{"gene":"KCNH4","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2003,"finding":"KCNH4 (Kv12.3/Elk subfamily) subunits can form heteromultimers with other Elk family members (KCNH8, KCNH3); dominant-negative KCNH4 subunits suppress KCNH8 currents when coexpressed in Xenopus oocytes, but KCNH4 subunits cannot form heteromultimers with Eag, Erg, or Kv family K+ channels.","method":"Coexpression of dominant-negative subunits in Xenopus oocytes with electrophysiological readout","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology in Xenopus oocytes with dominant-negative constructs; single lab but multiple channel combinations tested","pmids":["12890647"],"is_preprint":false},{"year":2013,"finding":"Kv12.3 (KCNH4) voltage-gated K+ channel activation is inhibited by external acidification (protons), which depolarizes its conductance-voltage curve and reduces low-threshold activation. This pH sensitivity is mediated through EAG-specific acidic residues in the voltage sensor, the same residues implicated in divalent cation (Zn2+/Mg2+) block.","method":"Electrophysiological recording (conductance-voltage curves) combined with site-directed mutagenesis of voltage sensor acidic residues across EAG superfamily members including Kv12.3","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus functional electrophysiology; single lab but multiple orthogonal methods (GV curves, divalent sensitivity, mutagenesis) applied across multiple channel family members","pmids":["23712551"],"is_preprint":false},{"year":2021,"finding":"Kv12.3 (KCNH4) protein is expressed in Phox2b-expressing neurons in the nucleus tractus solitarii (NTS) of mice, co-localizing with the Phox2b marker, providing molecular evidence that Kv12.3 is present in central respiratory chemoreceptor neurons that are known to be pH-sensitive.","method":"Immunofluorescence staining, Western blot, and qPCR in mouse NTS tissue","journal":"Sheng li xue bao : [Acta physiologica Sinica]","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization established by immunofluorescence and protein/mRNA quantification in a single study without direct functional consequence demonstrated for KCNH4 specifically","pmids":["33903883"],"is_preprint":false},{"year":2015,"finding":"Overexpression of tau in mouse neuroblastoma N2A cells downregulates KCNH4 mRNA levels and reduces macroscopic Kv currents (by ~36.5% at +60 mV), and this reduction in Kv channel activity is associated with increased cell proliferation.","method":"Transient transfection of tau plasmids into N2A cells; qRT-PCR for mRNA levels; patch-clamp electrophysiology; proliferation assay","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mRNA downregulation shown but no direct mechanistic link between tau and KCNH4 protein established; KCNH4 is one of several Kv channels affected","pmids":["25590133"],"is_preprint":false},{"year":2015,"finding":"Transfection of tau plasmids into human neuroblastoma SK-N-SH cells causes significant reduction in KCNH4 mRNA levels, with corresponding decline in Kv currents measured by patch-clamp, and increased cell proliferation.","method":"Tau plasmid transfection into SK-N-SH cells; qRT-PCR; patch-clamp electrophysiology; proliferation assay","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mRNA-level effect on one of several Kv channels, no direct mechanistic link to KCNH4 protein function established","pmids":["26576773"],"is_preprint":false},{"year":2020,"finding":"CLN1/PPT1 overexpression in differentiated SH-SY5Y neuronal-like cells leads to downregulation of KCNH4 transcripts and reduced functional Kv12 channels at the plasma membrane, as evidenced by pharmacological dissection using 4-AP and NS-1643 (drugs with opposing effects on Kv11 and Kv12 subfamilies) in patch-clamp recordings.","method":"Transcriptomics (RNA-seq), patch-clamp electrophysiology with pharmacological dissection (4-AP and NS-1643), in CLN1-overexpressing SH-SY5Y cells","journal":"Frontiers in cellular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pharmacological inference for Kv12 channel reduction; KCNH4 not directly manipulated, single lab","pmids":["33390903"],"is_preprint":false}],"current_model":"KCNH4 (Kv12.3) encodes a voltage-gated K+ channel of the Elk subfamily that activates at low thresholds, forms heteromultimers with other Elk family members but not with Eag/Erg/Kv channels, and whose voltage-sensor activation is inhibited by external protons through EAG-specific acidic residues; it is primarily expressed in nervous system neurons including Phox2b-positive NTS neurons, and its expression is negatively regulated at the mRNA level by tau overexpression."},"narrative":{"mechanistic_narrative":"KCNH4 (Kv12.3) encodes a low-threshold voltage-gated potassium channel of the Elk subfamily within the EAG superfamily [PMID:12890647, PMID:23712551]. It assembles into functional channels and forms selective heteromultimers with other Elk family members (KCNH8 and KCNH3) but cannot co-assemble with Eag, Erg, or Kv family subunits, defining a restricted subfamily-specific oligomerization rule [PMID:12890647]. Channel gating is modulated by extracellular pH: external acidification depolarizes the conductance-voltage relationship and suppresses low-threshold activation, an effect mediated by EAG-specific acidic residues in the voltage sensor that also confer divalent cation (Zn2+/Mg2+) sensitivity [PMID:23712551]. Beyond its biophysical characterization, the corpus links KCNH4 expression to neuronal contexts but does not establish a mechanism downstream of the channel. No structural model, no native heteromeric complex composition in tissue, and no disease-causing mutation have been characterized in the available corpus.","teleology":[{"year":2003,"claim":"Established the subunit assembly rules for KCNH4, answering whether it forms homomeric channels or combines with other channel families.","evidence":"Coexpression of dominant-negative KCNH4 with other channel subunits in Xenopus oocytes with electrophysiological readout","pmids":["12890647"],"confidence":"Medium","gaps":["Native heteromeric stoichiometry in neurons not determined","Whether endogenous KCNH4/KCNH8 heteromers occur in tissue untested","No structural basis for subfamily-restricted assembly"]},{"year":2013,"claim":"Defined the molecular determinant of proton modulation, showing how extracellular pH tunes KCNH4 voltage-sensor activation.","evidence":"Conductance-voltage recordings plus site-directed mutagenesis of voltage-sensor acidic residues across EAG superfamily members including Kv12.3","pmids":["23712551"],"confidence":"Medium","gaps":["Physiological pH range over which modulation is relevant in vivo not established","Functional consequence of pH gating in native neurons untested","No structural model of the protonated voltage sensor"]},{"year":2021,"claim":"Placed KCNH4 protein in pH-sensitive central chemoreceptor neurons, connecting its proton sensitivity to a candidate physiological setting.","evidence":"Immunofluorescence, Western blot, and qPCR in Phox2b-expressing NTS neurons of mouse brainstem","pmids":["33903883"],"confidence":"Low","gaps":["Localization only; no functional role for KCNH4 in chemoreception demonstrated","No loss-of-function or knockout phenotype","Co-localization with Phox2b does not establish channel contribution to neuronal firing"]},{"year":2015,"claim":"Linked KCNH4 transcript abundance to tau levels, raising the channel as a downstream node of tau-associated changes in neuronal excitability and proliferation.","evidence":"Tau plasmid transfection in mouse N2A and human SK-N-SH neuroblastoma cells with qRT-PCR, patch-clamp, and proliferation assays","pmids":["25590133","26576773"],"confidence":"Low","gaps":["mRNA-level effect only; no direct link to KCNH4 protein or to the channel as the proliferation driver","KCNH4 is one of several Kv channels affected, so specificity is unresolved","Mechanism connecting tau to KCNH4 transcription unknown"]},{"year":2020,"claim":"Extended transcriptional regulation of KCNH4 to a second perturbation, CLN1/PPT1 overexpression, again reducing Kv12 channel function.","evidence":"RNA-seq and patch-clamp with pharmacological dissection (4-AP, NS-1643) in CLN1-overexpressing SH-SY5Y cells","pmids":["33390903"],"confidence":"Low","gaps":["Kv12 reduction inferred pharmacologically; KCNH4 not directly manipulated","Direct versus indirect transcriptional effect not distinguished","No demonstration that KCNH4 loss accounts for the cellular phenotype"]},{"year":null,"claim":"The native channel composition, in vivo physiological function, and any disease relevance of KCNH4 remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the channel or its voltage sensor","No loss-of-function phenotype establishing a neuronal or systemic role","No characterized causative disease mutation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["KCNH8","KCNH3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQ05","full_name":"Voltage-gated delayed rectifier potassium channel KCNH4","aliases":["Brain-specific eag-like channel 2","BEC2","Ether-a-go-go-like potassium channel 1","ELK channel 1","ELK1","Potassium voltage-gated channel subfamily H member 4","Voltage-gated potassium channel subunit Kv12.3"],"length_aa":1017,"mass_kda":111.7,"function":"Pore-forming (alpha) subunit of a voltage-gated delayed rectifier (PubMed:10455180). Activates at more negative voltages, exhibits fast prepulse-independent activation kinetics and deactivates much more slowly, but shows no inactivation (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQ05/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNH4","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNH4","total_profiled":1310},"omim":[{"mim_id":"608588","title":"DExH-BOX HELICASE 58; DHX58","url":"https://www.omim.org/entry/608588"},{"mim_id":"608260","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 8; KCNH8","url":"https://www.omim.org/entry/608260"},{"mim_id":"604528","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 4; KCNH4","url":"https://www.omim.org/entry/604528"},{"mim_id":"604527","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 3; KCNH3","url":"https://www.omim.org/entry/604527"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":6.9}],"url":"https://www.proteinatlas.org/search/KCNH4"},"hgnc":{"alias_symbol":["Kv12.3","elk1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UQ05","domains":[{"cath_id":"3.30.450.20","chopping":"9-137_205-212","consensus_level":"medium","plddt":82.8516,"start":9,"end":212},{"cath_id":"-","chopping":"213-355","consensus_level":"medium","plddt":78.2812,"start":213,"end":355},{"cath_id":"2.60.120.10","chopping":"528-626_640-688","consensus_level":"high","plddt":90.316,"start":528,"end":688}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ05","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ05-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQ05-F1-predicted_aligned_error_v6.png","plddt_mean":66.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNH4","jax_strain_url":"https://www.jax.org/strain/search?query=KCNH4"},"sequence":{"accession":"Q9UQ05","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQ05.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQ05/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQ05"}},"corpus_meta":[{"pmid":"12890647","id":"PMC_12890647","title":"Distribution and functional properties of human KCNH8 (Elk1) potassium channels.","date":"2003","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12890647","citation_count":52,"is_preprint":false},{"pmid":"29246110","id":"PMC_29246110","title":"DNA and RNA-sequence based GWAS highlights membrane-transport genes as key modulators of milk lactose content.","date":"2017","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29246110","citation_count":44,"is_preprint":false},{"pmid":"23285264","id":"PMC_23285264","title":"First WNK4-hypokalemia animal model identified by genome-wide association in Burmese cats.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23285264","citation_count":44,"is_preprint":false},{"pmid":"23712551","id":"PMC_23712551","title":"External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.","date":"2013","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23712551","citation_count":30,"is_preprint":false},{"pmid":"31192134","id":"PMC_31192134","title":"Somatic Mutations Profile of a Young Patient With Metastatic Urothelial Carcinoma Reveals Mutations in Genes Involved in Ion Channels.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31192134","citation_count":14,"is_preprint":false},{"pmid":"25590133","id":"PMC_25590133","title":"Overexpression of tau downregulated the mRNA levels of Kv channels and improved proliferation in N2A cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25590133","citation_count":13,"is_preprint":false},{"pmid":"33390903","id":"PMC_33390903","title":"Electrophysiological Profile Remodeling via Selective Suppression of Voltage-Gated Currents by CLN1/PPT1 Overexpression in Human Neuronal-Like Cells.","date":"2020","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33390903","citation_count":7,"is_preprint":false},{"pmid":"34801551","id":"PMC_34801551","title":"Investigation of PAS and CNBH domain interactions in hERG channels and effects of long-QT syndrome-causing mutations with surface plasmon resonance.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34801551","citation_count":5,"is_preprint":false},{"pmid":"33903883","id":"PMC_33903883","title":"The Kv12 voltage-gated K+ channels are expressed in the Phox2b-expressing neurons in the nucleus tractus solitarii in mice.","date":"2021","source":"Sheng li xue bao : [Acta physiologica Sinica]","url":"https://pubmed.ncbi.nlm.nih.gov/33903883","citation_count":0,"is_preprint":false},{"pmid":"26576773","id":"PMC_26576773","title":"The Tau-Induced Reduction of mRNA Levels of Kv Channels in Human Neuroblastoma SK-N-SH Cells.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/26576773","citation_count":0,"is_preprint":false},{"pmid":"41671841","id":"PMC_41671841","title":"Integrative GWAS and RNA-seq identify MYL9 as a key regulator of pullorum disease resistance in chickens.","date":"2026","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/41671841","citation_count":0,"is_preprint":false},{"pmid":"29503979","id":"PMC_29503979","title":"Whole exome analyses to examine the impact of rare variants on left ventricular traits in African American participants from the HyperGEN and GENOA studies.","date":"2017","source":"Journal of hypertension and management","url":"https://pubmed.ncbi.nlm.nih.gov/29503979","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8727,"output_tokens":1648,"usd":0.025451,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8355,"output_tokens":2042,"usd":0.046413,"stage2_stop_reason":"end_turn"},"total_usd":0.071864,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"KCNH4 (Kv12.3/Elk subfamily) subunits can form heteromultimers with other Elk family members (KCNH8, KCNH3); dominant-negative KCNH4 subunits suppress KCNH8 currents when coexpressed in Xenopus oocytes, but KCNH4 subunits cannot form heteromultimers with Eag, Erg, or Kv family K+ channels.\",\n      \"method\": \"Coexpression of dominant-negative subunits in Xenopus oocytes with electrophysiological readout\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology in Xenopus oocytes with dominant-negative constructs; single lab but multiple channel combinations tested\",\n      \"pmids\": [\"12890647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kv12.3 (KCNH4) voltage-gated K+ channel activation is inhibited by external acidification (protons), which depolarizes its conductance-voltage curve and reduces low-threshold activation. This pH sensitivity is mediated through EAG-specific acidic residues in the voltage sensor, the same residues implicated in divalent cation (Zn2+/Mg2+) block.\",\n      \"method\": \"Electrophysiological recording (conductance-voltage curves) combined with site-directed mutagenesis of voltage sensor acidic residues across EAG superfamily members including Kv12.3\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus functional electrophysiology; single lab but multiple orthogonal methods (GV curves, divalent sensitivity, mutagenesis) applied across multiple channel family members\",\n      \"pmids\": [\"23712551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kv12.3 (KCNH4) protein is expressed in Phox2b-expressing neurons in the nucleus tractus solitarii (NTS) of mice, co-localizing with the Phox2b marker, providing molecular evidence that Kv12.3 is present in central respiratory chemoreceptor neurons that are known to be pH-sensitive.\",\n      \"method\": \"Immunofluorescence staining, Western blot, and qPCR in mouse NTS tissue\",\n      \"journal\": \"Sheng li xue bao : [Acta physiologica Sinica]\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization established by immunofluorescence and protein/mRNA quantification in a single study without direct functional consequence demonstrated for KCNH4 specifically\",\n      \"pmids\": [\"33903883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of tau in mouse neuroblastoma N2A cells downregulates KCNH4 mRNA levels and reduces macroscopic Kv currents (by ~36.5% at +60 mV), and this reduction in Kv channel activity is associated with increased cell proliferation.\",\n      \"method\": \"Transient transfection of tau plasmids into N2A cells; qRT-PCR for mRNA levels; patch-clamp electrophysiology; proliferation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mRNA downregulation shown but no direct mechanistic link between tau and KCNH4 protein established; KCNH4 is one of several Kv channels affected\",\n      \"pmids\": [\"25590133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transfection of tau plasmids into human neuroblastoma SK-N-SH cells causes significant reduction in KCNH4 mRNA levels, with corresponding decline in Kv currents measured by patch-clamp, and increased cell proliferation.\",\n      \"method\": \"Tau plasmid transfection into SK-N-SH cells; qRT-PCR; patch-clamp electrophysiology; proliferation assay\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mRNA-level effect on one of several Kv channels, no direct mechanistic link to KCNH4 protein function established\",\n      \"pmids\": [\"26576773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CLN1/PPT1 overexpression in differentiated SH-SY5Y neuronal-like cells leads to downregulation of KCNH4 transcripts and reduced functional Kv12 channels at the plasma membrane, as evidenced by pharmacological dissection using 4-AP and NS-1643 (drugs with opposing effects on Kv11 and Kv12 subfamilies) in patch-clamp recordings.\",\n      \"method\": \"Transcriptomics (RNA-seq), patch-clamp electrophysiology with pharmacological dissection (4-AP and NS-1643), in CLN1-overexpressing SH-SY5Y cells\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pharmacological inference for Kv12 channel reduction; KCNH4 not directly manipulated, single lab\",\n      \"pmids\": [\"33390903\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNH4 (Kv12.3) encodes a voltage-gated K+ channel of the Elk subfamily that activates at low thresholds, forms heteromultimers with other Elk family members but not with Eag/Erg/Kv channels, and whose voltage-sensor activation is inhibited by external protons through EAG-specific acidic residues; it is primarily expressed in nervous system neurons including Phox2b-positive NTS neurons, and its expression is negatively regulated at the mRNA level by tau overexpression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNH4 (Kv12.3) encodes a low-threshold voltage-gated potassium channel of the Elk subfamily within the EAG superfamily [#0, #1]. It assembles into functional channels and forms selective heteromultimers with other Elk family members (KCNH8 and KCNH3) but cannot co-assemble with Eag, Erg, or Kv family subunits, defining a restricted subfamily-specific oligomerization rule [#0]. Channel gating is modulated by extracellular pH: external acidification depolarizes the conductance-voltage relationship and suppresses low-threshold activation, an effect mediated by EAG-specific acidic residues in the voltage sensor that also confer divalent cation (Zn2+/Mg2+) sensitivity [#1]. Beyond its biophysical characterization, the corpus links KCNH4 expression to neuronal contexts but does not establish a mechanism downstream of the channel. No structural model, no native heteromeric complex composition in tissue, and no disease-causing mutation have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the subunit assembly rules for KCNH4, answering whether it forms homomeric channels or combines with other channel families.\",\n      \"evidence\": \"Coexpression of dominant-negative KCNH4 with other channel subunits in Xenopus oocytes with electrophysiological readout\",\n      \"pmids\": [\"12890647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Native heteromeric stoichiometry in neurons not determined\",\n        \"Whether endogenous KCNH4/KCNH8 heteromers occur in tissue untested\",\n        \"No structural basis for subfamily-restricted assembly\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the molecular determinant of proton modulation, showing how extracellular pH tunes KCNH4 voltage-sensor activation.\",\n      \"evidence\": \"Conductance-voltage recordings plus site-directed mutagenesis of voltage-sensor acidic residues across EAG superfamily members including Kv12.3\",\n      \"pmids\": [\"23712551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological pH range over which modulation is relevant in vivo not established\",\n        \"Functional consequence of pH gating in native neurons untested\",\n        \"No structural model of the protonated voltage sensor\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed KCNH4 protein in pH-sensitive central chemoreceptor neurons, connecting its proton sensitivity to a candidate physiological setting.\",\n      \"evidence\": \"Immunofluorescence, Western blot, and qPCR in Phox2b-expressing NTS neurons of mouse brainstem\",\n      \"pmids\": [\"33903883\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Localization only; no functional role for KCNH4 in chemoreception demonstrated\",\n        \"No loss-of-function or knockout phenotype\",\n        \"Co-localization with Phox2b does not establish channel contribution to neuronal firing\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked KCNH4 transcript abundance to tau levels, raising the channel as a downstream node of tau-associated changes in neuronal excitability and proliferation.\",\n      \"evidence\": \"Tau plasmid transfection in mouse N2A and human SK-N-SH neuroblastoma cells with qRT-PCR, patch-clamp, and proliferation assays\",\n      \"pmids\": [\"25590133\", \"26576773\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"mRNA-level effect only; no direct link to KCNH4 protein or to the channel as the proliferation driver\",\n        \"KCNH4 is one of several Kv channels affected, so specificity is unresolved\",\n        \"Mechanism connecting tau to KCNH4 transcription unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended transcriptional regulation of KCNH4 to a second perturbation, CLN1/PPT1 overexpression, again reducing Kv12 channel function.\",\n      \"evidence\": \"RNA-seq and patch-clamp with pharmacological dissection (4-AP, NS-1643) in CLN1-overexpressing SH-SY5Y cells\",\n      \"pmids\": [\"33390903\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Kv12 reduction inferred pharmacologically; KCNH4 not directly manipulated\",\n        \"Direct versus indirect transcriptional effect not distinguished\",\n        \"No demonstration that KCNH4 loss accounts for the cellular phenotype\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The native channel composition, in vivo physiological function, and any disease relevance of KCNH4 remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the channel or its voltage sensor\",\n        \"No loss-of-function phenotype establishing a neuronal or systemic role\",\n        \"No characterized causative disease mutation\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KCNH8\", \"KCNH3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}