ATP2B2

Summary: ATP binding supplies the energy for the PMCA2 transport cycle.

Reason: ATP binding is intrinsic to the P-type calcium-export cycle; the broader nucleotide-binding InterPro inference is valid but does not define another function.

Summary: Human PMCA2 function is consistent with ATP-dependent calcium export.

Reason: The human hearing-loss/PMCA2 study is consistent with the directly established pump activity. Full NEJM methods were not accessed; retain the curated activity on the independently supported biochemical mechanism, without inventing its assay details.

Summary: Expressed PMCA2 splice variants and mutants alter calcium-transient clearance in CHO cells.

Reason: PMCA2 splice forms and the G293S/G283S mutants were expressed in CHO cells, and calcium-transient clearance was measured. These experiments support the pump mechanism. Human-family genetics and separate mouse hair-cell experiments are distinguished; the Methods do not independently resolve the donor species of every parental construct.

Summary: PMCA2 retains the ancestral P-type calcium-pump activity.

Reason: Conserved P-type calcium export is supported directly on human PMCA2. Preserve the PAINT ancestral-node assertion; the target in its descendant evidence is not circular, and no unsupported donor-count objection is made.

Summary: The family, enzyme and reaction mappings agree with calcium-pump biochemistry.

Reason: The combined family/EC/RHEA mapping matches an ATP-driven calcium-exporting P-type pump and independent target-specific activity evidence.

Summary: The original human cloning record identifies the calcium-pump isoform.

Reason: The human cloning source and NAS attribution are consistent with the subsequently demonstrated calcium pump. Do not upgrade this NAS row to a direct assay.

Summary: Reactome places PMCA2 among plasma-membrane calcium-exporting ATPases.

Reason: Reactome418309 explicitly assigns calcium export to the ATP2B1–4 catalyst set. This agrees with direct human PMCA2 evidence; the family reaction is not a unique PMCA2 cardiac experiment.

Summary: Endogenous human PMCA2 associates with calcineurin, a protein phosphatase.

Reason: The complete cached and official abstract explicitly reports endogenous human PMCA2-calcineurin interaction, with the strongest association among the PMCA isoforms examined. This positive target-specific evidence supports protein phosphatase binding rather than leaving the entire molecular-function assertion unresolved. Refine the generic term to GO:0019903, whose verified definition is binding to a protein phosphatase. The source supporting entity UniProtKB:P01258 remains CALCA/calcitonin and is preserved unchanged; its mapping to this interaction has not been resolved, and no calcineurin subunit accession is substituted. The abstract does not establish a purified direct-binding assay or the complete interaction-record mapping. This is a contextual regulatory interaction, not a second calcium-pump core, and no separate signaling-process assertion is added.

Proposed replacements: protein phosphatase binding

Summary: The exact ATP2B2–SCRIB interaction remains unverified in the target-specific supplementary data.

Reason: The staged original describes human C-terminal peptide selections against Scribble PDZ domains, but the ATP2B2/SCRIB pair, peptide state and target-specific supplementary row were not verified. Preserve this experimental assertion pending that check.

Summary: Human PMCA2 binds ATP during formation of its phosphorylated intermediate.

Reason: ATP is the pump substrate and forms a phosphorylated enzyme intermediate in human PMCA2 constructs. The binding annotation is valid as a component of the transport mechanism.

Summary: Human corneal epithelial cells show cytoplasmic PMCA2 immunoreactivity.

Reason: The complete human corneal-epithelium abstract explicitly reports cytoplasmic PMCA2 immunoreactivity in basal/wing cells and limbus. Retain this contextual protein distribution; do not infer a soluble cytosolic catalytic core.

Summary: Ensembl projection of a mouse PMCA2 ER annotation that rests on ER retention of overexpressed recombinant pump in CHO cells, which the authors call inactive; an overexpression artefact of a plasma-membrane pump, so over-annotated.

Reason: ORGANELLES check (2026-11-04), changed from UNDECIDED now that the donor is traced. The source is mouse Q9R0K7, whose only GO:0005783 row is an IDA from PMID:17234811 (MGI), the same paper behind this review's EXP plasma-membrane and transporter rows. In it, PMCA2 variants were transiently overexpressed in CHO cells; half of the positive cells showed a pure plasma-membrane pattern and the rest showed rim plus ER patterns, and the authors state that ER-retained PMCA units are normally inactive. That is retention of overexpressed protein (plus biosynthetic transit), not a resident ER pool, and the cached full text mentions no ER marker. UniProt lists no ER location for human PMCA2. No sub-compartment row is added.

Summary: Expressed PMCA2 variants reach the CHO-cell plasma membrane.

Reason: PMID17234811 directly reports plasma-membrane delivery of the recombinant PMCA2 variants, separately from partially ER-retained overexpression.

Summary: Plasma-membrane localization is consistent with the conserved export mechanism.

Reason: Plasma-membrane deployment is coherent with target-specific localization and export. Retain the curated PAINT placement; no node-loss or target divergence is established.

Summary: Electronic localization evidence places the pump in the plasma membrane.

Reason: The combined electronic PM localization matches the measured and curated human pump location.

Summary: Independent localization studies corroborate the original plasma-membrane assignment.

Reason: Keep the human cloning source as NAS and the independently corroborated plasma-membrane location; no assay upgrade.

Summary: The Reactome calcium-export reaction places its ATP2B catalysts in the plasma membrane.

Reason: The curated ATP2B1–4 export reaction places its catalyst at the plasma membrane, consistent with human PMCA2 experiments.

Summary: Mouse olfactory sensory neurons localize PMCA2 to genuine cilia.

Reason: PMID16855061 directly localizes PMCA2 in isolated mouse olfactory sensory-neuron cilia by isoform-specific immunostaining. The authors report absent staining in PMCA2-knockout neurons, explicitly as data not shown. This supports the existing mouse-ortholog localization transfer. Olfactory cilia are distinct from actin-based hair-cell stereocilia; no direct human localization assay or olfactory-response mechanism is asserted.

Summary: PMCA2 activity contributes to calcium clearance in recombinant cells and mouse hair cells.

Reason: PMCA2 expression and mutant measurements in CHO cells support calcium transport through altered calcium-transient clearance. Mouse hair-cell uncaging experiments independently support physiological calcium removal. Human G293S genetics does not turn every recombinant parental construct into a verified human-protein experiment.

Summary: Calcium transport is the mechanism of the cloned human pump.

Reason: Calcium transport is the directly established pump mechanism; retain the original human cloning/NAS attribution.

Summary: Human PMCA2 variants modify hearing loss and can also cause monogenic deafness.

Reason: Human hearing-loss modification is supported by the complete cited abstract. Retain auditory physiology as a consequence of calcium pumping, without claiming all variants or all hearing loss share the same genotype. Independent PMID30535804 reports de novo and familial heterozygous predicted loss-of-function variants associated with progressive human hearing impairment, supporting a monogenic deafness association as well as the earlier modifier context.

Summary: Human genetics and mouse hair-cell physiology connect PMCA2 dysfunction with hearing impairment.

Reason: The human G293S family and the separate mouse deafwaddler/knockout experiments connect PMCA2 dysfunction with hearing. Retain this auditory role as non-core physiology of the calcium pump; the CHO and mouse assays are not collapsed into one human assay. Independent PMID30535804 reports de novo and familial heterozygous predicted loss-of-function variants associated with progressive human hearing impairment, supporting a monogenic deafness association as well as the earlier modifier context.

Summary: PMCA2 is an integral multipass membrane protein.

Reason: PMCA2 is a multipass membrane pump; broad membrane annotation is valid and needs no duplicate replacement.

Summary: A-site splicing changes basolateral targeting of expressed PMCA2 variants.

Reason: The complete official abstract and UniProt isoform records support basolateral PM localization. In polarized MDCK expression, x/b, z/b and z/a are basolateral; w forms also reach the apical domain. Do not apply one targeting pattern to all eight products.

Summary: UniProt records basolateral targeting for particular splice products.

Reason: The UniProt basolateral mapping is corroborated by the splice-sensitive localization study. Retain the existing machine row and explain its product-dependent scope.

Summary: PMCA2 w variants reach the apical membrane in polarized MDCK cells.

Reason: The complete official abstract supports apical targeting of w/a and w/b constructs in polarized MDCK cells. This does not imply that every PMCA2 splice product is apical.

Summary: Apical targeting is independently supported for the w splice forms.

Reason: The apical electronic mapping is independently corroborated for the w products; mouse donor provenance is not a human IDA claim.

Summary: ATP hydrolysis powers calcium export by PMCA2.

Reason: ATP hydrolysis is part of the P-type transport cycle, supported by human recombinant enzyme assays. It is not a second independent core activity.

Summary: PMCA2 abundance and calcium clearance increase after experimentally induced neuronal differentiation.

Reason: Complete original Methods and selected Results in PMID11259493 show that dibutyryl-cAMP and BrdU induce differentiation in human IMR-32 cells, followed by increased PMCA2/3/4 expression and faster calcium clearance. Recombinant PMCA2-expressing COS cells are immunoblot controls; acute lanthanum experiments test clearance, not differentiation. The inspected design establishes differentiation-associated pump upregulation, not a PMCA2-dependent differentiation step. Mark the process attribution as likely over-annotated without claiming a wrong gene or excluding other differentiation roles.

Summary: Human recombinant PMCA2 has calcium-dependent ATPase activity.

Reason: Calcium-dependent ATPase activity fits direct recombinant human PMCA2 biochemistry; retain the mouse-based IEA as an inference, without upgrading its evidence.

Summary: A curated rat-to-human transfer places PMCA2 in dendritic-spine membrane.

Reason: Retain the manually transferred rat dendritic-spine membrane location as a specialized neuronal context. The donor primary experiment was not freshly inspected; no target-specific loss or conflicting localization is established.

Summary: PMCA2 carries out the calcium-export step within the P-type ATPase pathway.

Reason: The P-type ATPase pathway includes the actual ATP2B1–4 calcium-export reaction. Broad ion transport is correct and already refined by existing calcium-specific rows.

Summary: Orthology-based evidence places PMCA2 in a presynaptic calcium-clearance context.

Reason: Presynaptic localization is coherent with UniProt’s explicitly orthology-based presynaptic calcium-efflux description; it is not presented as newly observed human anatomy.

Summary: Mouse-derived evidence supports neuronal cell-body localization.

Reason: Keep neuronal cell-body localization as a conserved contextual distribution of the neuronal pump. The source remains mouse-derived electronic evidence, not a new human assay.

Summary: UniProt assigns PMCA2 a synaptic location without specifying transmitter class.

Reason: The UniProt synapse vocabulary mapping is consistent with the curated neuronal function; retain contextual localization without promoting a particular neurotransmitter class.

Summary: Curator-reviewed mouse evidence supports a general synaptic location.

Reason: Retain the curated mouse-to-human synapse transfer, distinct from the unresolved more specific SynGO source links below.

Summary: Calcium export directly lowers cytosolic calcium concentration.

Reason: Lowering cytosolic calcium through export is the established mechanism. Preserve the phylogenetic assertion without challenging its donor number or target self-support.

Summary: Target-specific pump assays corroborate electronic calcium-homeostasis inference.

Reason: The electronic cytosolic calcium-regulation assertion is directly corroborated by target-specific pumping/clearance evidence.

Summary: PMCA2 splice forms and mutations change the decay of cellular calcium transients.

Reason: Recombinant PMCA2 splice forms and mutants alter the decay of cytosolic calcium transients in CHO cells. The ATP addition activates host P2Y signaling in this assay; it is not a direct measurement of ATP turnover. Separate mouse hair-cell calcium-uncaging experiments support the physiological interpretation.

Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions.

Reason: Plasma-membrane Ca2+-ATPase. Transmembrane/lipid-anchored protein of the plasma membrane or endosomal system (UniProt); such proteins are expected EV contents (MISEV2018 (PMID:30637094) category 1). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: UNDECIDED.)

Summary: The pump moves calcium across the plasma membrane.

Reason: ATP-coupled extrusion directly crosses the plasma membrane and therefore supports calcium transmembrane transport.

Summary: Hearing phenotypes do not resolve the separate cochlear-development assertion.

Reason: Auditory dysfunction and calcium-clearance phenotypes do not by themselves resolve a developmental role. The mouse donor’s cochlea-development assay was not inspected; preserve the IEA pending that distinction.

Summary: The specific photoreceptor ribbon donor evidence remains unverified.

Reason: The photoreceptor ribbon-specific mouse donor localization was not freshly verified. General neuronal/synaptic function does not resolve this precise retinal compartment.

Summary: PAINT assigns a conserved postsynaptic-density membrane location.

Reason: Keep the manually curated PAINT postsynaptic-density membrane assertion as specialized localization. No node-placement defect or target-specific loss was established; the rat donor experiment was not freshly reread.

Summary: The source linkage for the glutamatergic compartment remains unresolved.

Reason: The glutamatergic compartment linkage needs its SynGO source dossier; targeted primary reading did not close it.

Summary: The electronic glutamatergic specialization needs donor-level evidence.

Reason: The electronic glutamatergic specialization needs donor/source tracing beyond general synaptic function.

Summary: The glutamatergic IMP attribution requires its compartment-specific source dossier.

Reason: The glutamatergic IMP attribution needs its source dossier; do not infer a localization experiment from pump biochemistry.

Summary: The glutamatergic NAS attribution remains unverified at compartment level.

Reason: The glutamatergic NAS attribution remains unresolved at this source-specific level.

Summary: The source linkage for the GABAergic compartment remains unresolved.

Reason: The GABAergic compartment linkage needs its SynGO source dossier; targeted primary reading did not close it.

Summary: The GABAergic electronic rule needs target-specific supporting evidence.

Reason: The electronic GABAergic specialization needs the rule’s target-specific supporting evidence.

Summary: The GABAergic IMP attribution remains unverified at compartment level.

Reason: The GABAergic IMP attribution remains unresolved; no contradictory target experiment was established.

Summary: The GABAergic NAS attribution needs its original neuronal context.

Reason: The GABAergic NAS attribution needs its source-specific neuronal context.

Summary: The postsynaptic inference depends on an unresolved upstream activity assertion.

Reason: This logical inference depends on unresolved postsynaptic-specific activity; preserve the upstream limitation.

Summary: Target-specific support for the electronic cardiac-conduction assertion remains unresolved.

Reason: The ARBA cardiac-conduction rule’s target-specific support is not established here. General calcium export cannot identify its cardiac physiological setting. UniProt cites PMID8245032 for brain-predominant expression with low heart-muscle expression. The study concerns tissue transcripts and splicing; low abundance does not exclude a cardiac role. The linked erratum body remains unread, and no specific electrophysiological contradiction has been established. Preserve uncertainty rather than convert incomplete target evidence into a negative finding.

Summary: Reactome embeds a family calcium-export reaction in a cardiac pathway.

Reason: The complete Reactome summary is a cardiac pathway overview containing an ATP2B1–4 reaction, not a target-specific ATP2B2 cardiac assay. Defer the specificity rather than reject the curated pathway from incomplete literature. UniProt cites PMID8245032 for brain-predominant expression with low heart-muscle expression. The study concerns tissue transcripts and splicing; low abundance does not exclude a cardiac role. The linked erratum body remains unread, and no specific electrophysiological contradiction has been established. Preserve uncertainty rather than convert incomplete target evidence into a negative finding.

Summary: The postsynaptic qualification requires evidence beyond general calcium transport.

Reason: General transporter activity is secure; the extra postsynaptic condition needs the SynGO evidence linkage.

Summary: The IMP source has not yet verified the postsynaptic qualification.

Reason: The additional postsynaptic condition remains unverified for this IMP source attribution.

Summary: The NAS source has not yet verified the postsynaptic qualification.

Reason: The additional postsynaptic condition remains unverified for this NAS source attribution.