BEST1

Summary: Human BEST1 forms a calcium-sensitive chloride channel.

Reason: The source demonstrates chloride currents after heterologous expression of human bestrophin and their sensitivity to intracellular calcium. Mutant comparisons support the channel interpretation; modern purified human structures independently establish the pore-forming assembly.

Summary: Human BEST1 has the calcium-gated anion conductance characteristic of bestrophins.

Reason: The cited structure-function study tests bestrophin channel properties and supports the existing human activity assertion. Independent human expression and structural evidence establish calcium-dependent chloride conduction; no experimental annotation is rejected from a paralog-containing paper title.

Summary: Human BEST1 conducts chloride as well as bicarbonate.

Reason: The source separately measures expressed human BEST1 among several bestrophin paralogs. Its bicarbonate comparison presupposes and measures chloride current; bicarbonate permeability does not contradict the calcium-gated chloride-channel activity.

Summary: Wild-type human BEST1 supports chloride conductance in the disease-variant comparison.

Reason: The normal abstract reports whole-cell recordings in transfected HEK293T cells, reduced currents for the tested variants and preserved plasma-membrane localization. It supports the channel activity without implying that every disease variant acts through the same defect. Detailed original panels were not independently inspected.

Summary: Purified human BEST1 forms a calcium-regulated anion pore.

Reason: Selected human cryo-EM Results establish the pentameric channel and calcium-dependent changes at its permeation constrictions. Calcium-bound wild-type BEST1 is observed in partially open conformations; the fully open BEST2 conformation must not be assigned to BEST1.

Summary: BEST1 channel dysfunction is demonstrated in a human recessive-retinopathy study.

Reason: The source links biallelic human variants to altered whole-cell chloride currents. The normal abstract and the independent wild-type channel evidence support this activity. Disease necessity alone is not being used to invent a new biochemical function.

Summary: The retinitis-pigmentosa variants perturb BEST1 current and/or trafficking.

Reason: The normal abstract reports altered channel behavior and localization in variant comparisons. Separately inspected primary text places expressed wild-type BEST1 basolaterally in MDCKII cells. Mutant mislocalization is not evidence against wild-type chloride-channel activity.

Summary: Human BEST1 variant assays support the underlying calcium-gated chloride-channel activity.

Reason: The source compares wild-type and recessive-bestrophinopathy variants in whole-cell recordings and polarized-cell localization assays. Its normal abstract is sufficient to corroborate the established activity, while individual construct details beyond the inspected material remain unclaimed.

Summary: BEST1 retains anion-channel activity in the tested patient-specific mutant combination.

Reason: The source title does not deny BEST1 channel function: it reports a patient whose particular variant combination preserves channel activity. Human iPSC-RPE and expressed-protein comparisons therefore support the existing activity while limiting a universal loss-of-current explanation for recessive disease.

Summary: The chloride-channel activity can be specified as intracellularly calcium-gated.

Reason: The original epithelial study links BEST1 to calcium-activated chloride currents, including human-cell knockdown and expression assays. Although that early paper discusses channel-versus-regulator alternatives, later direct human structures establish channel capability. The original contributes_to relation is preserved as a source assertion; it is not a requirement to qualify every BEST1 channel annotation. Later human structures support a BEST1 homopentamer, not an obligatory channel-forming partner from a different gene.

Proposed replacements: intracellularly calcium-gated chloride channel activity

Summary: The chloride-channel activity can be specified as intracellularly calcium-gated.

Reason: The original epithelial study links BEST1 to calcium-activated chloride currents, including human-cell knockdown and expression assays. Although that early paper discusses channel-versus-regulator alternatives, later direct human structures establish channel capability.

Proposed replacements: intracellularly calcium-gated chloride channel activity

Summary: The bestrophin family mapping can be refined using direct human channel evidence.

Reason: The InterPro-derived chloride-channel assertion is biologically sound. Human expression and purified-channel studies establish intracellular calcium gating, providing a more informative existing term without criticizing the family mapping.

Proposed replacements: intracellularly calcium-gated chloride channel activity

Summary: The Reactome chloride-conducting activity is calcium-regulated.

Reason: R-HSA-2744361 describes bestrophin-mediated chloride movement across the plasma membrane. Direct human channel evidence supplies the calcium-gated refinement; the reaction direction does not make the passive channel an irreversible outward pump.

Proposed replacements: intracellularly calcium-gated chloride channel activity

Summary: Intracellular BEST1 staining does not resolve the strict cytosol compartment.

Reason: The selected PMID:17003041 Discussion uses intracellular/cytosol language while explicitly allowing association with vesicular membranes. GO:0005829 excludes organelles. This does not establish a soluble cytosolic BEST1 pool, but it is also insufficient to dismiss the original observation. Retain uncertainty pending compartment-resolved evidence; no experimental misattribution is alleged.

Summary: Plasma-membrane BEST1 is supported by direct human evidence as well as PAINT.

Reason: The IBA from PTN008504815 agrees with human RPE surface labeling and functional membrane currents. The target O76090 appearing among descendant evidence is expected and not circular. No contrary phylogenetic placement or target-specific loss is established.

Summary: Wild-type BEST1 is associated with the plasma membrane in the tested epithelial systems.

Reason: The source examines BEST1 distribution and function in human iPSC-RPE and expressed-protein systems. Variant-specific trafficking changes do not negate the positive wild-type plasma-membrane annotation.

Summary: The electronic plasma-membrane location agrees with direct localization.

Reason: Human RPE surface biotinylation, detergent partitioning and expressed-protein experiments support an integral plasma-membrane protein. Retain the conservative UniProt subcellular-location mapping.

Summary: The Reactome chloride reaction places BEST1 in the plasma membrane.

Reason: The cited bestrophin transport reaction has cytosolic and extracellular chloride pools. Independent RPE localization supports the membrane compartment; reaction direction is not evidence that BEST1 can only conduct outward.

Summary: The Reactome bicarbonate reaction places BEST1 in the plasma membrane.

Reason: The cited bestrophin transport reaction has cytosolic and extracellular bicarbonate pools. Independent RPE localization supports the membrane compartment; reaction direction is not evidence that BEST1 can only conduct outward.

Summary: BEST1 mediates chloride movement across a membrane.

Reason: The source measures calcium-activated chloride currents in epithelial and expressed-protein systems. The more specific chloride-transmembrane-transport term describes the channel’s direct contribution to the measured ion flux.

Proposed replacements: chloride transmembrane transport

Summary: BEST1 supports visual function through RPE physiology.

Reason: The original human disease-gene evidence connects BEST1 to loss of central vision. Retain this tissue-level role as non-core; it does not make BEST1 a photopigment or a direct phototransduction component.

Summary: Basal plasma-membrane BEST1 is consistent with established RPE polarity.

Reason: The source is a human RPE apical/basolateral surface-proteomics study. Its normal cache is abstract-only and the BEST1-specific table was not obtained, so this exact measurement is accepted by curator deference rather than claimed as independently reread. Established basolateral localization supports the compartment and there is no contrary evidence.

Summary: Channel-mediated glutamate secretion is a supported, context-dependent neural role.

Reason: The explicit mouse O88870 donor has Best1-dependent astrocytic glutamate-release evidence (PMID:23021213) and astrocyte-specific functional rescue affecting postsynaptic NMDA responses (PMID:25645137). PMID:32848599 disputes detectable astroglial expression in its preparations, so the literature is not uniform. Human BEST1-dependent glutamate currents in iPSC-RPE (PMID:39277606) support permeation capability, but do not demonstrate endogenous human astrocyte secretion or physiological RPE flux direction. Retain the transferred role as non-core, with these species and context limits.

Summary: Channel-mediated glutamate secretion is a supported, context-dependent neural role.

Reason: The explicit mouse O88870 donor has Best1-dependent astrocytic glutamate-release evidence (PMID:23021213) and astrocyte-specific functional rescue affecting postsynaptic NMDA responses (PMID:25645137). PMID:32848599 disputes detectable astroglial expression in its preparations, so the literature is not uniform. Human BEST1-dependent glutamate currents in iPSC-RPE (PMID:39277606) support permeation capability, but do not demonstrate endogenous human astrocyte secretion or physiological RPE flux direction. Retain the transferred role as non-core, with these species and context limits.

Summary: BEST1 provides a bicarbonate-conducting pore.

Reason: The Reactome transporter activity can be refined to the bicarbonate-channel term already present in the source set. Direct human BEST1 permeability and conductance measurements establish pore-mediated bicarbonate flux, matching GO:0160133.

Proposed replacements: bicarbonate channel activity

Summary: The generic channel mapping can name the established chloride and bicarbonate activities.

Reason: ARBA channel activity is compatible with BEST1 biology but loses the substrate and gating information established experimentally. The two existing specific activities describe the same oligomeric pore; no extra channel or new annotation row is proposed.

Proposed replacements: intracellularly calcium-gated chloride channel activity bicarbonate channel activity

Summary: BEST1 itself conducts bicarbonate across membranes.

Reason: The combined electronic mapping agrees with direct human BEST1 bicarbonate permeability. Because the protein supplies the ion-conducting pore, this is direct participation in bicarbonate transport rather than a downstream consequence or substrate-only relationship.

Summary: The broad membrane location can be specified for the established RPE context.

Reason: The original mutation paper is retained, while independent RPE localization and expressed wild-type studies support the basolateral plasma membrane. This refinement describes an established site and does not assert that BEST1 is exclusively basolateral in every cell type.

Proposed replacements: basolateral plasma membrane

Summary: BEST1 has well-supported basolateral RPE localization.

Reason: The paper combines human RPE surface biotinylation and detergent partitioning with macaque/porcine tissue staining and human protein expressed in rat RPE-J cells. These complementary assays support basolateral location; the native tissue staining must not all be described as human.

Summary: Expressed wild-type BEST1 localizes basolaterally in the polarized-cell assay.

Reason: The protected normal cache is abstract-only. Separately inspected primary full text compares basolateral wild-type BEST1 in MDCKII cells with mislocalized disease variants. This supports the positive location without treating mutant trafficking defects as the behavior of all BEST1.

Summary: The wild-type localization in the mutant-comparison study supports basolateral BEST1.

Reason: The normal abstract reports localization assays in polarized MDCKII cells alongside human BEST1 functional testing. Independent RPE evidence corroborates the curated basolateral assertion; canine host cells expressing human protein are not native human tissue.

Summary: BEST1 basolateral localization is retained in the examined epithelial context.

Reason: The source compares wild-type and disease-associated BEST1 in human iPSC-RPE and MDCK systems. Retain the curated positive location without generalizing every mutant’s trafficking behavior or disease mechanism.

Summary: The electronic basolateral location is supported by independent experiments.

Reason: The UniProt subcellular-location mapping agrees with RPE and polarized-cell observations. This is an established major location, not a claim of exclusive localization across tissues.

Summary: Refine broad ligand gating to the directly assayed GABA-gated chloride-channel activity.

Reason: GO:0005229 already descends from GO:0022834 through GO:0141147, so calcium gating does not justify an additional broad core assertion. The more specific proposal uses independent human BEST1 evidence in PMID:39277606: an extracellular GABA-bound structure and increased chloride currents in HEK293 cells, with a reported GABA EC50 of 371 nM. Figure 6 recordings used 1 micromolar intracellular calcium; this is GABA-promoted opening in a calcium-containing assay, not calcium-independent gating. GO:0022851 captures GABA-dependent chloride conduction without requiring membership in the canonical GABA-A receptor protein family. The original orthology evidence, qualifiers and donors remain unchanged; they are not relabeled as the newer human experiment. This refinement does not establish endogenous human neural receptor function, GABA secretion, or physiological GABA flux direction.

Proposed replacements: GABA-gated chloride ion channel activity

Summary: Refine broad ligand gating to the directly assayed GABA-gated chloride-channel activity.

Reason: GO:0005229 already descends from GO:0022834 through GO:0141147, so calcium gating does not justify an additional broad core assertion. The more specific proposal uses independent human BEST1 evidence in PMID:39277606: an extracellular GABA-bound structure and increased chloride currents in HEK293 cells, with a reported GABA EC50 of 371 nM. Figure 6 recordings used 1 micromolar intracellular calcium; this is GABA-promoted opening in a calcium-containing assay, not calcium-independent gating. GO:0022851 captures GABA-dependent chloride conduction without requiring membership in the canonical GABA-A receptor protein family. The original orthology evidence, qualifiers and donors remain unchanged; they are not relabeled as the newer human experiment. This refinement does not establish endogenous human neural receptor function, GABA secretion, or physiological GABA flux direction.

Proposed replacements: GABA-gated chloride ion channel activity

Summary: BEST1 contributes a channel step to epithelial chloride transport.

Reason: The source combines human epithelial-cell calcium-activated chloride currents and knockdown with animal epithelial/transepithelial observations. This supports direct ion-conduction participation in transepithelial transport. The selected material does not justify describing all tissue-level assays as human or BEST1 as the sole route across an epithelium.

Summary: The monoatomic-ion transport assertion can be refined to chloride transport.

Reason: The source annotation is specifically monoatomic ion transmembrane transport, although its broader Reactome pathway contains several ion types. Chloride is the directly measured single-atom ion transported by human BEST1, so chloride transmembrane transport is the appropriate refinement. Bicarbonate is polyatomic and remains supported in separate bicarbonate annotations and the bicarbonate-channel core; it is not a refinement of this monoatomic-ion term.

Proposed replacements: chloride transmembrane transport

Summary: BEST1 is a structural subunit of a chloride-channel complex.

Reason: The early source’s complex-subunit interpretation is consistent with the directly observed human BEST1 homopentamer. The complex is the pore-forming assembly, not an invented separate signaling complex.

Summary: Human BEST1 self-association is supported, while transport is the defining activity.

Reason: The source demonstrates N/C-terminal interactions and multimeric membrane channels. Some mutations impair terminal interactions without abolishing oligomerization, so the findings must not be collapsed into a universal assembly-loss mechanism. Retain identical-protein binding as non-core; modern human structures supply pentamer stoichiometry.

Summary: Best1-dependent astrocytic glutamate can modulate synaptic plasticity in the mouse experiments.

Reason: PMID:25645137 reports loss of PAR1-triggered potentiation in Best1-deficient slices and recovery through astrocyte-specific relief of Best1 silencing. This supplies functional cell-type evidence beyond localization. The human annotation remains orthology-based and non-core; PMID:32848599’s negative expression results in other preparations remain a genuine unresolved context discrepancy.

Summary: Best1-dependent astrocytic glutamate can modulate synaptic plasticity in the mouse experiments.

Reason: PMID:25645137 reports loss of PAR1-triggered potentiation in Best1-deficient slices and recovery through astrocyte-specific relief of Best1 silencing. This supplies functional cell-type evidence beyond localization. The human annotation remains orthology-based and non-core; PMID:32848599’s negative expression results in other preparations remain a genuine unresolved context discrepancy.

Summary: BEST1 oligomerization contributes the structure of its functional channel.

Reason: The cited coimmunoprecipitation and functional comparisons support BEST1 assembly. Purified human structures independently establish a homopentamer. Retain the assembly process because BEST1 supplies the structural subunits; do not infer that every pathogenic allele prevents oligomerization.

Summary: Best1-dependent glial GABA release contributes to tonic inhibition in defined mouse preparations.

Reason: The O88870 donor is supported by the original glial release/silencing/rescue work (PMID:20929730) and later astrocyte-specific deletion with reduced tonic inhibition (PMID:39266474). PMID:32848599 challenges detectable astroglial expression in its preparations but does not repeat every functional rescue experiment. The term describes GABA release by a cell during neurotransmission and does not require vesicular release from a neuron. Retain the transferred human role as non-core; human iPSC-RPE GABA influx under imposed ionic conditions is not evidence for human glial GABA secretion.

Summary: Best1-dependent glial GABA release contributes to tonic inhibition in defined mouse preparations.

Reason: The O88870 donor is supported by the original glial release/silencing/rescue work (PMID:20929730) and later astrocyte-specific deletion with reduced tonic inhibition (PMID:39266474). PMID:32848599 challenges detectable astroglial expression in its preparations but does not repeat every functional rescue experiment. The term describes GABA release by a cell during neurotransmission and does not require vesicular release from a neuron. Retain the transferred human role as non-core; human iPSC-RPE GABA influx under imposed ionic conditions is not evidence for human glial GABA secretion.

Summary: Presynaptic BEST1 has independent mouse localization support.

Reason: The original electronic inference from GABA secretion alone would not distinguish a glial release site from a neuronal presynapse. However, PMID:39466647 independently reports mouse cortical BEST1 at glutamatergic and GABAergic terminals using WT/KO comparisons and marker colocalization. Holistic retention as non-core is therefore justified, with human localization inferred rather than directly demonstrated. Negative astroglial findings in PMID:32848599 concern a different localization question.

Summary: Best1 localization to astrocytic membrane microdomains is supported in the donor study.

Reason: PMID:23021213 places mouse Best1 in astrocytic microdomains near synapses and links it to the calcium-dependent glutamate-release mode. PMID:32848599 reports very low brain expression and no specific astroglial staining under its conditions. Retain this contextual ortholog-derived location as non-core while preserving the unresolved discrepancy; do not infer a wrong donor or invalidate transfer from donor number.

Summary: Best1 localization to astrocytic membrane microdomains is supported in the donor study.

Reason: PMID:23021213 places mouse Best1 in astrocytic microdomains near synapses and links it to the calcium-dependent glutamate-release mode. PMID:32848599 reports very low brain expression and no specific astroglial staining under its conditions. Retain this contextual ortholog-derived location as non-core while preserving the unresolved discrepancy; do not infer a wrong donor or invalidate transfer from donor number.

Summary: Human BEST1 directly conducts bicarbonate.

Reason: The original measurements distinguish human BEST1 from other human bestrophins and mouse Best2. Human BEST1 has substantial bicarbonate permeability and conductance, so the specific bicarbonate-channel term is supported rather than borrowed from a paralog.

Summary: The PAINT chloride-transport assertion agrees with direct BEST1 pore function.

Reason: The PTN008504815 inference is a phylogenetic placement, not a weak pairwise transfer because only one experimental donor is listed. Direct human chloride-channel experiments support the asserted transmembrane transport; no target-specific loss or contrary placement is established.