{"gene":"KCNK15","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2001,"finding":"TASK-5 (KCNK15) does not form functional K+ channels as a homodimer when expressed in Xenopus oocytes or COS-7 cells; chimeric TASK-5/TASK-3 constructs containing the region between M1 and M3 of TASK-3 did produce K+-selective currents, indicating a non-functional pore region in TASK-5 alone.","method":"Heterologous expression in Xenopus oocytes and COS-7 cells; chimeric channel electrophysiology","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — electrophysiological reconstitution with chimeric constructs, independently replicated in three separate 2001 studies (PMIDs 11749039, 11409881, 11680614)","pmids":["11749039","11409881","11680614"],"is_preprint":false},{"year":2001,"finding":"TASK-5 does not form functional heteromers with TASK-1; co-expression of TASK-5 with a proton-insensitive TASK-1 H98N mutant did not rescue proton sensitivity, in contrast to wild-type TASK-1 co-expression which did rescue it through heteromeric channels.","method":"Xenopus oocyte co-expression; proton-sensitivity rescue assay with TASK-1 H98N mutant","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous functional assay with mutagenesis controls, but single lab, single paper","pmids":["11680614"],"is_preprint":false},{"year":2001,"finding":"TASK-5 protein is present at the plasma membrane in HEK293 cells at a distribution similar to TASK-1, suggesting the lack of current is not due to failure of membrane trafficking; removal of a putative ER retention sequence did not restore channel activity.","method":"Subcellular localization in HEK293 cells; ER retention sequence deletion mutagenesis; electrophysiology","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment combined with mutagenesis, single lab","pmids":["11680614"],"is_preprint":false},{"year":2001,"finding":"TASK-5 mRNA is expressed predominantly in the central auditory pathway (olfactory bulb mitral cells and Purkinje cells also), as determined by in situ hybridization in rat brain, suggesting a specialized role in auditory signal processing.","method":"In situ hybridization in rat brain","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by ISH, single lab, no functional consequence tested at this point","pmids":["11749039"],"is_preprint":false},{"year":2024,"finding":"TASK-5 (KCNK15) forms functional heterodimeric channel complexes with TASK-1 and TASK-3; as a homodimer it remains non-functional. These heteromeric complexes show altered single-channel conductance, altered Gq-coupled receptor-mediated channel inhibition, and changed sensitivity to TASK modulators compared to TASK-1 or TASK-3 homodimers. TASK-5 also negatively modulates surface expression of TASK channels.","method":"Heterologous co-expression; single-channel electrophysiology; pharmacological characterization; surface expression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-channel reconstitution with multiple orthogonal functional readouts (conductance, receptor inhibition, pharmacology, surface expression) in one rigorous study","pmids":["39215006"],"is_preprint":false},{"year":2024,"finding":"A common single-nucleotide polymorphism in KCNK15 alters the pharmacology of TASK-1/TASK-5 heterodimers, demonstrating that TASK-5 sequence variation functionally impacts the drug-sensitivity profile of the heteromeric channel.","method":"Heterologous expression of polymorphic TASK-5 variants; electrophysiology with pharmacological probes","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional electrophysiology with defined genetic variant, single lab","pmids":["39215006"],"is_preprint":false},{"year":2024,"finding":"Loss of Task5 in knock-out mice alters neuronal excitability in bushy cells of the ventral cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body, and changes auditory brainstem responses to loud sounds, establishing Task5 as a functionally active K2P subunit contributing to auditory processing in vivo.","method":"Task5 knock-out mice; whole-cell electrophysiology in brainstem neurons; auditory brainstem response (ABR) recording","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular electrophysiological phenotype and in vivo auditory readout, two orthogonal methods","pmids":["39553828"],"is_preprint":false}],"current_model":"KCNK15 (TASK-5) is a two-pore domain K+ channel subunit that is non-functional as a homodimer but forms functional heterodimeric channels with TASK-1 and TASK-3, negatively modulating their surface expression and conferring altered single-channel conductance, Gq-receptor inhibition, and pharmacological sensitivity; in vivo, it contributes to neuronal excitability in the auditory brainstem and is required for normal auditory processing as demonstrated by Task5 knock-out mice."},"narrative":{"mechanistic_narrative":"KCNK15 (TASK-5) is a two-pore domain (K2P) potassium channel subunit that regulates neuronal excitability by acting as a modulatory partner of other TASK channels rather than as an autonomous conductance [PMID:39215006, PMID:39553828]. As a homodimer it does not form functional K+ channels in heterologous systems, and this is not attributable to defective trafficking, since TASK-5 protein reaches the plasma membrane normally and removal of a putative ER retention sequence fails to restore activity; chimeric constructs show its intrinsic pore region is non-conducting [PMID:11749039, PMID:11409881, PMID:11680614]. Instead, TASK-5 assembles into functional heterodimeric channels with TASK-1 and TASK-3, conferring altered single-channel conductance, altered Gq-coupled receptor-mediated inhibition, and changed sensitivity to TASK modulators, while also negatively modulating the surface expression of these channels [PMID:39215006]. A common KCNK15 polymorphism alters the pharmacology of TASK-1/TASK-5 heterodimers, indicating that TASK-5 sequence variation shapes the drug-sensitivity profile of the heteromeric channel [PMID:39215006]. In vivo, KCNK15 is expressed predominantly along the central auditory pathway, and Task5 knock-out mice show altered excitability of bushy cells of the ventral cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body together with changed auditory brainstem responses, establishing a role in auditory processing [PMID:11749039, PMID:39553828].","teleology":[{"year":2001,"claim":"Whether TASK-5 forms a functional channel on its own was the first question; establishing that it does not redefined it from a candidate pore-former to a non-conducting subunit.","evidence":"Heterologous expression in Xenopus oocytes and COS-7 cells with TASK-5/TASK-3 chimeric channel electrophysiology","pmids":["11749039","11409881","11680614"],"confidence":"High","gaps":["Did not test whether TASK-5 could function in heteromeric assemblies","Did not identify the structural basis of the non-conducting pore beyond the M1–M3 region"]},{"year":2001,"claim":"To distinguish silence from mislocalization, it was important to learn whether the lack of current reflected a trafficking failure; demonstrating membrane localization placed the defect at the pore/assembly level.","evidence":"Subcellular localization in HEK293 cells with ER retention sequence deletion mutagenesis and electrophysiology","pmids":["11680614"],"confidence":"Medium","gaps":["Single lab, single paper","Did not resolve why a membrane-localized subunit produces no current","Did not test heteromeric assembly partners"]},{"year":2001,"claim":"Early heteromerization testing with TASK-1 (via a proton-insensitive H98N rescue assay) was needed to ask if TASK-5 could partner with other TASK subunits; the negative result initially argued against functional heteromers.","evidence":"Xenopus oocyte co-expression with TASK-1 H98N proton-sensitivity rescue assay","pmids":["11680614"],"confidence":"Medium","gaps":["Single assay design later contradicted by single-channel work","Did not test TASK-3 as a partner","Proton-rescue readout may not detect all functional heteromers"]},{"year":2001,"claim":"Defining the expression domain addressed where TASK-5 might act physiologically; its enrichment in the central auditory pathway pointed to a specialized role in auditory signal processing.","evidence":"In situ hybridization in rat brain","pmids":["11749039"],"confidence":"Medium","gaps":["mRNA distribution without functional consequence tested at this stage","No protein-level confirmation in the auditory pathway"]},{"year":2024,"claim":"The central question of whether TASK-5 has any channel function was resolved by showing it forms functional heterodimers with TASK-1 and TASK-3 that alter conductance, receptor regulation, pharmacology, and surface expression — reframing TASK-5 as an active modulatory subunit.","evidence":"Heterologous co-expression with single-channel electrophysiology, pharmacological characterization, and surface expression assays","pmids":["39215006"],"confidence":"High","gaps":["Single rigorous study","Stoichiometry and structural interface of the heteromer not resolved","Mechanism by which TASK-5 lowers surface expression not defined"]},{"year":2024,"claim":"Linking genetic variation to function, a common KCNK15 polymorphism was shown to alter TASK-1/TASK-5 heterodimer pharmacology, establishing that TASK-5 sequence shapes the drug response of the complex.","evidence":"Heterologous expression of polymorphic TASK-5 variants with electrophysiology and pharmacological probes","pmids":["39215006"],"confidence":"Medium","gaps":["Single lab","Physiological or clinical impact of the polymorphism not established","Effect on TASK-3 heterodimers not tested"]},{"year":2024,"claim":"An in vivo loss-of-function model was needed to confirm physiological relevance; Task5 knock-out mice with altered brainstem neuron excitability and auditory responses established TASK-5 as a functionally active K2P subunit in auditory processing.","evidence":"Task5 knock-out mice with whole-cell electrophysiology in brainstem neurons and auditory brainstem response recording","pmids":["39553828"],"confidence":"High","gaps":["Did not define which TASK partner mediates the in vivo phenotype","Behavioral/hearing-threshold consequences beyond ABR not fully characterized"]},{"year":null,"claim":"The molecular determinants of how TASK-5 silences its own pore yet modulates TASK-1/TASK-3 conductance, surface expression, and pharmacology remain structurally undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of TASK-5-containing heterodimers","Heteromer stoichiometry and assembly determinants unknown","Mechanism of negative regulation of TASK channel surface expression unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6]}],"complexes":["TASK-1/TASK-5 heterodimeric K2P channel","TASK-3/TASK-5 heterodimeric K2P channel"],"partners":["KCNK3","KCNK9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H427","full_name":"Potassium channel subfamily K member 15","aliases":["Acid-sensitive potassium channel protein TASK-5","TWIK-related acid-sensitive K(+) channel 5","Two pore potassium channel KT3.3","Two pore K(+) channel KT3.3"],"length_aa":330,"mass_kda":36.2,"function":"Probable potassium channel subunit. No channel activity observed in heterologous systems. May need to associate with another protein to form a functional channel","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9H427/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNK15","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNK15","total_profiled":1310},"omim":[{"mim_id":"607368","title":"POTASSIUM CHANNEL, SUBFAMILY K, MEMBER 15; KCNK15","url":"https://www.omim.org/entry/607368"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":23.4}],"url":"https://www.proteinatlas.org/search/KCNK15"},"hgnc":{"alias_symbol":["K2p15.1","dJ781B1.1","KT3.3","KIAA0237","TASK5","TASK-5"],"prev_symbol":["KCNK11","KCNK14"]},"alphafold":{"accession":"Q9H427","domains":[{"cath_id":"1.10.287.70","chopping":"78-257","consensus_level":"medium","plddt":90.0994,"start":78,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H427","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H427-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H427-F1-predicted_aligned_error_v6.png","plddt_mean":79.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNK15","jax_strain_url":"https://www.jax.org/strain/search?query=KCNK15"},"sequence":{"accession":"Q9H427","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H427.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H427/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H427"}},"corpus_meta":[{"pmid":"30032148","id":"PMC_30032148","title":"ALKBH5 Inhibits Pancreatic Cancer Motility by Decreasing Long Non-Coding RNA KCNK15-AS1 Methylation.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30032148","citation_count":210,"is_preprint":false},{"pmid":"11749039","id":"PMC_11749039","title":"Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K(+) channel subunit, TASK-5, associated with the central auditory nervous system.","date":"2001","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/11749039","citation_count":115,"is_preprint":false},{"pmid":"11409881","id":"PMC_11409881","title":"TASK-5, a new member of the tandem-pore K(+) channel family.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11409881","citation_count":93,"is_preprint":false},{"pmid":"11680614","id":"PMC_11680614","title":"TASK-5, a novel member of the tandem pore K+ channel family.","date":"2001","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11680614","citation_count":69,"is_preprint":false},{"pmid":"34853296","id":"PMC_34853296","title":"ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34853296","citation_count":66,"is_preprint":false},{"pmid":"31788071","id":"PMC_31788071","title":"Silencing of KCNK15-AS1 inhibits lung cancer cell proliferation via upregulation of miR-202 and miR-370.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31788071","citation_count":11,"is_preprint":false},{"pmid":"39215006","id":"PMC_39215006","title":"Potassium channel TASK-5 forms functional heterodimers with TASK-1 and TASK-3 to break its silence.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39215006","citation_count":10,"is_preprint":false},{"pmid":"41023574","id":"PMC_41023574","title":"Hypermethylated Long Non-Coding RNA Genes KCNK15-AS1, MAGI2-AS3, and SSTR5-AS1 in Ovarian Cancer and Their Diagnostic Potential.","date":"2025","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41023574","citation_count":0,"is_preprint":false},{"pmid":"39553828","id":"PMC_39553828","title":"Effects of the two-pore potassium channel subunit Task5 on neuronal function and signal processing in the auditory brainstem.","date":"2024","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39553828","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6697,"output_tokens":1672,"usd":0.022586,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8447,"output_tokens":2684,"usd":0.054668,"stage2_stop_reason":"end_turn"},"total_usd":0.077254,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"TASK-5 (KCNK15) does not form functional K+ channels as a homodimer when expressed in Xenopus oocytes or COS-7 cells; chimeric TASK-5/TASK-3 constructs containing the region between M1 and M3 of TASK-3 did produce K+-selective currents, indicating a non-functional pore region in TASK-5 alone.\",\n      \"method\": \"Heterologous expression in Xenopus oocytes and COS-7 cells; chimeric channel electrophysiology\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — electrophysiological reconstitution with chimeric constructs, independently replicated in three separate 2001 studies (PMIDs 11749039, 11409881, 11680614)\",\n      \"pmids\": [\"11749039\", \"11409881\", \"11680614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TASK-5 does not form functional heteromers with TASK-1; co-expression of TASK-5 with a proton-insensitive TASK-1 H98N mutant did not rescue proton sensitivity, in contrast to wild-type TASK-1 co-expression which did rescue it through heteromeric channels.\",\n      \"method\": \"Xenopus oocyte co-expression; proton-sensitivity rescue assay with TASK-1 H98N mutant\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous functional assay with mutagenesis controls, but single lab, single paper\",\n      \"pmids\": [\"11680614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TASK-5 protein is present at the plasma membrane in HEK293 cells at a distribution similar to TASK-1, suggesting the lack of current is not due to failure of membrane trafficking; removal of a putative ER retention sequence did not restore channel activity.\",\n      \"method\": \"Subcellular localization in HEK293 cells; ER retention sequence deletion mutagenesis; electrophysiology\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment combined with mutagenesis, single lab\",\n      \"pmids\": [\"11680614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TASK-5 mRNA is expressed predominantly in the central auditory pathway (olfactory bulb mitral cells and Purkinje cells also), as determined by in situ hybridization in rat brain, suggesting a specialized role in auditory signal processing.\",\n      \"method\": \"In situ hybridization in rat brain\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by ISH, single lab, no functional consequence tested at this point\",\n      \"pmids\": [\"11749039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TASK-5 (KCNK15) forms functional heterodimeric channel complexes with TASK-1 and TASK-3; as a homodimer it remains non-functional. These heteromeric complexes show altered single-channel conductance, altered Gq-coupled receptor-mediated channel inhibition, and changed sensitivity to TASK modulators compared to TASK-1 or TASK-3 homodimers. TASK-5 also negatively modulates surface expression of TASK channels.\",\n      \"method\": \"Heterologous co-expression; single-channel electrophysiology; pharmacological characterization; surface expression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-channel reconstitution with multiple orthogonal functional readouts (conductance, receptor inhibition, pharmacology, surface expression) in one rigorous study\",\n      \"pmids\": [\"39215006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A common single-nucleotide polymorphism in KCNK15 alters the pharmacology of TASK-1/TASK-5 heterodimers, demonstrating that TASK-5 sequence variation functionally impacts the drug-sensitivity profile of the heteromeric channel.\",\n      \"method\": \"Heterologous expression of polymorphic TASK-5 variants; electrophysiology with pharmacological probes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional electrophysiology with defined genetic variant, single lab\",\n      \"pmids\": [\"39215006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Task5 in knock-out mice alters neuronal excitability in bushy cells of the ventral cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body, and changes auditory brainstem responses to loud sounds, establishing Task5 as a functionally active K2P subunit contributing to auditory processing in vivo.\",\n      \"method\": \"Task5 knock-out mice; whole-cell electrophysiology in brainstem neurons; auditory brainstem response (ABR) recording\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular electrophysiological phenotype and in vivo auditory readout, two orthogonal methods\",\n      \"pmids\": [\"39553828\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNK15 (TASK-5) is a two-pore domain K+ channel subunit that is non-functional as a homodimer but forms functional heterodimeric channels with TASK-1 and TASK-3, negatively modulating their surface expression and conferring altered single-channel conductance, Gq-receptor inhibition, and pharmacological sensitivity; in vivo, it contributes to neuronal excitability in the auditory brainstem and is required for normal auditory processing as demonstrated by Task5 knock-out mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNK15 (TASK-5) is a two-pore domain (K2P) potassium channel subunit that regulates neuronal excitability by acting as a modulatory partner of other TASK channels rather than as an autonomous conductance [#4, #6]. As a homodimer it does not form functional K+ channels in heterologous systems, and this is not attributable to defective trafficking, since TASK-5 protein reaches the plasma membrane normally and removal of a putative ER retention sequence fails to restore activity; chimeric constructs show its intrinsic pore region is non-conducting [#0, #2]. Instead, TASK-5 assembles into functional heterodimeric channels with TASK-1 and TASK-3, conferring altered single-channel conductance, altered Gq-coupled receptor-mediated inhibition, and changed sensitivity to TASK modulators, while also negatively modulating the surface expression of these channels [#4]. A common KCNK15 polymorphism alters the pharmacology of TASK-1/TASK-5 heterodimers, indicating that TASK-5 sequence variation shapes the drug-sensitivity profile of the heteromeric channel [#5]. In vivo, KCNK15 is expressed predominantly along the central auditory pathway, and Task5 knock-out mice show altered excitability of bushy cells of the ventral cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body together with changed auditory brainstem responses, establishing a role in auditory processing [#3, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Whether TASK-5 forms a functional channel on its own was the first question; establishing that it does not redefined it from a candidate pore-former to a non-conducting subunit.\",\n      \"evidence\": \"Heterologous expression in Xenopus oocytes and COS-7 cells with TASK-5/TASK-3 chimeric channel electrophysiology\",\n      \"pmids\": [\"11749039\", \"11409881\", \"11680614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not test whether TASK-5 could function in heteromeric assemblies\",\n        \"Did not identify the structural basis of the non-conducting pore beyond the M1\\u2013M3 region\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"To distinguish silence from mislocalization, it was important to learn whether the lack of current reflected a trafficking failure; demonstrating membrane localization placed the defect at the pore/assembly level.\",\n      \"evidence\": \"Subcellular localization in HEK293 cells with ER retention sequence deletion mutagenesis and electrophysiology\",\n      \"pmids\": [\"11680614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single paper\",\n        \"Did not resolve why a membrane-localized subunit produces no current\",\n        \"Did not test heteromeric assembly partners\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Early heteromerization testing with TASK-1 (via a proton-insensitive H98N rescue assay) was needed to ask if TASK-5 could partner with other TASK subunits; the negative result initially argued against functional heteromers.\",\n      \"evidence\": \"Xenopus oocyte co-expression with TASK-1 H98N proton-sensitivity rescue assay\",\n      \"pmids\": [\"11680614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single assay design later contradicted by single-channel work\",\n        \"Did not test TASK-3 as a partner\",\n        \"Proton-rescue readout may not detect all functional heteromers\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining the expression domain addressed where TASK-5 might act physiologically; its enrichment in the central auditory pathway pointed to a specialized role in auditory signal processing.\",\n      \"evidence\": \"In situ hybridization in rat brain\",\n      \"pmids\": [\"11749039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"mRNA distribution without functional consequence tested at this stage\",\n        \"No protein-level confirmation in the auditory pathway\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The central question of whether TASK-5 has any channel function was resolved by showing it forms functional heterodimers with TASK-1 and TASK-3 that alter conductance, receptor regulation, pharmacology, and surface expression \\u2014 reframing TASK-5 as an active modulatory subunit.\",\n      \"evidence\": \"Heterologous co-expression with single-channel electrophysiology, pharmacological characterization, and surface expression assays\",\n      \"pmids\": [\"39215006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Single rigorous study\",\n        \"Stoichiometry and structural interface of the heteromer not resolved\",\n        \"Mechanism by which TASK-5 lowers surface expression not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking genetic variation to function, a common KCNK15 polymorphism was shown to alter TASK-1/TASK-5 heterodimer pharmacology, establishing that TASK-5 sequence shapes the drug response of the complex.\",\n      \"evidence\": \"Heterologous expression of polymorphic TASK-5 variants with electrophysiology and pharmacological probes\",\n      \"pmids\": [\"39215006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab\",\n        \"Physiological or clinical impact of the polymorphism not established\",\n        \"Effect on TASK-3 heterodimers not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An in vivo loss-of-function model was needed to confirm physiological relevance; Task5 knock-out mice with altered brainstem neuron excitability and auditory responses established TASK-5 as a functionally active K2P subunit in auditory processing.\",\n      \"evidence\": \"Task5 knock-out mice with whole-cell electrophysiology in brainstem neurons and auditory brainstem response recording\",\n      \"pmids\": [\"39553828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define which TASK partner mediates the in vivo phenotype\",\n        \"Behavioral/hearing-threshold consequences beyond ABR not fully characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular determinants of how TASK-5 silences its own pore yet modulates TASK-1/TASK-3 conductance, surface expression, and pharmacology remain structurally undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of TASK-5-containing heterodimers\",\n        \"Heteromer stoichiometry and assembly determinants unknown\",\n        \"Mechanism of negative regulation of TASK channel surface expression unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"TASK-1/TASK-5 heterodimeric K2P channel\",\n      \"TASK-3/TASK-5 heterodimeric K2P channel\"\n    ],\n    \"partners\": [\n      \"KCNK3\",\n      \"KCNK9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}