ANO5 (TMEM16E) is a multipass membrane protein of the anoctamin family with calcium-dependent phospholipid scramblase activity. It resides mainly in the endoplasmic reticulum and reaches the plasma membrane in particular expression and injury contexts. Human ANO5 supports transbilayer lipid redistribution and associated nonselective ion conductance in cell assays. In muscle, ANO5 supports membrane repair and coordinated annexin trafficking after injury; a scrambling-defective chimera can rescue repair, indicating separable functions. Endothelial ANO5 contributes to surface phosphatidylserine exposure. Recessive ANO5 variants cause limb-girdle muscular dystrophy R12 or Miyoshi muscular dystrophy 3, whereas specific dominant variants cause gnathodiaphyseal dysplasia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001778 plasma membrane repair | IMP PMID:33496727 ANO5 ensures trafficking of annexins in wounded myofibers. | ACCEPT | Summary: ANO5 supports repair of wounded muscle plasma membrane. Reason: The actual Results and construct Methods of PMID:33496727 show human ANO5 rescue of isolated Ano5-deficient mouse fibers, recruitment near wounds, altered annexin trafficking, and defective repair in human R58W patient myocytes. These support the existing repair assertion. The scrambling-defective ANO5-1-5 chimera also restores repair, so this role is not equated with phospholipid scrambling, direct annexin binding or membrane-fusion chemistry. Supporting Evidence: PMID:33496727 Both ANO5 and ANO5-1-5 expression in ANO5-KO myofibers restored normal repair PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage |
| GO:0005229 intracellularly calcium-gated chloride channel activity | IDA NOT PMID:22075693 ANOs 3-7 in the anoctamin/Tmem16 Cl- channel family are intr... | UNDECIDED | Summary: The NOT calcium-gated chloride-channel assertion remains unresolved across assay contexts. Reason: The original NOT flag and the negative result remain intact. PMID:22075693 tested human ANO5 IMAGE100061756 with a C-terminal EGFP tag: whole-cell recordings at about 24 Β΅M free intracellular calcium were negative, with intracellular retention. The authors explicitly leave intrinsic channel capacity unresolved. The ANO5 halide assay in PMID:20056604 and the negative channel interpretation in PMID:23047743 add contrary evidence. However, PMID:22946059 reports small ionomycin-evoked human ANO5 currents, and PMID:29124309 reports calcium-favored nonselective currents from human 898- and 913-residue constructs with matched negative controls. PMID:39337485 further demonstrates dependence on the ANO6 expression background; its Discussion places ANO5-associated currents in the absence, not the presence, of ANO6. These different localization, construct and stimulation conditions do not resolve a context-independent NOT assertion. UNDECIDED records that unresolved biological scope, rather than denying the original negative experiment or claiming its Methods were inaccessible. Supporting Evidence: PMID:22075693 Expression of ANOs 3-7 in HEK293 cells did not generate Cl(-) currents activated by intracellular Ca(2+), as determined by whole cell patch clamp electrophysiology. PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. PMID:20056604 When expressed in Fisher Rat Thyroid (FTR) cells, all ANO proteins localized to the plasma membrane but only ANO1, 2, 6, and 7 produced Ca(2+)-activated Cl(-) conductance, as analyzed by ATP-induced iodide quenching of YFP fluorescence. |
| GO:0005229 intracellularly calcium-gated chloride channel activity | IDA PMID:22946059 Anoctamins are a family of Ca2+-activated Cl- channels. | KEEP AS NON CORE | Summary: Human ANO5 supports calcium-evoked chloride-permeable currents in an expression assay. Reason: The original human ANO5 Results, Figure 3 legend and Methods in PMID:22946059 support small transient currents after ionomycin in HEK293 cells; its anion-ranking subset was ANO1/4/6/10, not ANO5. Independent PMID:29124309 human 898- and 913-residue constructs yield calcium-favored, poorly selective currents in HEK293 cells, with the 898-residue construct also tested in CHO cells. At 3 Β΅M intracellular calcium, large currents required strong depolarization; matched controls lacked comparable currents, and calcium favored rather than absolutely determined activation. GO:0005229 requires calcium-responsive chloride passage but does not require exclusion of other ions. Negative ANO5 results in PMID:20056604, PMID:22075693 and PMID:23047743, and the ANO6-background effects in PMID:39337485, restrict confidence in native channel physiology. The latter reports ANO5-associated currents in ANO6-deficient cells; it does not identify these currents as endogenous ANO6. Retain this positive experimental assertion as secondary and conditional, while the broader scope of the separate NOT row remains unresolved. Supporting Evidence: PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 This study provides direct evidence for phospholipid scrambling and non-selective ion transport activity of TMEM16E PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. PMID:20056604 When expressed in Fisher Rat Thyroid (FTR) cells, all ANO proteins localized to the plasma membrane but only ANO1, 2, 6, and 7 produced Ca(2+)-activated Cl(-) conductance, as analyzed by ATP-induced iodide quenching of YFP fluorescence. PMID:29124309 the presence of cytosolic Ca2+ was not strictly necessary for TMEM16E activation, but strongly favored it |
| GO:0005254 chloride channel activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad chloride-channel activity has independent target-specific support. Reason: The exact ARBA00026476 rule has not been reconstructed, so its transfer is not independently endorsed. Target-specific human experiments in PMID:22946059 and PMID:29124309 nevertheless support chloride-permeable, nonselective conductance. GO:0005254 requires facilitated chloride passage through a membrane pore, not chloride-exclusive selectivity. The independent human constructs and matched controls in PMID:29124309 prevent this judgment from resting only on a family-wide description. Negative findings in PMID:20056604, PMID:22075693 and PMID:23047743 and ANO6-background dependence in PMID:39337485 limit this to a secondary expression-assay activity. The 2024 study reports ANO5-associated currents when ANO6 is absent; it does not establish that all earlier currents were carried by ANO6. Retain NON_CORE on the combined target evidence, without claiming ANO1-like epithelial physiology or a resolved electronic rule. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026476 UNRESOLVED Exact rule antecedents were not reconstructed; independent target experiments support the retained secondary term. Supporting Evidence: PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 This study provides direct evidence for phospholipid scrambling and non-selective ion transport activity of TMEM16E PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. |
| GO:0005254 chloride channel activity | TAS Reactome:R-HSA-2684901 | KEEP AS NON CORE | Summary: The Reactome channel assertion is retained as a secondary expression-assay activity. Reason: R-HSA-2684901 cites Tian et al. (PMID:22946059), whose human ANO5 experiments support a small ionomycin-evoked current. PMID:29124309 adds independent human-construct currents and low ion selectivity; the broad chloride-channel definition does not demand exclusive chloride selectivity. The contrary ANO5 assays in PMID:20056604, PMID:22075693 and PMID:23047743 and the ANO6-background dependence in PMID:39337485 are material limits, so retain a secondary conditional activity rather than an established native epithelial role. The Reactome summary does not by itself resolve these contradictions or transfer every ANO1/ANO2 property to ANO5. Its unrelated CLCA proteolysis passage provides no evidence about ANO5. Supporting Evidence: PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:15124103 The novel gene encoding a putative transmembrane protein is ... | ACCEPT | Summary: ANO5 localizes to the endoplasmic reticulum membrane. Reason: The PMID:15124103 abstract explicitly reports ER localization. This is corroborated by original human construct localization in PMID:29124309 and human patient-myoblast experiments in PMID:31341644. Its original suggestion of a calcium-homeostasis role is not a direct calcium-channel assay. Context-dependent surface localization is compatible with ER distribution. Supporting Evidence: PMID:15124103 Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis. PMID:29124309 EGFP-tagged TMEM16E localized mostly to intracellular membranes, showing significant overlap with the ER marker CellLight ER-RFP PMID:31341644 co-expression of ANO5-GFP with an RFP-tagged ER luminal marker (RFP-KDEL or ER-RFP) in healthy human myoblasts showed overlapping reticular staining of both proteins |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt ER-membrane mapping is consistent with direct localization evidence. Reason: The preserved UniProt SL-0097 source and PMID:15124103 support ER-membrane residence, with human target corroboration in PMID:29124309 and PMID:31341644. This retains the compartment assertion without assigning an intrinsic calcium pump or channel mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0097 SUPPORTS TRANSFER The preserved human UniProt ER-membrane statement agrees with target localization experiments. Supporting Evidence: PMID:15124103 Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis. PMID:31341644 co-expression of ANO5-GFP with an RFP-tagged ER luminal marker (RFP-KDEL or ER-RFP) in healthy human myoblasts showed overlapping reticular staining of both proteins |
| GO:0005886 plasma membrane | EXP PMID:20056604 Expression and function of epithelial anoctamins. | ACCEPT | Summary: ANO5 can occupy the plasma membrane in expression and injury contexts. Reason: Original PMID:20056604 indexed cDNA Methods identify human ANO5 cloned from A549 cells; FRT is the rat thyroid host. Targeted His-tag/Ξ²-catenin localization Results support a surface pool without exclusive plasma-membrane residence. Independent human ANO5 surface biotinylation in PMID:30257928 and wound-adjacent recruitment in PMID:33496727 corroborate the location. The negative halide assay in PMID:20056604 does not negate this compartment assertion. Supporting Evidence: PMID:20056604 When expressed in Fisher Rat Thyroid (FTR) cells, all ANO proteins localized to the plasma membrane PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage PMID:30257928 We found that a small fraction of ANO5 trafficked to the PM. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The broad plasma-membrane IBA agrees with direct human ANO5 evidence. Reason: Human ANO5 surface staining in original PMID:22946059 and wound-adjacent recruitment in PMID:33496727 independently support the target location. The exact PTN000267334 IBD placement and phylogeny were not reconstructed. ANO5 appearing among descendant evidence is legitimate, not circular, and neither donor number nor other family members determines this decision. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000267334 UNRESOLVED Original PAINT node retained. Exact IBD/tree not reconstructed; independent human target evidence supports the broad location. Self-derived experimental descendants are legitimate. Supporting Evidence: PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage |
| GO:0005886 plasma membrane | IDA PMID:22946059 Anoctamins are a family of Ca2+-activated Cl- channels. | ACCEPT | Summary: The cited human ANO5 experiment supports plasma-membrane localization. Reason: Original PMID:22946059 Figure 8 localization Results and immunostaining/cDNA Methods identify human ANO5 at the HEK293 cell surface. Human constructs in PMID:29124309 and PMID:33496727 corroborate surface distribution under specific conditions. Retain this location independently of uncertainty about physiological channel function; most protein may still be intracellular in other contexts. Supporting Evidence: PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage PMID:29124309 EGFP signals partially lined the cell boundaries and co-localized with the PM marker FM4-64 |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt plasma-membrane mapping is supported in defined contexts. Reason: The SL-0039 annotation is consistent with human ANO5 surface staining in PMID:22946059 and injury-associated recruitment in PMID:33496727. Accepting the compartment does not imply that ANO5 is exclusively at the surface or that every construct traffics there equally. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The preserved human UniProt location agrees with target surface-localization experiments. Supporting Evidence: PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2684901 | ACCEPT | Summary: The Reactome plasma-membrane location is independently supported for ANO5. Reason: Although R-HSA-2684901 groups family channel activities, the location itself agrees with original human ANO5 surface staining in PMID:22946059 and wound recruitment in PMID:33496727. Retain the compartment without transferring the entire ANO1/ANO2 functional profile. Supporting Evidence: PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9854657 | ACCEPT | Summary: Surface ANO5 contributes to phospholipid exposure in endothelial cells. Reason: R-HSA-9854657 is specifically supported by PMID:36951953 human endothelial knockdown experiments showing reduced surface phosphatidylserine exposure and procoagulant activity. These complement direct human ANO5 surface localization and scrambling assays. Platelet phospholipid exposure is attributed to ANO6 in this source and is not transferred to ANO5. Supporting Evidence: PMID:36951953 PS externalization in response to TNF-Ξ± or Ca2+ ionophore was markedly inhibited in HUVECs following silencing of TMEM16E or TMEM16F PMID:29124309 EGFP signals partially lined the cell boundaries and co-localized with the PM marker FM4-64 PMID:33496727 We observed fast accumulation of ANO5 at the plasma membrane in WT fibers adjacent to the site of damage |
| GO:0031982 vesicle | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse-donor vesicle localization needs its original experimental chain. Reason: The official indexed UniProt Q75UR0 record resolves mouse Ano5, ENSMUSP00000046884.6 and an MGI-derived vesicle annotation. The recovered PMID:15882990 is abstract-only and describes mouse cDNA/splicing/differentiation; it does not expose the exact donor localization experiment or historical Ensembl transfer event. ER residence or wound proximity alone does not establish this vesicle assertion. The original donor identifiers remain intact. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q75UR0 UNRESOLVED Official indexed UniProt verifies mouse Ano5 and MGI vesicle annotation, but its exact experimental citation has not been traced. ensembl:ENSMUSP00000046884 UNRESOLVED Product identity matches the versioned mouse UniProt cross-reference; the exact historical Compara evidence chain remains unresolved. Supporting Evidence: PMID:15882990 In this study, we characterized the complete cDNA sequence and genomic organization of the mouse GDD1 gene. |
| GO:0034220 monoatomic ion transmembrane transport | TAS Reactome:R-HSA-983712 | KEEP AS NON CORE | Summary: ANO5-associated ion transport is retained as a secondary activity. Reason: This broad Reactome pathway placement is consistent with ion movement measured after human ANO5 expression in PMID:29124309, including sodium/chloride replacement and reversal-potential experiments that show poor selectivity. It is retained as secondary because the large currents require particular expression and stimulation conditions. The negative ANO5 assays in PMID:20056604, PMID:22075693 and PMID:23047743 and the ANO6-dependent expression context in PMID:39337485 prevent assigning a general native ion-homeostasis role from this broad pathway entry. This decision neither makes ANO5 a selective chloride channel nor assigns a new physiological process. Supporting Evidence: PMID:29124309 This study provides direct evidence for phospholipid scrambling and non-selective ion transport activity of TMEM16E PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. |
| GO:0045332 phospholipid translocation | IBA GO_REF:0000033 | ACCEPT | Summary: ANO5 supports transbilayer phospholipid movement. Reason: The broad phospholipid-translocation IBA agrees with human ANO5 scrambling assays in PMID:29124309 and endothelial phosphatidylserine-exposure experiments in PMID:36951953. It is supported by target evidence rather than universal transfer from all anoctamins. The exact PTN001389043 IBD placement remains untraced. Existing process coverage is retained; no redundant narrower NEW process is proposed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001389043 UNRESOLVED Exact IBD placement remains untraced; direct human ANO5 evidence independently supports phospholipid translocation. Supporting Evidence: PMID:29124309 we observed clear fluorescence signals lining the cell boundaries of EGFP-positive cells after 5β10Β min, but not of non-transfected neighboring cells PMID:36951953 PS externalization in response to TNF-Ξ± or Ca2+ ionophore was markedly inhibited in HUVECs following silencing of TMEM16E or TMEM16F |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | UNDECIDED | Summary: The dimerization-domain mapping is not yet independently resolved for ANO5. Reason: IPR032394 is present in the preserved UniProt record, but the exact InterPro entry and supporting evidence could not be accessed through the live route. The ANO5 dimer depicted in PMID:31341644 is a homology model, not a direct physical oligomerization experiment. A domain label or modeled assembly is insufficient to independently establish this activity, but absence of such an assay in the material read is not evidence for removal. Propagation Review Root cause: UNRESOLVED Sources checked: InterPro:IPR032394 UNRESOLVED Dimerization-domain label occurs in the preserved record; exact live InterPro support and a target physical assembly assay were not recovered. Supporting Evidence: PMID:31341644 As ANO5 has not been structurally characterized we first built a homology model of the protein |
| GO:1902476 chloride transmembrane transport | IDA PMID:22946059 Anoctamins are a family of Ca2+-activated Cl- channels. | KEEP AS NON CORE | Summary: The source supports chloride transport in an ANO5 expression assay. Reason: PMID:22946059 reports transient calcium-evoked currents after expression of human ANO5, supporting the original chloride-transport assertion within that assay. Its detailed anion-ranking experiments did not include ANO5. PMID:29124309 independently supports poorly selective ion movement by human ANO5 constructs; nonselectivity does not exclude chloride transport. Negative ANO5 findings in PMID:20056604, PMID:22075693 and PMID:23047743 and ANO6-background effects in PMID:39337485 argue against treating this as a general native physiological role. Retain the existing source-specific process as secondary; the distinct NOT channel row remains unresolved across these contexts. Supporting Evidence: PMID:22946059 Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. PMID:29124309 This study provides direct evidence for phospholipid scrambling and non-selective ion transport activity of TMEM16E PMID:29124309 Under identical experimental conditions, non-transfected control cells presented only small background currents lacking any time dependence PMID:39337485 ion currents attributed to the expression of ANO5, ANO9, or ANO10 were dependent on the presence (ANO9) or absence (ANO5 and -10) of ANO6 PMID:23047743 However, recent data together with our own experiments reported here add weight to the hypothesis that ANO5 may not function as calcium-activated chloride channel. |
| GO:0017128 phospholipid scramblase activity | IDA PMID:29124309 Gain of function of TMEM16E/ANO5 scrambling activity caused ... | NEW | Summary: Human ANO5 exhibits calcium-dependent phospholipid scrambling in cell assays. Reason: Original PMID:29124309 Results and Methods identify human 898-aa ANO5 constructs with calcium-stimulated annexin-V exposure, together with localization and mock controls. This is a direct molecular-activity proposal, corroborated by PMID:30257928 and by ANO5 scrambling in an ANO6-knockout background in PMID:39337485. It is not a purified-protein reconstitution result, and no unverified UniProt isoform suffix is assigned to the tested construct. The ATP-independent transbilayer-lipid MF is not covered by an existing molecular-function term; the broader existing phospholipid-translocation BP is retained without adding a redundant process. PMID:32112655 provides abstract-level corroboration that tested muscular-dystrophy and GDD variants have opposite loss- and gain-of-function effects on scrambling; this does not establish the mechanism of every disease variant. PMID:32517157 reports no added scrambling for engineered CFP-CAAX surface-targeted constructs. That negative result is retained as a construct- and assay-specific limit, alongside the positive non-CAAX ANO5 experiments, rather than omitted or generalized to all native ANO5. Supporting Evidence: PMID:29124309 we observed clear fluorescence signals lining the cell boundaries of EGFP-positive cells after 5β10Β min, but not of non-transfected neighboring cells PMID:30257928 Ca2+ stimulation elicited PtdSer exposure in the vast majority of cells expressing exogenous ANO5 in contrast to parental HEK293 cells PMID:39337485 Overall, endogenous ANO6 provides a small scramblase activity in addition to the PL scramblase induced by ANO3 and ANO5, but not by ANO9 PMID:32112655 Our results collectively demonstrate that, on the level of protein function, MD mutations are associated to loss-of-function and GDD mutations to gain-of-function phenotypes, confirming conjectures made on the basis of inheritance modes. PMID:32517157 In our study, we could not confirm scrambling activity for TMEM16E, TMEM16J and TMEM16K |
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Download this section (compressed HTML)Q: Which molecular step performed by ANO5 coordinates annexin trafficking and membrane repair independently of its scrambling domain?
Q: How do ANO5 isoform length, membrane targeting and endogenous ANO6 alter intrinsic versus indirect current measurements and reconcile the positive and NOT calcium-gated chloride annotations?
Q: Which original mouse localization experiment and historical Compara assertion establish the vesicle transfer, and what direct evidence supports ANO5 dimerization?
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Which molecular activity of ANO5 supports muscle membrane repair independently of its phospholipid-scrambling domain remains unresolved in the reviewed experiments.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: ANO5 loss disrupts repair and annexin trafficking; human ANO5 restores repair in deficient mouse fibers, and the scrambling-defective ANO5-1-5 chimera also restores repair. Human patient myocytes show defective repair. These observations establish the repair role without identifying the molecular step performed by ANO5.
What would resolve it: Separate direct ANO5-dependent membrane or partner activities from downstream annexin redistribution and calcium changes, using repair-competent and repair-defective constructs with independently measured scrambling.
Provenance (the field's own admissions):
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