteins for apical sorting unknown
    • In vivo validation in hair cells not performed with chimeric constructs
  13. 2016 High

    PMCA2 was found to interact with HER2 in actin-rich membrane domains and be required for HER2 membrane retention, HSP90 association, and downstream oncogenic signaling; PMCA2 knockout inhibited mammary tumor formation in MMTV-Neu mice, establishing PMCA2 as a functional partner in HER2-driven oncogenesis.

    Evidence Co-immunoprecipitation, PMCA2 knockdown/knockout, HER2 signaling and membrane localization assays, MMTV-Neu in vivo tumor model

    PMID:26729871

    Open questions at the time
    • Direct versus calcium-mediated mechanism of HER2 stabilization not fully resolved
    • Therapeutic targetability of PMCA2–HER2 axis not explored
  14. 2017 Medium

    Cortical actin dynamics were identified as a direct modulator of PMCA2 specific activity: actin disruption enhanced and actin stabilization abolished Ca²⁺ extrusion without altering surface expression, indicating cytoskeletal gating of pump function.

    Evidence Real-time Ca²⁺ monitoring in PMCA2-transfected HEK293 cells treated with cytochalasin D and jasplakinolide, surface biotinylation

    PMID:28527708

    Open questions at the time
    • Whether actin contacts the pump directly or via intermediary proteins unknown
    • Relevance to native stereociliary or dendritic actin dynamics not tested
  15. 2018 High

    Biophysical characterization showed that the PMCA2w/a splice variant uniquely provides sustained, calmodulin-independent Ca²⁺ extrusion with minimal activity modulation by rapid Ca²⁺ rises—a property essential for stereociliary calcium homeostasis—and that deafness-causing mutations specifically disrupt this homeostatic mode.

    Evidence Biochemical and biophysical characterization of PMCA2w/a, mouse genetic models with functional hearing and calcium assays

    PMID:29452611

    Open questions at the time
    • Structural basis for calmodulin-independent activity of w/a variant not resolved
    • Whether other tissues exploit this constitutive extrusion mode unknown
  16. 2019 High

    NHERF1 was shown to be required for apical PMCA2 localization in lactating mammary epithelium; its loss mislocalized PMCA2, disrupted polarity, and triggered premature Stat3 activation and lysosome-mediated cell death, linking PMCA2 apical scaffolding to epithelial survival.

    Evidence Co-immunoprecipitation, NHERF1 knockout mice, immunofluorescence, Stat3 activation and lactation phenotype analysis

    PMID:31087002

    Open questions at the time
    • Whether NHERF2 can compensate for NHERF1 loss not tested
    • Mechanism linking PMCA2 mislocalization to Stat3 activation not delineated
  17. 2023 High

    De novo ATP2B2 missense and frameshift variants were shown to cause a novel neurodevelopmental syndrome (ataxia, dystonia, intellectual disability, seizures) with both loss- and gain-of-function calcium handling defects, establishing that bidirectional disruption of PMCA2-mediated calcium homeostasis impairs neurodevelopment.

    Evidence Exome/genome sequencing in multiple families, trio-based analysis, cell-based cytosolic calcium handling assays for each variant

    PMID:37675773

    Open questions at the time
    • Neurodevelopmental cellular mechanisms not elucidated
    • Genotype-phenotype correlation for gain- versus loss-of-function variants not fully established
    • No animal model recapitulating the full syndrome

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for calmodulin-independent activity of the w/a splice variant, the identity of apical sorting machinery that reads the w-insert signal, the direct versus calcium-mediated mechanism of HER2 stabilization, and the in vivo significance of lysosomal PMCA2–NPC1 complexes for neurodegeneration.
  • No high-resolution structure of full-length PMCA2 in any splice form
  • Mechanism by which w-insert directs apical sorting unknown
  • Lysosomal PMCA2–NPC1 complex reported only in preprint

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140657 ATP-dependent activity 6
Localization
GO:0005886 plasma membrane 7 GO:0005856 cytoskeleton 2
Pathway
R-HSA-382551 Transport of small molecules 8 R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-9709957 Sensory Perception 3 R-HSA-5357801 Programmed Cell Death 2
Partners
DLG4ERBB2GRM1HOMER3ITPR1PPP3CASLC9A3R1SLC9A3R2
Complex memberships
PMCA2/HER2/HSP90 complexmGluR1/Homer/IP3R1/PMCA2 complexα7-nAChR/PSD-95/PMCA2 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The human ATP2B2 gene was isolated and characterized, encoding a plasma membrane Ca2+-pumping ATPase isoform PMCA2. Human and rat cDNA sequences showed 95% homology in the coding domain and >98% homology at the deduced protein sequence level. The gene was localized to human chromosome 3. cDNA cloning, sequencing, somatic cell hybrid Southern blot analysis Genomics High 1427863
1993 PMCA2 undergoes alternative splicing at two major regulatory sites (site A in the first intracellular loop and site C in the C-terminal calmodulin-binding domain), generating multiple isoforms. PMCA2 and PMCA3 transcripts are expressed in a tissue-specific manner, with highest levels in fetal skeletal muscle and brain, in contrast to the ubiquitous PMCA1 and PMCA4. Quantitative RT-PCR with isoform-specific primers across seven human tissues The Journal of biological chemistry High 8245032
1994 ATP2B2 (PMCA2) was localized to human chromosome 3p26→p25 by fluorescence in situ hybridization (FISH), analysis of somatic cell hybrids, and genetic linkage analyses. FISH, somatic cell hybrid analysis, genetic linkage Cytogenetics and cell genetics High 8187550
2001 The PMCA2b C-terminal tail interacts with multiple members of the membrane-associated guanylate kinase (MAGUK)/SAP family, including SAP90/PSD95, PSD93/chapsyn-110, and SAP97, but not SAP102, whereas PMCA4b interacts promiscuously with all four SAPs. PMCA2b colocalized with SAP90/PSD95 in hippocampal neuron dendrites and dendritic spines. Yeast two-hybrid screen, co-immunoprecipitation, confocal immunofluorescence microscopy in polarized MDCK cells and hippocampal neurons The Journal of biological chemistry High 11274188
2001 PMCA2 is expressed in the P-type ATPase family characterized by formation of an aspartyl-phosphate intermediate during the reaction cycle. Alternative splicing of PMCA2 at the first intracellular loop (site A) and C-terminal tail (site C) generates isoforms with different calmodulin regulation, phospholipid sensitivity, and PDZ-domain protein interactions. The PMCA2w/a splice variant is the major form in hair cell stereocilia. Biochemical characterization, review of splice variant expression and functional differences Physiological reviews High 11152753
2004 PMCA2 is localized to hair cell stereocilia in mouse inner ear (demonstrated by immunocytochemistry), where it contributes to maintaining endolymph calcium homeostasis. Deafwaddler2J (dfw2J) mice lacking functional PMCA2 in stereocilia have significantly lower endolymph calcium concentrations compared to controls, linking PMCA2 stereociliary activity to endolymph Ca2+ levels and hearing/balance function. Immunocytochemistry, calcium-sensitive fluorescent dye measurement using aspirating microelectrode in dfw2J vs. control mouse endolymph Journal of the Association for Research in Otolaryngology : JARO High 15357414
2005 A heterozygous, hypofunctional variant (V586M) in PMCA2 (ATP2B2) acts as a modifier of sensorineural hearing loss severity. In siblings homozygous for a CDH23 mutation, those also carrying V586M had more severe hearing loss. V586M was also found in unrelated individuals with increased hearing loss caused by other factors (MYO6 mutation or noise exposure), establishing PMCA2 as a genetic modifier of hearing loss severity. Genetic analysis of human families with SNHL, functional characterization of V586M as hypofunctional variant The New England journal of medicine High 15829536
2006 Differential membrane targeting of PMCA1 and PMCA2 in hair cells is determined by distinct molecular signals: a Leu-Ile motif in 'b'-tail splice variants promotes basolateral sorting of PMCA1b and PMCA2b, while apical targeting of PMCA2 depends on the size of the A-site splice insert in the first cytosolic loop, suggesting the loop conformation plays a role in apical targeting. Expression of PMCA isoforms and splice variants with mutagenesis in hair cells and cell lines, immunofluorescence targeting assays Journal of cell science High 16803870
2006 PMCA2 co-immunoprecipitates with the metabotropic glutamate receptor 1 (mGluR1), Homer 3, and IP3R1 in the cerebellum, indicating that PMCA2 is a constituent of the mGluR1 signaling complex. In PMCA2-null mice, the levels of mGluR1, IP3R1, Homer 1b/c, and Homer 3 are specifically reduced in Purkinje neurons but not in hippocampus, perturbing the mGluR1 signaling complex and likely contributing to cerebellar deficits. Co-immunoprecipitation, immunohistochemistry, Western blotting in PMCA2-null vs. wild-type mouse cerebellum Molecular and cellular neurosciences High 17150372
2006 Atp2b2 expression is regulated through four distinct transcriptional start regions (alpha, beta, mu, delta) with tissue-specific usage. The alpha transcript is dominant in cochlear hair cells and cerebellar Purkinje neurons, while mu and delta are novel variants expressed predominantly in lactating mammary gland. The alpha and beta first-exon regions show high conservation in mammals. 5'-RACE, real-time RT-PCR, microdissection of cochlea, in situ hybridization, comparative genomics Neuroscience High 16675132
2008 The Oblivion (Obl) ENU-induced mouse mutation causes a S877F substitution in transmembrane domain 6 of PMCA2. Unlike other transmembrane domain mutations, the protein is correctly targeted to the plasma membrane, but biochemical and biophysical characterization showed significant loss of non-stimulated Ca2+ exporting ability, explaining progressive hearing loss. ENU mutagenesis, sequencing, immunofluorescence of mutant pump in hair cells, biochemical/biophysical characterization of Ca2+ export in CHO model cells PLoS genetics High 18974863
2010 The Tommy ENU mutation (E629K in the second intracellular loop/active site) impairs long-term, non-stimulated calcium extrusion activity of PMCA2 in CHO cells. Direct calcium imaging with flash photolysis of caged calcium in neonatal organotypic utricle cultures confirmed impairment of calcium export in both Tommy heterozygotes and homozygotes, establishing that cytosolic calcium clearance in hair cells requires PMCA2 active-site integrity. Ca2+ extrusion assay in CHO cells expressing mutant PMCA2, confocal imaging with flash photolysis of caged Ca2+ in utricle sensory epithelium organotypic cultures The Journal of biological chemistry High 20826782
2010 PMCA2 is the dominant mechanism for Ca2+ clearance in cerebellar Purkinje neuron dendrites. Heterozygous PMCA2 knockout mice expressing half-normal PMCA2 levels showed nearly doubled calcium transient recovery times, weaker climbing fiber responses, prolonged Ca2+-dependent K+ currents, and reduced action potential firing frequency, demonstrating that PMCA2 level directly controls dendritic calcium dynamics and cerebellar motor coordination precision. Calcium imaging in brain slices, whole-cell patch clamp recording, beam-walking motor tests in PMCA2+/- vs. wild-type mice The Journal of physiology High 20083513
2010 PMCA2 is down-regulated early during mammary gland involution following weaning, and this loss raises intracellular calcium and sensitizes mammary epithelial cells (MECs) to apoptosis. Conversely, overexpression of PMCA2 in T47D breast cancer cells lowers intracellular calcium and protects them from apoptosis, identifying PMCA2 as a calcium extrusion pump that regulates apoptotic threshold in MECs. Western blotting, calcium imaging, apoptosis assays in PMCA2 knockdown/overexpression MECs and T47D cells, mammary gland involution model Proceedings of the National Academy of Sciences of the United States of America High 20534448
2010 In PMCA2-/- Purkinje neurons, basal calcium levels are elevated, calcium recovery kinetics are severely impaired, membrane potentials are hyperpolarized, spontaneous action potential frequency is reduced and irregular, complex spikes are curtailed, and Ca2+-dependent outward K+ currents are sustained. These electrophysiological changes represent adaptations that limit pathological calcium rises but are insufficient to maintain normal cerebellar output. Whole-cell patch clamp recording and calcium imaging in PMCA2-/- vs. wild-type Purkinje neurons Functional neurology High 21232211
2011 Analysis of the human PMCA2 V586M mutant (associated with modified hearing loss in patients) and a murine mutant in model cells revealed that the human mutant does not impair Ca2+ ejection by the pump, whereas the murine mutant shows defects in both basal pump activity and long-range Ca2+ ejection. The PMCA2w/a splice variant can eject Ca2+ to the endolymph even in the absence of calmodulin, satisfying the special Ca2+ homeostasis requirements of stereocilia. Expression of mutant PMCA2 in model cells, Ca2+ ejection assays, comparison of human and murine mutants Cell calcium High 22047666
2012 PMCA2 inhibits the calcineurin/NFAT signaling pathway in breast cancer cells through a direct inhibitory interaction with calcineurin. Disruption of the PMCA2/calcineurin interaction activates calcineurin/NFAT signaling, upregulates pro-apoptotic Fas Ligand expression, reduces cell viability through increased apoptosis, and enhances paclitaxel-mediated cytotoxicity. Co-immunoprecipitation, calcineurin/NFAT pathway activation assays, Fas Ligand expression, apoptosis assays, viability assays in multiple breast cancer cell lines Carcinogenesis High 22962307
2012 PMCA2 is associated with α7-nicotinic acetylcholine receptors (α7-nAChRs) in rat brain via the scaffold protein PSD-95. PMCA2 activity limits the duration of calcium elevations produced by α7-nAChR activation in hippocampal interneurons. PMCA2 inhibition triggers rapid, CaMKII- and proteasome-dependent loss of α7-nAChR clusters through a mechanism that requires PSD-95 linkage and depends on the second intracellular loop of the α7 subunit. Functional proteomics on rat brain, co-immunoprecipitation, calcium imaging, single-particle tracking, pharmacological inhibition, siRNA knockdown in hippocampal interneuron cultures The Journal of neuroscience High 22593058
2012 The alternatively spliced w-insert of PMCA2 provides autonomous apical targeting information. When inserted into the corresponding location of the normally basolateral PMCA4 isoform, it confers apical membrane targeting. Optimizing the PDZ ligand at the C-terminus for NHERF2 interaction further enhanced apical targeting. Both apical and basolateral pump configurations handled ATP-induced Ca2+ signals with similar kinetics, indicating the targeting signal does not alter intrinsic pump function. Chimeric PMCA4(2w)/b construct expression in polarized epithelial cells, immunofluorescence localization, Ca2+ signaling assays, mutagenesis of di-leucine and PDZ ligand motifs Cell calcium High 22252018
2013 PMCA2 knockdown in PC12 cells accelerates neuronal differentiation and formation of longer neurites. Loss of PMCA2 triggers apoptosis and DNA laddering during differentiation, accompanied by compensatory upregulation of PMCA1, PMCA4, and SERCA, as well as altered expression of voltage-dependent calcium channels (VDCCs) with increased contribution to Ca2+ influx. Antisense-mediated stable knockdown in PC12 cells, differentiation assays with dibutyryl-cAMP, apoptosis/DNA laddering assays, immunoblotting for calcium handling proteins, functional VDCC assays Cell calcium Medium 22921123
2013 PMCA2 activity is required for maintaining dendritic calcium equilibrium and controlling Purkinje cell dendritic growth in organotypic cerebellar slice cultures. Pharmacological inhibition of PMCA2 with carboxyeosin moderately reduced Purkinje cell dendritic tree size. Combining PMCA2 inhibition with type I mGluR stimulation partially rescued dendritic morphology by triggering compensatory inactivation of voltage-gated calcium channels. Carboxyeosin pharmacological inhibition of PMCA2 activity in organotypic cerebellar slice cultures, immunofluorescence, dendritic morphometry Neural plasticity Medium 24288624
2013 PMCA2 downregulation by MPP+ (mitochondrial complex I inhibitor) in SH-SY5Y neuroblastoma cells and primary mesencephalic neurons leads to elevated cytosolic calcium and increased neuronal vulnerability. Two other Ca2+ efflux mediators (SERCA, NCX) were unaffected, indicating PMCA2-specific role in neuronal calcium homeostasis. siRNA knockdown of PMCA2 impaired cell survival, while PMCA2 overexpression conferred resistance to complex I inhibition. MPP+ treatment, Western blotting, calcium imaging, siRNA knockdown and overexpression in SH-SY5Y and primary mesencephalic neurons Neurotoxicology Medium 24269647
2016 PMCA2 interacts with HER2 in actin-rich membrane domains in breast cancer cells. Knocking down PMCA2 raises intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and causes internalization and degradation of HER2. PMCA2 knockout inhibits mammary tumor formation in MMTV-Neu mice, demonstrating that PMCA2 is required for HER2 membrane retention, stability, and oncogenic signaling. Co-immunoprecipitation, PMCA2 knockdown and knockout, HER2 signaling assays, subcellular fractionation, intracellular calcium measurement, in vivo MMTV-Neu tumor model Proceedings of the National Academy of Sciences of the United States of America High 26729871
2017 Disrupting the actin cytoskeleton with cytochalasin D significantly increases PMCA2-mediated Ca2+ extrusion (~50-100%) in living HEK293 cells, while stabilizing F-actin with jasplakinolide fully inhibits it. Disrupting microtubules with colchicine decreases PMCA activity (~40-60%). These effects occur without changing surface expression levels, indicating regulation of specific activity. Real-time cytosolic calcium monitoring in PMCA2-transfected HEK293 cells treated with cytoskeletal drugs, surface biotinylation assays Biochimica et biophysica acta. Molecular cell research Medium 28527708
2017 PMCA2-interacting complex in kidney cells was characterized by immunoprecipitation followed by nanoLC-ESI mass spectrometry, identifying 474 PMCA2-interacting proteins (8 known, 20 predicted, 446 novel). A novel functional role of PMCA2 as a calcium oxalate monohydrate (COM) crystal-binding protein was identified and validated, showing that PMCA2 is required for crystal retention and cellular uptake in kidney cells. Immunoprecipitation-mass spectrometry, quantitative immuno-co-localization, COM crystal-protein binding assay, crystal-cell adhesion assay, crystal internalization assay, anti-PMCA2 antibody neutralization Cellular and molecular life sciences : CMLS Medium 29085954
2018 PMCA2 is required for estrogen receptor alpha (ERα) signaling in the female dorsal horn of the spinal cord. Female PMCA2+/- mice show increased mechanical pain sensitivity (52%) and reduced heat sensitivity (29%), while males do not. Intrathecal ERα agonist fails to activate ERα signaling in female PMCA2+/- mice but is effective in PMCA2+/+ females, establishing a female-specific link between PMCA2, ERα signaling, and pain modulation. Behavioral pain assays (von Frey, Hargreaves), ovariectomy/hormone replacement, intrathecal drug administration, western blotting of dorsal horn signaling proteins in PMCA2+/- vs +/+ mice Scientific reports Medium 30467368
2018 PMCA2w/a splice variant in hair cell stereocilia increases its activity only marginally in response to rapid cytoplasmic Ca2+ elevation (unlike other PMCA2 variants which are strongly stimulated), enabling sustained calcium extrusion independent of calmodulin activation. Missense mutations of PMCA2w/a that cause deafness correlate with defects in homeostatic regulation of stereociliary Ca2+, decreased mechanotransduction channel sensitivity, and progressive organ of Corti degeneration. Biophysical and biochemical characterization of PMCA2w/a splice variant, mouse genetic models with functional hearing and calcium assays Neuroscience letters High 29452611
2019 NHERF1 interacts with PMCA2 at the apical membrane of secretory luminal epithelial cells during lactation and is required for proper apical localization of PMCA2. NHERF1 knockout disrupts PMCA2 apical targeting, impairs apical-basal polarity, and leads to premature Stat3 activation and lysosome-mediated mammary epithelial cell death. PMCA2 also interacts with the closely related NHERF2 at the apical membrane. Co-immunoprecipitation, immunofluorescence localization, NHERF1 knockout mice, Western blotting for Stat3 activation, lactation and involution phenotype analysis Endocrinology High 31087002
2019 Decreased PMCA2 expression in the dorsal horn is paralleled by increased neuropathic pain in EAE (MS model) and spinal cord injury mice. In pure spinal cord neuronal cultures, IL-1β directly downregulates PMCA2 levels, acting as an effector that reduces neuronal PMCA2 expression and thereby perturbs calcium signaling contributing to pain sensitization. EAE and SCI mouse models, behavioral pain testing, Western blotting of dorsal horn PMCA2, cytokine profiling, pure SC neuronal culture treatment with IL-1β, TNFα, IL-6 Journal of neuroinflammation Medium 31703709
2023 De novo ATP2B2 missense variants affecting evolutionarily conserved sites, and frameshift variants in the penultimate exon, cause a neurodevelopmental syndrome with ataxia, dystonia, intellectual disability, autism, and seizures. Cell-based functional studies showed that all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects, establishing that precise PMCA2-mediated calcium regulation is essential for neurodevelopment and cerebellar function. Exome/genome sequencing, trio-based genomics, in silico analyses, cell-based cytosolic calcium handling assays Genetics in medicine High 37675773
2025 A splice variant-dependent localization of PMCA2 to the lysosome was discovered. Lysosomal PMCA2 forms an evolutionarily conserved complex with NPC1 (the lysosomal membrane protein defective in Niemann-Pick disease type C). This lysosomal PMCA2-NPC1 interaction is involved in maintaining lysosomal calcium levels, and its disruption contributes to the pathophysiology of both NPC disease and Parkinson's disease, revealing a previously unrecognized intracellular role for PMCA2 in lysosomal calcium and lipid regulation. Splice variant localization studies, co-immunoprecipitation/complex identification with NPC1, lysosomal calcium measurements, disease models (NPC, Parkinson's) bioRxivpreprint Medium bio_10.1101_2025.10.01.679724
2025 ATP2B2 exhibits marked expression deficits at the synaptic proteome level in dorsolateral prefrontal cortex of individuals with schizophrenia. Structural analysis using AlphaFold3 models identified an enrichment of neuropsychiatric disease-associated deleterious missense variants in close spatial proximity to both the Ca2+ permeation tunnel and the ATP:Mg2+ coordination site. Cellular and biochemical analyses of canonical Ca2+-binding site variants confirmed clear loss-of-function effects on Ca2+ extrusion, linking genetic variants to impaired Ca2+ homeostasis in excitatory neurons. Single-nucleus RNA-seq, synaptic proteomics, AlphaFold3 structural modeling, case-control missense variant analysis, cellular/biochemical Ca2+ extrusion assays bioRxivpreprint Medium bio_10.1101_2025.08.25.672202
2025 Exosomal PIP (prolactin-induced protein) from atrial fibrillation patients suppresses ATP2B2 expression, thereby inhibiting the cGMP/PKG signaling pathway and promoting myocardial fibrosis. ATP2B2 overexpression reversed the pro-fibrotic effects of PIP on cardiac fibroblasts and endothelial cells, while AAV-shPIP reduced AF incidence in rats. Activation of cGMP/PKG is beneficial for alleviating fibrosis, but this is mitigated by ATP2B2 knockdown. Exosome characterization, shRNA knockdown and overexpression of PIP and ATP2B2, CF and HUVEC functional assays, AAV-mediated shPIP in rat AF model, cGMP/PKG pathway analysis Antioxidants & redox signaling Medium 40094760

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews 1645 30280653
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Structural organization, ion transport, and energy transduction of P-type ATPases. Biochimica et biophysica acta 618 8634322
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2001 Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiological reviews 469 11152753
2004 Biology, structure and mechanism of P-type ATPases. Nature reviews. Molecular cell biology 447 15071553
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
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