FRRS1L

Summary: ER-membrane localization supports the AMPAR-biogenesis role.

Reason: The original Ensembl transfer comes from mouse B1AXV0. Current exact mouse ER-membrane records cite PMID:31604597 and include postsynaptic extensions that are absent from the human original; that later localization experiment remains unverified here because its full text was inaccessible. Independently, selected PMID:28675162 Methods/Results establish endogenous rat ER immunogold localization and ER-associated localization/coassembly of the reported human construct in heterologous cells, with CPT1c-dependent retention. These accessible experiments support the unextended ER-membrane claim and its core biological role without certifying the inaccessible donor experiment or adding its postsynaptic extension.

Summary: The subcellular-location mapping is consistent with limited surface-localization evidence.

Reason: The original electronic source is UniProtKB-SubCell:SL-0039. Independent selected PMID:29276473 and PMID:28675162 experiments support surface localization in defined expression contexts, with rare endogenous rat membrane-associated particles and CPT1c-dependent redistribution toward ER. Retain plasma membrane as a contextual location. This does not make it the dominant endogenous compartment, imply permanent mature AMPAR membership, or change the original located_in qualifier and source.

Summary: Retain experimentally plausible surface localization as contextual rather than dominant.

Reason: The original ISS transfer from mouse B1AXV0 is retained. PMID:29276473 detects tagged mouse FRRS1L at the surface of heterologous cells and cultured neurons, while PMID:28675162 reports surface localization of the expressed human construct alone, ER redistribution with CPT1c, and a small minority of endogenous rat particles at or near the plasma membrane. These data support a capacity for surface localization but do not establish it as the principal physiological site of receptor biogenesis. The current mouse same-term chain includes ISO evidence back to human PR:Q9P0K9; that literal record is preserved without treating the chain as an independent human experiment or a proven historical circular error.

Summary: Replace broad complex binding with receptor-partner-specific ionotropic glutamate receptor binding.

Reason: The Ensembl IEA retains its mouse B1AXV0 orthology provenance. The exact mouse donor claim cites PMID:29276473: Figure 1A and the co-immunoprecipitation Methods show association of mouse FRRS1L with GluA1 or GluA2 in HEK cells. Independent PMID:28675162 identifies selective native rat AMPAR complexes and cooperative association with GluA1/A2 and CPT1c in heterologous experiments whose Methods list human FRRS1L NM_014334. GO:0035255 identifies the experimentally supported receptor partner. This is an evidence-based replacement between binding categories, not an asserted is_a narrowing of GO:0044877. Co-IP, affinity purification and coassembly support receptor association without establishing purified binary affinity, every pairwise contact, permanent membership in mature surface receptors, or sequence identity of the historical experimental clone to the current reference. Preserve the original evidence, qualifier and donor groups.

Proposed replacements: ionotropic glutamate receptor binding

Summary: Retain uncertainty about synaptic localization while recording the negative rat sampling result.

Reason: This IEA derives from UniProtKB-SubCell:SL-0258 rather than a directly inspected human localization assay. PMID:28675162 Results and Figure 5 report 815 of 848 immunoparticles at ER membranes in 29 sampled rat neurons, with the remaining 33 at or near plasma membrane; staining was concentrated in somata or proximal dendrites and was not observed in the sampled synaptic compartment. That is actual negative localization evidence in that preparation. Separately, PMID:29276473 Figure 1F and Discussion report only a minor fraction of expressed mouse HA-FRRS1L overlapping PSD-95 in cultured hippocampal neurons. The broad located_in annotation is nonexclusive and does not claim dominant or constitutive synaptic residence. MARK_AS_OVER_ANNOTATED would not require proving universal absence, but the sampled negative result and distinct partial-positive context do not yet settle whether the human transfer exceeds its support. The later mouse PMID:31604597 experimental postsynaptic-ER annotations remain unverified here because the original assays were inaccessible. Since postsynapse is part_of synapse, the unresolved later context also matters to the broad term. Retain UNDECIDED without treating the earlier negative finding as absent or the later curator assertion as independently verified. Plasma-membrane non-core retention rests on positive surface-expression evidence as well as the rare rat particles, not on a symmetric conversion of any negative observation into a rejection.

Summary: Keep the manual sequence transfer unresolved across distinct localization experiments.

Reason: This ISS is a curator-mediated sequence-similarity transfer from mouse B1AXV0, not an automatically generated electronic annotation; the current same-term mouse donor row is separately IEA. PMID:28675162 reports no synaptic staining in its sampled rat somatic/proximal-dendritic preparation, alongside 815 of 848 particles at ER membranes in 29 neurons and 33 at or near plasma membrane. PMID:29276473 Figure 1F and Discussion instead describe minor PSD-95 overlap of overexpressed mouse HA-FRRS1L, with most labeling outside synapses. These distinct assays favor an ER-centered role. The broad located_in annotation does not assert dominant or constitutive residence, and an over-annotation judgment does not require universal absence; the present sampled negative and partial-positive observations leave the transferred scope unresolved. The later mouse PMID:31604597 postsynapse and ER-membrane-part_of-postsynapse experimental records are retained literally; their original Methods and localization experiment could not be inspected. Because a postsynaptic location would also support the broader synapse context, keep the human transfer UNDECIDED pending that source-specific adjudication. This does not infer localization merely from regulation of synaptic AMPARs, nor claim a source or species error.

Summary: Dynein intermediate-chain binding remains unresolved by the intact-vesicle assay.

Reason: This Ensembl IEA traces to mouse B1AXV0 IPI evidence in PMID:29276473. The selected Vesicle Immunoisolation Methods and Figure 2 describe anti-DIC isolation of detergent-free hippocampal membrane vesicles containing FRRS1L and AMPARs. The antibody target does not establish which vesicle protein contacts the intermediate chain. The exact GO term requires binding to that chain, whereas the inspected experiment resolves vesicle association. Retain the original assertion as undecided pending evidence that distinguishes direct or complex-mediated FRRS1L association with DIC from carriage in the same vesicle. This assay limitation neither demonstrates absence of the activity nor establishes a curation or species error.

Summary: The exact postsynaptic localization evidence has not been inspected.

Reason: The Ensembl IEA donor B1AXV0 has current postsynapse IEP/IMP/IDA records citing PMID:31604597; some related donor ER annotations explicitly carry part_of postsynapse. The authentic abstract supports neuronal ER assembly but does not expose the localization assays needed to resolve this particular claim. Publisher routes returned 403 and the inspected institutional repository restricts the original article and supplement. Keep the assertion undecided rather than refuting it from older rat somatic/proximal ER localization or from receptor-function measurements. Species, compartment and assay differ, and the human original has no extension to alter.

Summary: Inherited control of postsynaptic receptor abundance is a characteristic FRRS1L function.

Reason: The actual PTHR46902 tree places human AN10/PTN002508553 below AN1/PTN002930507, and the literal IBD for GO:0099072 has RGD:1309978 as its descendant evidence. That rat identifier resolves to D3ZE85, whose exact current experimental records cite PMID:28675162. Rat perturbation and AMPAR-selective biochemical/electrophysiological experiments, independently complemented by mouse surface/total GluA1 deletion and rescue evidence in PMID:29276473 and receptor-maturation/fractionation evidence in PMID:30692144, support regulation of postsynaptic receptor levels. The role concerns AMPA receptors in the tested neuronal settings; it does not imply control of every receptor class or require FRRS1L itself to reside in the postsynaptic plasma membrane. The original ancestral node and literal donor remain intact.

Summary: Rat ortholog evidence supports regulation of postsynaptic AMPAR abundance.

Reason: This Ensembl IEA transfers from rat D3ZE85/ENSRNOP00000031856. The exact same-term rat IDA/IMP records cite PMID:28675162 and carry a donor-only anatomical extension. Selected original rat experiments link FRRS1L manipulation to synaptic and somatic AMPAR responses with receptor and presynaptic controls. Mouse single-cell deletion/rescue and surface/total GluA1 measurements in PMID:29276473 and knockout receptor maturation/postsynaptic fractionation in PMID:30692144 provide independent support for the characteristic receptor-abundance role. Retain the unrestricted human source context without copying the rat extension or broadening the demonstrated AMPAR scope to all neurotransmitter receptors.

Summary: The human experimental descendant supports a valid inherited signaling-regulation assertion.

Reason: The literal GO:1900449 IBD is at AN1/PTN002930507 on the actual human PTHR46902 target path. Its UniProtKB:Q9P0K9 donor is the human target itself, legitimately contributing experimental descendant evidence to the ancestral inference. PMID:27236917 supplies the independent human SH-SY5Y knockdown and AMPA-response experiment, and mammalian receptor-biogenesis studies corroborate the function. Self-inclusion in WITH/FROM is not circularity and donor count does not weaken the node placement. Accept the core regulatory process while retaining the original IBA node/donor and avoiding a direct channel-gating or enzymatic mechanism claim.

Summary: The family-based signaling annotation agrees with direct human and mammalian evidence.

Reason: The original source is the InterPro IPR042789 mapping, not an experimental assay. Independently, the selected original text and Figure 4 of PMID:27236917 show reduced AMPA-evoked calcium entry and inward currents after FRRS1L knockdown in neuronally differentiated human SH-SY5Y cells. Rat and mouse studies PMID:28675162, PMID:29276473 and PMID:30692144 support AMPAR biogenesis and abundance as a mechanism affecting glutamatergic signaling. These results justify retaining the regulatory process as core while preserving the IEA provenance. The human assay alone does not resolve trafficking versus gating, and the annotation does not assert that FRRS1L forms the ion-conducting channel.

Summary: Human FRRS1L knockdown directly alters AMPA-evoked responses.

Reason: The selected original PMID:27236917 functional paragraph and Figure 4 caption report FRRS1L siRNA in neuronally differentiated human SH-SY5Y cells, with reduced AMPA-induced calcium influx and inward current. This directly supports regulation of glutamate receptor signaling and is more specific than clinical necessity evidence alone. The original paper was consulted through retained indexed main-text extraction; the failed direct XML retrieval and unread supplements are not treated as complete full-text inspection. The tested response does not by itself distinguish receptor maturation, delivery or gating. The original human IMP annotation remains unchanged.