ATP1A2

Summary: The InterPro nucleotide-binding prediction is consistent with the ATP-dependent pump.

Reason: The InterPro nucleotide-binding prediction is consistent with the ATP-dependent pump. Retain this broad binding description as non-core; ATP binding and coupled sodium/potassium transport provide the mechanistic specificity.

Summary: The donor is mouse alpha2 Q6PIE5.

Reason: The donor is mouse alpha2 Q6PIE5. The independently read PMID12805306 abstract reports impaired glutamate and GABA uptake in Atp1a2-deficient mouse preparations. Retain the conserved support of neurotransmitter uptake through ion-gradient maintenance, without assigning direct neurotransmitter transport to ATP1A2.

Summary: Mouse alpha2 Q6PIE5 is the ortholog donor.

Reason: Mouse alpha2 Q6PIE5 is the ortholog donor. PMID12805306 reports enhanced fear/anxiety behavior in heterozygous mice. This is a supported neural phenotype downstream of ion homeostasis, not the defining molecular activity or a direct human behavioral experiment.

Summary: The mouse alpha2 donor and cardiac alpha2 literature support modulation of contractile force through sodium/calcium coupling.

Reason: The mouse alpha2 donor and cardiac alpha2 literature support modulation of contractile force through sodium/calcium coupling. The selected cardiac review distinguishes alpha2-dependent local calcium handling from the pump reaction itself; retain this physiological regulatory role as non-core.

Summary: This separate transfer names mouse alpha1 Q8VDN2, not mouse alpha2.

Reason: This separate transfer names mouse alpha1 Q8VDN2, not mouse alpha2. Both alpha isoforms can influence cardiac force through sodium/calcium balance, although their perturbation phenotypes differ. Retain the direction-neutral regulation term with that donor-specific limit; it does not establish identical isoform control mechanisms.

Summary: The donor is mouse alpha2.

Reason: The donor is mouse alpha2. The complete official PMID15564586 abstract describes embryonic brainstem-spinal respiratory rhythm defects, chloride regulation and KCC2 association in Atp1a2-null mice. Retain the conserved neural respiratory-regulation context as non-core, without converting it into human respiratory physiology measured directly.

Summary: The complete PMID10636900 abstract describes functional human alpha1/alpha2/alpha3 combinations with human beta subunits in Xenopus oocytes, with pump current and ion-affinity measurements.

Reason: The complete PMID10636900 abstract describes functional human alpha1/alpha2/alpha3 combinations with human beta subunits in Xenopus oocytes, with pump current and ion-affinity measurements. Coupled sodium/potassium transport is the defining ATP1A2 function; the amphibian expression host does not make the alpha2 construct amphibian.

Summary: The integrated electronic sources, including the sodium/potassium pump reaction and rat alpha2, agree with independently measured human alpha2 pump activity.

Reason: The integrated electronic sources, including the sodium/potassium pump reaction and rat alpha2, agree with independently measured human alpha2 pump activity. Accept this exact coupled transporter function as core; the automatic evidence is not the sole basis for the judgment.

Summary: PMID18052210 describes active purified human alpha2 paired with porcine beta1 P05027 after expression in Pichia.

Reason: PMID18052210 describes active purified human alpha2 paired with porcine beta1 P05027 after expression in Pichia. Retain the human catalytic-subunit pump function, preserving the mixed-species partner and detergent preparation rather than claiming a completely human reconstituted complex.

Summary: Complete PMID18728015 Methods and Results support pump currents and rubidium uptake from human alpha2/beta1 in Xenopus oocytes.

Reason: Complete PMID18728015 Methods and Results support pump currents and rubidium uptake from human alpha2/beta1 in Xenopus oocytes. Its reference alpha2 carries Q116R/N127D for ouabain resistance. The measured coupled transport supports the core activity, with that engineered-background boundary.

Summary: PMID20100892 uses human alpha2/beta1 in Xenopus oocytes and measures normal outward Na/K pump current as well as conditional leak currents.

Reason: PMID20100892 uses human alpha2/beta1 in Xenopus oocytes and measures normal outward Na/K pump current as well as conditional leak currents. The reference construct includes Q116R/N127D. Accept the normal coupled pump activity; mutant leakage does not replace it.

Summary: The PMID12539047 abstract establishes ATP1A2 haploinsufficiency in familial hemiplegic migraine, but its full functional Methods were not independently read.

Reason: The PMID12539047 abstract establishes ATP1A2 haploinsufficiency in familial hemiplegic migraine, but its full functional Methods were not independently read. Accept the correctly assigned pump activity by curator deference and the independent direct human alpha2 functional studies, not by claiming an assay from this abstract.

Summary: The PMID23954377 abstract reports ATP1A2 variants affecting Na/K-ATPase function and ion affinities.

Reason: The PMID23954377 abstract reports ATP1A2 variants affecting Na/K-ATPase function and ion affinities. Although the complete Methods were not accessible here, this exact core function is independently established and consistent with the curator IMP assertion.

Summary: The ISS donor is mouse alpha1 Q8VDN2.

Reason: The ISS donor is mouse alpha1 Q8VDN2. Coupled Na/K transport is conserved across these catalytic alpha subunits and has direct human alpha2 confirmation. Accept the function without pretending the transferred experiment used the human target.

Summary: Ouabain binding is retained as a non-core inhibitor-binding property of the pump.

Reason: The supplied CHEBI:472805 ligand is ouabain. The official ChEBI record explicitly asserts CHEBI:472805 is_a CHEBI:26764 (steroid hormone) and CHEBI:472805 is_a CHEBI:38092 (cardenolide glycoside), and also places it under hydroxy-steroid classes. Retain the existing steroid-binding assertion as non-core relative to ion pumping. This chemical classification does not establish an endogenous endocrine role; the exact relationships and access date are recorded in the notes.

Summary: The existing human beta1 interaction is more informatively represented as alpha2/beta1 heterodimerization.

Reason: The recorded IPI partner P05026 is human beta1. The complete PMID:23954377 abstract locates G900R/E902K at the alpha/beta interface and reports that these variants likely hamper subunit interaction and reduce activity. Together with the curated partner assertion and the established functional alpha2/beta1 pump assembly, this supports refining the generic molecular function to GO:0046982 protein heterodimerization activity. The abstract does not independently establish the partner accession, assay protocol, or a new stoichiometry; those claims are not added. GO:0046982 describes association with a nonidentical protein to form a heterodimer. The existing separate complex annotation remains a cellular-component statement, not the replacement molecular function. No additional NEW row is needed.

Proposed replacements: protein heterodimerization activity

Summary: ATP binding is an essential substrate-binding component of alpha2 catalytic transport.

Reason: ATP binding is an essential substrate-binding component of alpha2 catalytic transport. The conserved P-type ATPase domains and rat alpha2 inference agree with direct human pump biochemistry; accept as part of the core mechanism.

Summary: PMID23954377 is a variant study of the ATP1A2 catalytic protein.

Reason: PMID23954377 is a variant study of the ATP1A2 catalytic protein. Its abstract does not expose every ATP-affinity experiment, so retain the curator IMP attribution with independent ATP-dependent alpha2 pump evidence, rather than inventing a direct ATP-binding assay read here.

Summary: Retain the experimental broad cytoplasm localization with curator deference.

Reason: Retain the experimental broad cytoplasm localization with curator deference. The full PMID12539047 localization experiment was not independently read; the term does not imply a soluble pump and is ancillary to the well-supported plasma-membrane complex.

Summary: This broad ARBA cytoplasm assignment is compatible with the cellular distribution of the membrane protein but adds little localization specificity.

Reason: This broad ARBA cytoplasm assignment is compatible with the cellular distribution of the membrane protein but adds little localization specificity. Retain it as non-core without substituting cytosol or a soluble-protein interpretation.

Summary: The automatic donor is rat alpha2 P06686.

Reason: The automatic donor is rat alpha2 P06686. Endosomal trafficking of a surface pump is biologically compatible with the target, but it is not the defining site of its established transport function. Retain the localization as non-core and preserve its transferred evidence status.

Summary: Ensembl projection of a mouse alpha2 ER annotation that rests on ER retention of an overexpressed FHM2 mutant; wild-type alpha2 shows only slight ER staining, a biosynthetic transit pool, so the ER claim (and the is_active_in qualifier) is an over-annotation.

Reason: ORGANELLES check (2026-11-04), changed from KEEP_AS_NON_CORE. The source is mouse Q6PIE5, whose GO:0005783 row is an is_active_in IDA from PMID:21731499 (MGI). In that paper Myc-tagged alpha2 was overexpressed in HeLa cells: wild-type protein was mainly at the plasma membrane with slight ER staining, while the R887 migraine mutant colocalized with calnexin and was degraded by the proteasome. The ER pool is therefore biosynthetic transit of a plasma-membrane pump plus quality-control retention of a misfolded, overexpressed mutant; UniProt lists no ER location for human alpha2. Qualifier note: the row is is_active_in, but neither the source paper nor this review shows pumping activity in the ER, so the qualifier is not supported either; left unchanged as instructed. No sub-compartment row is added.

Summary: Plasma-membrane localization is directly corroborated by human alpha2 functional expression and targeting studies.

Reason: Plasma-membrane localization is directly corroborated by human alpha2 functional expression and targeting studies. The PAINT assertion is therefore consistent with the target. The target in WITH/FROM is legitimate experimental grounding, not circular evidence; the family tree was not independently reconstructed.

Summary: Plasma-membrane placement is central to ATP1A2 pump function and independently corroborated by human alpha2 studies.

Reason: Plasma-membrane placement is central to ATP1A2 pump function and independently corroborated by human alpha2 studies. Retain the PMID12539047 IDA assertion by curator deference without claiming its unavailable full localization assay was reread.

Summary: The UniProt/ortholog-derived plasma-membrane assignment agrees with human alpha2 expression and transport evidence.

Reason: The UniProt/ortholog-derived plasma-membrane assignment agrees with human alpha2 expression and transport evidence. This is the core cellular location of the coupled pump.

Summary: PMID19372756 explicitly distinguishes defective plasma-membrane targeting and temperature-dependent stability among ATP1A2 mutants.

Reason: PMID19372756 explicitly distinguishes defective plasma-membrane targeting and temperature-dependent stability among ATP1A2 mutants. The abstract identifies HEK293FT cells and oocytes; retain the normal targeting location without treating every mutant defect as a different wild-type compartment.

Summary: PMID19751721 reports human alpha isoform/beta1 preparations and cardiac glycoside binding, with atrial localization context.

Reason: PMID19751721 reports human alpha isoform/beta1 preparations and cardiac glycoside binding, with atrial localization context. Retain the surface pump location supported independently by functional human alpha2 studies; complete source-specific imaging Methods were not reread.

Summary: The normal Reactome summary places the alpha/beta/FXYD sodium-potassium exchange complex at the plasma membrane.

Reason: The normal Reactome summary places the alpha/beta/FXYD sodium-potassium exchange complex at the plasma membrane. This matches independently established human alpha2 function and is a core location, not a new pathway assertion.

Summary: The glycoside-binding Reactome event concerns the plasma-membrane alpha/beta/FXYD pump.

Reason: The glycoside-binding Reactome event concerns the plasma-membrane alpha/beta/FXYD pump. Its location agrees with the core transport complex even though inhibitor binding is ancillary to transport.

Summary: ATP1A2 is the catalytic alpha2 component of the sodium/potassium ATPase complex.

Reason: ATP1A2 is the catalytic alpha2 component of the sodium/potassium ATPase complex. The PAINT assertion has target and ortholog grounding and agrees with functional alpha2/beta preparations; self-WITH/FROM is not circular. No unread ancestral-node topology is asserted.

Summary: The inferred complex membership follows the established alpha2 coupled pump activity and independently tested alpha/beta assemblies.

Reason: The inferred complex membership follows the established alpha2 coupled pump activity and independently tested alpha/beta assemblies. Accept the IC assertion while retaining its original PMID12539047 and inference from GO:0005391.

Summary: PMID10636900 compares functional human alpha/beta isozyme combinations, directly supporting alpha2 as part of a sodium/potassium ATPase complex.

Reason: PMID10636900 compares functional human alpha/beta isozyme combinations, directly supporting alpha2 as part of a sodium/potassium ATPase complex. Beta isoform pairing affects kinetics but does not alter the basic complex identity.

Summary: PMID23954377 examines alpha2 domain and alpha/beta-interface variants.

Reason: PMID23954377 examines alpha2 domain and alpha/beta-interface variants. Retain the curator complex-membership assertion with independent human alpha2/beta biochemical support; the abstract is not claimed to resolve every physical interaction measurement.

Summary: The integrated rat-alpha2/ARBA complex assignment agrees with conserved pump architecture and direct human alpha2/beta activity.

Reason: The integrated rat-alpha2/ARBA complex assignment agrees with conserved pump architecture and direct human alpha2/beta activity. This complex is part of the core function.

Summary: PMID18052210 purifies an active complex containing human alpha2 and porcine beta1.

Reason: PMID18052210 purifies an active complex containing human alpha2 and porcine beta1. Accept membership in the sodium/potassium ATPase complex, retaining the species identity of the beta1 partner.

Summary: The human alpha2 and beta1 coexpression, membrane detection and pump activity in PMID18728015 support the functional complex.

Reason: The human alpha2 and beta1 coexpression, membrane detection and pump activity in PMID18728015 support the functional complex. The Q116R/N127D background and Xenopus host are explicit experimental limits, not evidence against human alpha2 membership.

Summary: PMID20100892 measures the coexpressed human alpha2/beta1 pump in Xenopus oocytes.

Reason: PMID20100892 measures the coexpressed human alpha2/beta1 pump in Xenopus oocytes. Retain complex membership without describing its current measurements as an isolated direct binary-binding assay.

Summary: Rat alpha2 P06686 provides the ISS donor, and independent human alpha2/beta functional preparations corroborate conserved sodium/potassium ATPase complex membership.

Reason: Rat alpha2 P06686 provides the ISS donor, and independent human alpha2/beta functional preparations corroborate conserved sodium/potassium ATPase complex membership.

Summary: Retain the rat-alpha2-derived caveolar localization as a specialized membrane context, not the universal location or a separate pump mechanism.

Reason: Retain the rat-alpha2-derived caveolar localization as a specialized membrane context, not the universal location or a separate pump mechanism. Its original imaging experiment was not reread, and no human caveola-specific assay is claimed.

Summary: Potassium transport is one half of the established coupled Na/K pump reaction.

Reason: Potassium transport is one half of the established coupled Na/K pump reaction. The family/ortholog inference is sound and represents core function, though the more informative coupled MF is used for synthesis.

Summary: PMID10642400 is a human genotype-by-training association study rather than an isolated transport assay.

Reason: PMID10642400 is a human genotype-by-training association study rather than an isolated transport assay. Nevertheless potassium transport is independently established for human alpha2, so retain this NAS assertion as core without mislabeling the association as direct flux evidence.

Summary: The rat alpha2 transfer is consistent with direct human alpha2 sodium transport.

Reason: The rat alpha2 transfer is consistent with direct human alpha2 sodium transport. Retain this core process and preserve the orthology-based evidence code.

Summary: The HERITAGE association paper supplies physiological context, not a direct sodium-flux assay in its abstract.

Reason: The HERITAGE association paper supplies physiological context, not a direct sodium-flux assay in its abstract. Sodium transport itself is well established by independent human alpha2 studies, supporting retention of the NAS process as core.

Summary: Intracellular sodium homeostasis follows alpha2-mediated sodium export and is supported by human pump measurements.

Reason: Intracellular sodium homeostasis follows alpha2-mediated sodium export and is supported by human pump measurements. The PAINT assertion is consistent with this mechanism; target inclusion among descendant evidence is expected and not circular.

Summary: The functional human isozyme measurements in PMID10636900 support the sodium-handling mechanism.

Reason: The functional human isozyme measurements in PMID10636900 support the sodium-handling mechanism. Retain the curator sodium-homeostasis assertion as core without inventing an additional intact-tissue homeostasis assay.

Summary: The mouse alpha2 transfer and cardiac/skeletal-muscle pump literature support modulation of contraction through ion gradients.

Reason: The mouse alpha2 transfer and cardiac/skeletal-muscle pump literature support modulation of contraction through ion gradients. This is a physiological consequence of the pump rather than its defining molecular reaction.

Summary: The ARBA striated-muscle regulation term is consistent with alpha2-dependent sodium/calcium handling.

Reason: The ARBA striated-muscle regulation term is consistent with alpha2-dependent sodium/calcium handling. Retain as a non-core physiological role; no additional muscle process is proposed.

Summary: PMID10642400 measures training-related cardiorespiratory associations in human families.

Reason: PMID10642400 measures training-related cardiorespiratory associations in human families. Keep the direction-neutral muscle-regulation assertion in physiological context, but do not present that abstract as a direct contraction or alpha2-flux experiment.

Summary: Cell communication is a very broad electronic description compatible with maintenance of excitability and neurotransmitter homeostasis.

Reason: Cell communication is a very broad electronic description compatible with maintenance of excitability and neurotransmitter homeostasis. Retain it as non-core; it does not establish a specific signaling or intercellular-channel activity.

Summary: Blood circulation is a broad physiological context for the cardiac and vascular ion pump.

Reason: Blood circulation is a broad physiological context for the cardiac and vascular ion pump. Retain this electronic assertion as non-core, without deriving a new dedicated circulation mechanism.

Summary: Alpha2-dependent sodium/calcium coupling can regulate heart contraction.

Reason: Alpha2-dependent sodium/calcium coupling can regulate heart contraction. Retain this direction-neutral ARBA assertion as non-core, keeping it distinct from the more specific and questionable intercellular electrical-coupling term.

Summary: P-type potassium transport is a valid broader component of the coupled sodium/potassium pump function.

Reason: P-type potassium transport is a valid broader component of the coupled sodium/potassium pump function. Retain it as non-core shorthand; the existing GO:0005391 activity is the appropriate specific core and no redundant replacement is needed.

Summary: Cell-surface localization transferred from mouse alpha2 is consistent with the established plasma-membrane pump.

Reason: Cell-surface localization transferred from mouse alpha2 is consistent with the established plasma-membrane pump. Retain this broader location as non-core; no additional extracellular orientation claim follows.

Summary: The electrogenic coupled pump directly maintains the transmembrane sodium/potassium electrochemical gradients.

Reason: The electrogenic coupled pump directly maintains the transmembrane sodium/potassium electrochemical gradients. This is a mechanistic process entailed by the existing activity, not a downstream phenotype.

Summary: The read section of PMID23608603 discusses alpha2 localization and sodium/calcium-exchanger coupling that affects calcium release and contractility.

Reason: The read section of PMID23608603 discusses alpha2 localization and sodium/calcium-exchanger coupling that affects calcium release and contractility. Retain the regulatory cardiac context, while distinguishing review synthesis and model-dependent coupling from direct calcium transport by ATP1A2.

Summary: The predicted auditory-response transfer identifies mouse alpha2 Q6PIE5, but the exact donor auditory experiment was not recovered.

Reason: The predicted auditory-response transfer identifies mouse alpha2 Q6PIE5, but the exact donor auditory experiment was not recovered. The available hearing-related search leads do not establish the precise stimulus-response assertion. Retain uncertainty rather than equating neurological disease with this process.

Summary: This separately curated ISS row uses the same mouse alpha2 donor.

Reason: This separately curated ISS row uses the same mouse alpha2 donor. The precise auditory-response primary evidence was not accessed, so the transfer cannot be independently adjudicated here. It is not rejected merely because it is non-core.

Summary: The rat-alpha2 intercalated-disc assignment describes a specialized cardiac membrane location.

Reason: The rat-alpha2 intercalated-disc assignment describes a specialized cardiac membrane location. Retain as non-core context, without turning localization into evidence that the pump itself conducts current through intercellular channels.

Summary: Membrane localization is unquestionably compatible with the multipass alpha2 pump, including PMID23954377.

Reason: Membrane localization is unquestionably compatible with the multipass alpha2 pump, including PMID23954377. Retain the experimental broad term as non-core because the specific plasma-membrane complex carries the core location.

Summary: The integrated membrane prediction is consistent with alpha2 topology.

Reason: The integrated membrane prediction is consistent with alpha2 topology. Keep this broad location as non-core rather than manufacturing a new specificity correction already covered by existing plasma-membrane rows.

Summary: Rat alpha2 membrane localization transfers plausibly and agrees with human functional preparations.

Reason: Rat alpha2 membrane localization transfers plausibly and agrees with human functional preparations. The broad term is retained as non-core alongside the more specific plasma-membrane evidence.

Summary: The donor is mouse alpha1 Q8VDN2, not alpha2.

Reason: The donor is mouse alpha1 Q8VDN2, not alpha2. An independently consulted alpha1-loop study reports phosphomonoester substrate hydrolysis, which prevents dismissal merely because the protein is called an ATPase. Its conservation in alpha2 has not been established here; ATP hydrolysis and transient phosphoenzyme dephosphorylation alone do not prove this distinct MF.

Summary: ATP hydrolysis supplies the energy for the alpha2 transport cycle and is catalyzed by its P-type ATPase machinery.

Reason: ATP hydrolysis supplies the energy for the alpha2 transport cycle and is catalyzed by its P-type ATPase machinery. Accept as a component of the core coupled reaction, not a separate uncoupled ATPase core.

Summary: The variant study concerns the ATP1A2 catalytic mechanism and the function is independently supported by human alpha2 pump biochemistry.

Reason: The variant study concerns the ATP1A2 catalytic mechanism and the function is independently supported by human alpha2 pump biochemistry. Retain the curator IMP ATP-hydrolysis assertion without claiming the full PMID23954377 assay Methods were reread.

Summary: The targeting/stability study in PMID19372756 concerns functional ATP-dependent alpha2 ion transport.

Reason: The targeting/stability study in PMID19372756 concerns functional ATP-dependent alpha2 ion transport. Accept this broader core transporter activity with source-specific curator deference; synthesize the already present Na/K-specific MF rather than a second generic core.

Summary: The rat-alpha2 transfer is compatible with directly demonstrated human alpha2 ATP-dependent cation transport.

Reason: The rat-alpha2 transfer is compatible with directly demonstrated human alpha2 ATP-dependent cation transport. This represents the broad parent of the established core activity.

Summary: The human alpha2/beta1 pump-current experiments in PMID20100892 support ATP-coupled cation transport.

Reason: The human alpha2/beta1 pump-current experiments in PMID20100892 support ATP-coupled cation transport. The same paper also describes conditional leaks, which must not be used to imply that every current is ATP-coupled.

Summary: The official PMID12805306 abstract reports neurodegeneration/apoptosis in the amygdala of Atp1a2-null mice.

Reason: The official PMID12805306 abstract reports neurodegeneration/apoptosis in the amygdala of Atp1a2-null mice. Retain the mouse-alpha2 developmental transfer as a non-core consequence of maintaining neural ionic homeostasis, not a new human morphogenesis mechanism.

Summary: The same mouse study documents piriform/olfactory cortical pathology in Atp1a2 deficiency.

Reason: The same mouse study documents piriform/olfactory cortical pathology in Atp1a2 deficiency. Retain the existing ortholog-derived development term as non-core with its species boundary; it does not make ATP1A2 a dedicated developmental regulator.

Summary: The alpha2 pump directly controls intracellular sodium and potassium concentrations.

Reason: The alpha2 pump directly controls intracellular sodium and potassium concentrations. This broad ARBA cation-homeostasis assertion is consistent with the core ion-handling mechanism.

Summary: Potassium homeostasis is a direct consequence of the conserved pump reaction, corroborated by human alpha2 assays.

Reason: Potassium homeostasis is a direct consequence of the conserved pump reaction, corroborated by human alpha2 assays. Retain the PAINT assertion without penalizing human target evidence in WITH/FROM or claiming an unread tree reconstruction.

Summary: PMID10636900 functionally compares human alpha2-containing pumps and potassium-dependent behavior.

Reason: PMID10636900 functionally compares human alpha2-containing pumps and potassium-dependent behavior. Retain the original IDA potassium-homeostasis assertion as core with the experiment/whole-tissue distinction intact.

Summary: The PMID23954377 abstract reports effects of ATP1A2 variants on potassium affinity and pump function.

Reason: The PMID23954377 abstract reports effects of ATP1A2 variants on potassium affinity and pump function. Potassium homeostasis is core and independently supported; full source-specific cell-homeostasis measurements were not reread.

Summary: The integrated rat/mouse/ARBA T-tubule assignment agrees with the specialized alpha2 cardiac membrane context discussed in the literature.

Reason: The integrated rat/mouse/ARBA T-tubule assignment agrees with the specialized alpha2 cardiac membrane context discussed in the literature. Retain the location as non-core tissue specialization rather than a universal compartment of ATP1A2.

Summary: PMID19751721 includes human cardiac isoform localization as well as human isozyme ligand binding.

Reason: PMID19751721 includes human cardiac isoform localization as well as human isozyme ligand binding. Keep T-tubule localization as non-core, preserving the original IGI and beta1 context without claiming complete image or construct-method verification.

Summary: Potassium binding is integral to the alpha2 transport cycle.

Reason: Potassium binding is integral to the alpha2 transport cycle. The PMID23954377 abstract explicitly reports altered apparent potassium affinity in variants, supporting retention of this core substrate-binding component without equating apparent affinity with an isolated equilibrium-binding assay.

Summary: Sodium binding is integral to coupled transport, and the PMID23954377 abstract reports altered sodium affinity in variants.

Reason: Sodium binding is integral to coupled transport, and the PMID23954377 abstract reports altered sodium affinity in variants. Retain the core binding component with the distinction between kinetic apparent affinity and a purified ligand-binding measurement.

Summary: The electronic transfer identifies rat alpha2 but its specific nicotine-response experiment has not been accessed.

Reason: The electronic transfer identifies rat alpha2 but its specific nicotine-response experiment has not been accessed. General neuronal ion pumping is insufficient to establish this particular stimulus response; retain source-specific uncertainty rather than reject the function from a broad gene description.

Summary: Mouse alpha2 disruption changes movement in a novel environment.

Reason: This electronic transfer identifies mouse alpha2 Q6PIE5. Recovered PMID12805306 Methods explicitly measure locomotor activity in a novel open field, light/dark compartment time and elevated-plus-maze entry; Results report altered behavior in adult heterozygotes while home-cage activity and rota-rod coordination are unchanged. GO:0035641 concerns movement in a novel environment. Retain the existing transfer as non-core with the mouse species and environmental context explicit; no direct human behavioral experiment is inferred.

Summary: Recovered mouse experiments support the existing exploration transfer.

Reason: The curated ISS assertion has the same mouse alpha2 donor. Complete recovered PMID12805306 Methods and Results support altered novel-environment exploration in heterozygotes, with unchanged home-cage activity and motor coordination as controls. Retain the existing ortholog transfer as non-core, rather than continuing an uncertainty caused by previously unavailable assay text. This is contextual mouse behavioral evidence, not a defining molecular activity or a direct human experiment.

Summary: Active human alpha2 paired with porcine beta1 in PMID18052210 supports the established sodium-translocation function.

Reason: Active human alpha2 paired with porcine beta1 in PMID18052210 supports the established sodium-translocation function. Retain the core process and mixed-species preparation boundary; do not claim this purification abstract alone shows vesicular sodium flux.

Summary: Sodium export across the plasma membrane is one direction of the established alpha2 pump reaction.

Reason: Sodium export across the plasma membrane is one direction of the established alpha2 pump reaction. Retain the PAINT inference with independent human grounding, without treating target participation in descendant evidence as circular.

Summary: The functional human alpha2 isozyme experiments support the electrogenic pump mechanism and its sodium-export direction.

Reason: The functional human alpha2 isozyme experiments support the electrogenic pump mechanism and its sodium-export direction. Retain the original IDA process as core without adding an unreported tracer assay.

Summary: PMID18728015 measures outward electrogenic pump currents and rubidium uptake in human alpha2/beta1-expressing oocytes.

Reason: PMID18728015 measures outward electrogenic pump currents and rubidium uptake in human alpha2/beta1-expressing oocytes. These support the normal coupled sodium-export mechanism, with the engineered ouabain-resistant background retained.

Summary: PMID20100892 distinguishes normal outward pump current from conditional inward leak.

Reason: PMID20100892 distinguishes normal outward pump current from conditional inward leak. Retain physiological sodium export as the core pump process; leak currents of mutant or strongly altered conditions are not evidence for reversing the normal core direction.

Summary: The ATP1A2 variant study supports the coupled pump mechanism, and sodium export is directly consistent with independent human alpha2 evidence.

Reason: The ATP1A2 variant study supports the coupled pump mechanism, and sodium export is directly consistent with independent human alpha2 evidence. Retain the IMP process by curator deference rather than claim an unavailable source-specific flux measurement.

Summary: Mouse movement phenotypes depend on genotype and assay context.

Reason: The mouse-alpha2 donor is supported by recovered PMID12805306 movement assays: heterozygous adults have altered novel-environment behavior and homozygous E18.5 embryos lack spontaneous movement. Adult heterozygous home-cage locomotion and rota-rod coordination were not significantly different from controls. Retain the existing broad locomotion transfer as non-core with those genotype and assay boundaries; do not claim a generalized adult motor deficit or a direct human locomotion assay.

Summary: Sarcolemmal localization is consistent with the alpha2 muscle pump and rat/mouse donor annotations.

Reason: Sarcolemmal localization is consistent with the alpha2 muscle pump and rat/mouse donor annotations. Retain this muscle-specific location as non-core context alongside the general plasma-membrane core.

Summary: Retain the mouse-alpha2-derived neuronal projection localization as a reported developmental/cell-type context.

Reason: Retain the mouse-alpha2-derived neuronal projection localization as a reported developmental/cell-type context. Adult astrocytic enrichment does not refute neuronal localization in other stages or preparations; no exact human projection imaging is claimed.

Summary: The mouse alpha2 cell-body localization is compatible with stage-dependent neuronal expression.

Reason: The mouse alpha2 cell-body localization is compatible with stage-dependent neuronal expression. Retain the electronic compartment as non-core and do not infer a new neuronal signaling mechanism from localization.

Summary: This separately curated ISS neuronal-cell-body assertion uses the same mouse ortholog.

Reason: This separately curated ISS neuronal-cell-body assertion uses the same mouse ortholog. Retain it as non-core with its transfer boundary; adult glial prominence alone is not evidence of a false donor annotation.

Summary: The rat-alpha2 dendritic-spine assignment is a specialized neural location.

Reason: The rat-alpha2 dendritic-spine assignment is a specialized neural location. Retain it as non-core without asserting direct spine imaging in human cells or rejecting it solely from the more familiar astrocytic expression pattern.

Summary: The alpha2 cardiac literature discusses increased contractility after alpha2 reduction/inhibition, consistent with a restraining effect on calcium-dependent contraction.

Reason: The alpha2 cardiac literature discusses increased contractility after alpha2 reduction/inhibition, consistent with a restraining effect on calcium-dependent contraction. Retain the mouse-alpha2 negative-regulation transfer as non-core and distinguish it from alpha1 perturbation phenotypes.

Summary: This positive-regulation transfer comes from mouse alpha1 Q8VDN2, whereas alpha2-selective perturbations can show the opposite contractile direction.

Reason: This positive-regulation transfer comes from mouse alpha1 Q8VDN2, whereas alpha2-selective perturbations can show the opposite contractile direction. The exact donor conditions and their conservation in alpha2 have not been resolved. Keep uncertainty rather than assert either universal positive regulation or a demonstrated loss.

Summary: ATP hydrolysis is the energy-transducing reaction performed by the alpha2 pump.

Reason: ATP1A2 itself catalyzes ATP hydrolysis during sodium/potassium transport, so this experimental ATP-metabolism annotation describes work in the core reaction. ACCEPT does not require repeating every broad parent in the distilled core_functions list: its GO:0005391 molecular function already specifies the ATP-driven transport mechanism. Retain the annotation without adding a redundant broad process or asserting ATP synthesis. The source term is GO:0046034, not GO:0006200.

Summary: Alpha2/beta heteromer formation is consistent with the functional pump assemblies, and the rat-alpha2 transfer is plausible.

Reason: Alpha2/beta heteromer formation is consistent with the functional pump assemblies, and the rat-alpha2 transfer is plausible. Retain this assembly-associated binding property as non-core; no additional homodimeric or signaling complex is inferred.

Summary: P05026 is beta1.

Reason: P05026 is beta1. PMID10636900 tests alpha/beta combinations, and the cardiac review explicitly describes beta-subunit chaperone roles in alpha folding and surface delivery. Retain the existing beta1-binding assertion as non-core; it does not say alpha2 itself is a folding chaperone.

Summary: P14415 is beta2, one of the human beta isoforms paired with alpha subunits in PMID10636900.

Reason: P14415 is beta2, one of the human beta isoforms paired with alpha subunits in PMID10636900. Retain the chaperone-partner binding context as non-core, with beta-mediated maturation distinguished from direct alpha2 chaperone activity.

Summary: P54709 is beta3.

Reason: P54709 is beta3. The human isozyme-combination study supports the assembly-partner context, while beta-subunit chaperone function supplies the label interpretation. Retain as non-core without inventing a separate protein-folding activity for alpha2.

Summary: Mouse-alpha2-dependent sodium gradients can favor calcium extrusion through sodium/calcium exchange and thereby restrain cytosolic calcium.

Reason: Mouse-alpha2-dependent sodium gradients can favor calcium extrusion through sodium/calcium exchange and thereby restrain cytosolic calcium. Retain this physiological regulation as non-core, explicitly mediated through other transport machinery rather than calcium pumping by ATP1A2.

Summary: PMID23954377 provides a neurological disease/pump-mechanism context; the independently read mouse alpha2 uptake study supplies corroborating glutamate-uptake evidence.

Reason: PMID23954377 provides a neurological disease/pump-mechanism context; the independently read mouse alpha2 uptake study supplies corroborating glutamate-uptake evidence. Retain this existing NAS regulatory role as non-core, distinguishing sodium-gradient support from direct glutamate translocation.

Summary: Alpha2-dependent ionic homeostasis and glutamate clearance provide a credible regulatory role in glutamatergic transmission.

Reason: Alpha2-dependent ionic homeostasis and glutamate clearance provide a credible regulatory role in glutamatergic transmission. Retain this existing NAS context as non-core; the PMID23954377 abstract alone is not a synaptic transmission experiment.

Summary: The PMID23224879 review addresses coordinated sodium/potassium pump and sodium/calcium exchanger regulation in cardiac cells.

Reason: The PMID23224879 review addresses coordinated sodium/potassium pump and sodium/calcium exchanger regulation in cardiac cells. Retain relaxation as a non-core physiological context, without making alpha2 the direct calcium-removal enzyme.

Summary: The same review supports a cardiac contraction context through ion handling.

Reason: The same review supports a cardiac contraction context through ion handling. Retain this broad process as non-core; pumping is the direct molecular work and contraction is its tissue-level consequence.

Summary: The rat-alpha2 mechanical-stimulus response is a specific transferred perturbation claim.

Reason: The rat-alpha2 mechanical-stimulus response is a specific transferred perturbation claim. Its original stimulus/assay evidence was not accessed, and general muscle activity is insufficient to verify it. Preserve the source and uncertainty.

Summary: PMID14742675 measures ouabain binding in microsomes prepared from human-alpha2-expressing oocytes; that assay alone does not establish a cellular response.

Reason: PMID14742675 measures ouabain binding in microsomes prepared from human-alpha2-expressing oocytes; that assay alone does not establish a cellular response. Independent PMID10636900 Methods and Figure 6 identify ouabain-sensitive human alpha2/beta1 pump currents in intact oocytes, providing functional corroboration. Retain this existing response as non-core; ouabain is classified as a steroid hormone, but no general endocrine signaling function is inferred. The chemical classification used here is the explicit ChEBI axiom CHEBI:472805 is_a CHEBI:26764, not a claim that every steroid is a hormone; the separate glycoside parent is CHEBI:38092.

Summary: The supplied integrated sources include rat/mouse alpha2 and ARBA.

Reason: The supplied integrated sources include rat/mouse alpha2 and ARBA. Independent PMID10636900 reports human alpha2/beta1 pump-current measurements before and after ouabain in intact oocytes. Retain the existing steroid-stimulus response as non-core pharmacological modulation; this functional evidence is distinct from ligand binding alone and does not establish a separate endocrine signaling core. The chemical classification used here is the explicit ChEBI axiom CHEBI:472805 is_a CHEBI:26764, not a claim that every steroid is a hormone; the separate glycoside parent is CHEBI:38092.

Summary: The active human-alpha2/porcine-beta1 preparation in PMID18052210 supports the established potassium-translocation component of the coupled pump.

Reason: The active human-alpha2/porcine-beta1 preparation in PMID18052210 supports the established potassium-translocation component of the coupled pump. Retain the core process while keeping purification/activity distinct from any unexamined tracer-flux experiment.

Summary: PMID18728015 directly measures rubidium uptake as a potassium-transport surrogate alongside pump currents in human alpha2/beta1-expressing oocytes.

Reason: PMID18728015 directly measures rubidium uptake as a potassium-transport surrogate alongside pump currents in human alpha2/beta1-expressing oocytes. This supports the core potassium transport process, with reference-construct substitutions and host species explicit.

Summary: The rat-alpha2 transfer fits regulation of cardiac contraction through sodium/calcium balance.

Reason: The rat-alpha2 transfer fits regulation of cardiac contraction through sodium/calcium balance. Retain this direction-neutral physiological role as non-core; it does not entail direct intercellular electrical coupling.

Summary: The electrogenic outward pump contributes to restoration and maintenance of membrane polarization.

Reason: The electrogenic outward pump contributes to restoration and maintenance of membrane polarization. Retain the existing TAS repolarization context as non-core, with independent review-level corroboration in PMID23608603. Its current is distinct from the fast voltage-gated depolarizing phase.

Summary: GO:0086012 specifically denotes the depolarizing phase of the cardiac action potential.

Reason: GO:0086012 specifically denotes the depolarizing phase of the cardiac action potential. The read PMID23608603 sections attribute depolarization to sodium-channel/NCX currents and describe the Na/K pump as outward and repolarizing. Alpha2 sustains permissive gradients, but the cited review does not establish it as performing this depolarizing phase. Mark the direct process assignment over-annotated; the existing repolarization row already covers the supported polarity context.

Summary: GO:0086064 requires current between adjacent cytoplasms through intercellular protein channels.

Reason: GO:0086064 requires current between adjacent cytoplasms through intercellular protein channels. Complete PMID19683723 Methods/Results/Discussion measure mouse beta1 deletion, secondary alpha1 reduction, unchanged alpha2 abundance, ATPase activity and calcium/contractility. Those data do not establish alpha2-mediated intercellular current. This is a specificity overreach from cardiac physiology, not a title-based wrong-gene claim.

Summary: The ATP1A2 targeting/stability paper supports the well-established cation-transport mechanism.

Reason: The ATP1A2 targeting/stability paper supports the well-established cation-transport mechanism. Retain this broad IDA core process with curator deference; no new transport activity beyond the existing coupled Na/K function is inferred.

Summary: GO:0150104 concerns directed movement through the blood-brain barrier.

Reason: GO:0150104 concerns directed movement through the blood-brain barrier. The staged PMID30280653 endothelial-ion-transport section discusses abluminal Na/K-ATPase at family level without resolving alpha2 in the read passage. Preserve this NAS assertion as uncertain rather than claim that a generic endothelial pump passage proves ATP1A2-specific barrier transport or that the whole paper excludes alpha2.

Summary: The original IEA is transferred from rat alpha2, but PMID20100892 independently reports conditional inward proton current for the human alpha2 reference pump under sodium/potassium-free acidic conditions.

Reason: The original IEA is transferred from rat alpha2, but PMID20100892 independently reports conditional inward proton current for the human alpha2 reference pump under sodium/potassium-free acidic conditions. Retain proton transport as a non-core side mode, not an obligatory H+ stoichiometry, normal physiological human proton-pump function, or a second core. Mutant sodium leak is separately distinguished.

Summary: The exact rat-alpha2 experiment behind negative regulation of calcium transmembrane transport was not recovered.

Reason: The exact rat-alpha2 experiment behind negative regulation of calcium transmembrane transport was not recovered. Alpha2 clearly affects calcium homeostasis through sodium/calcium exchange, but the sign of total calcium transport depends on gradients and the measured route. Do not infer this precise negative transport direction from lower cytosolic calcium alone.

Summary: This separate ISS row uses the same rat-alpha2 donor and precise negative calcium-transport direction.

Reason: This separate ISS row uses the same rat-alpha2 donor and precise negative calcium-transport direction. The source-specific route and perturbation conditions remain unresolved; retain uncertainty rather than generalize calcium-handling physiology into the stated sign.

Summary: The original IC inference from GO:1990239 concerns ouabain, a glycoside, but microsomal ligand binding in PMID14742675 alone does not demonstrate a response.

Reason: The original IC inference from GO:1990239 concerns ouabain, a glycoside, but microsomal ligand binding in PMID14742675 alone does not demonstrate a response. Independent PMID10636900 identifies ouabain-sensitive human alpha2/beta1 currents in intact oocytes. Retain the existing response as non-core with that separate functional support, preserving its IC provenance and avoiding a glycoside-metabolism claim.

Summary: The supplied sources are rat and mouse alpha2 proteins and their Ensembl records; this row does not list ARBA.

Reason: The supplied sources are rat and mouse alpha2 proteins and their Ensembl records; this row does not list ARBA. Independent PMID10636900 identifies ouabain-sensitive human alpha2/beta1 currents in intact oocytes. Retain the existing glycoside response as non-core pharmacological modulation, rather than treating ligand binding alone as the response endpoint.

Summary: The original ISS donor is rat alpha2 P06686.

Reason: The original ISS donor is rat alpha2 P06686. Independent PMID10636900 identifies ouabain-sensitive human alpha2/beta1 pump currents in intact oocytes, supporting the conserved response beyond ligand affinity alone. Retain as non-core while preserving the original ortholog-transfer provenance.

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

Reason: Plasma-membrane Na+/K+-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: Human alpha-isoform experiments support non-core ouabain binding; the steroid-hormone classification is explicit in ChEBI.

Reason: PMID:14742675 studies ouabain binding/accessibility in human alpha isoforms. The exact official relation is CHEBI:472805 (ouabain) is_a CHEBI:26764 (steroid hormone); this is separate from its is_a CHEBI:38092 (cardenolide glycoside) relation. Retain the existing ligand-binding term as non-core pharmacological context. This does not infer endocrine signaling from the steroid scaffold or make the pump a hormone-regulated transcription factor. Binding and cellular-response evidence are assessed separately.

Summary: The rat-alpha2 transfer for steroid-hormone binding is consistent with human alpha2 ouabain evidence and the authoritative ligand classification.

Reason: The supplied rat-alpha2 transfer is consistent with the independent human alpha2 ouabain-binding evidence. Official ChEBI explicitly asserts CHEBI:472805 is_a CHEBI:26764 (steroid hormone), supporting the ligand class used by the existing term. Retain this as non-core alongside the experimental annotation; no new endocrine mechanism or redundant NEW ligand-binding assertion follows.

Summary: Potassium import across the plasma membrane is the inward arm of the conserved coupled pump.

Reason: Potassium import across the plasma membrane is the inward arm of the conserved coupled pump. Retain the PAINT assertion with direct human target corroboration; self-WITH/FROM and donor count do not weaken it.

Summary: The functional human alpha2 isozyme study supports the normal potassium-inward pump mechanism.

Reason: The functional human alpha2 isozyme study supports the normal potassium-inward pump mechanism. Retain the IDA process as core with source-specific assay details limited to those actually read.

Summary: The PMID23954377 abstract reports variant effects on potassium affinity and pump function, consistent with potassium import.

Reason: The PMID23954377 abstract reports variant effects on potassium affinity and pump function, consistent with potassium import. Retain the original IMP assertion by curator deference and direct independent human alpha2 evidence, without inventing an unexamined potassium-uptake assay.