{"gene":"KCNN1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2001,"finding":"The mouse SK1 (KCNN1) gene encodes a complex pattern of alternatively spliced transcripts with at least four distinct 5'-sequence variants and eight variant C-terminal amino acid sequences. Alternative splicing can alter the putative S6 transmembrane span, modify the C-terminal cytoplasmic calmodulin-binding domain, and generate alternate predicted PDZ domain-binding sites. Only four of sixteen predicted polypeptide variants preserve the ability to bind calmodulin in a Ca2+-independent manner.","method":"Genomic cloning, RT-PCR, sequence analysis, calmodulin-binding domain assessment","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genomic and transcript characterization with calmodulin-binding domain analysis, single lab but multiple orthogonal methods","pmids":["11267657"],"is_preprint":false},{"year":1999,"finding":"The human KCNN1 gene (encoding SK1 small-conductance calcium-activated potassium channel) was mapped by radiation hybrid mapping to chromosome 19p13.1, and its exon-intron gene structure was defined.","method":"Radiation hybrid mapping, gene structure analysis","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping experiment, single lab, established gene locus","pmids":["10516439"],"is_preprint":false},{"year":2013,"finding":"KCNN1 (hSKCa1) channel activity is regulated by EGFR tyrosine kinase phosphorylation at Tyr109 in the N-terminus. Inhibition of EGFR kinase (by genistein, tyrphostin T25, or AG556) reduced tyrosine phosphorylation of hSKCa1 and inhibited channel current; the Y109F mutant lost the inhibitory response to EGFR inhibitors and showed dramatically reduced tyrosine phosphorylation and current density.","method":"Whole-cell patch voltage-clamp, immunoprecipitation, Western blotting, site-directed mutagenesis (Y109F) in HEK-293 cells expressing KCNN1","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology combined with mutagenesis and biochemical phosphorylation assays, multiple orthogonal methods in one study","pmids":["23496660"],"is_preprint":false},{"year":2022,"finding":"Calmodulin gating of SK (KCa2.x) channels requires Ca2+-dependent conformational changes in both the N-lobe and C-lobe of calmodulin interacting with the proximal C-terminal domain (SKp) of the channel. Isolated calmodulin lobes bind SKp with high affinity but fail to rescue SK2 (KCa2.2) activity; full-length calmodulin with both lobes is required for full activation. C-lobe binding to SKp changes with Ca2+ at concentrations that activate SK2, challenging the prior model that C-lobe binding is purely Ca2+-independent.","method":"Inside-out patch-clamp recording of SK2 channels with exogenous calmodulin application; composition-gradient multi-angle light-scattering; tryptophan emission spectra for calmodulin–SKp binding","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of calmodulin binding with multiple orthogonal biophysical methods plus electrophysiology, rigorous controls including isolated lobe experiments","pmids":["36583726"],"is_preprint":false},{"year":2017,"finding":"SK1 (KCNN1) and SK3 (KCNN3) channels are expressed in kidney connecting tubule/cortical collecting duct (CNT/CCD) cells and are activated by TRPV4-mediated Ca2+ influx. Early activation of SK1/3 and IK1 (KCNN4) channels is required for sufficient Ca2+ entry and intracellular Ca2+ elevation needed to activate the BK channel (KCNMA1), thereby coupling TRPV4 to BK-dependent K+ secretion.","method":"Pharmacological inhibition (apamin for SK1/3, TRAM-34 for IK1, iberiotoxin for BK) with membrane potential measurement and intracellular Ca2+ imaging in mCCDcl1 cells","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with functional readouts (membrane potential + [Ca2+]i), single lab, two complementary measurement methods","pmids":["28274924"],"is_preprint":false},{"year":2021,"finding":"KCNN1 (KCa2.1) channel expression in atrial myocytes is directly regulated by histone deacetylases (HDACs). Knockdown of HDAC2, 3, 6, or 7 decreased Kcnn1 mRNA levels, while knockdown of HDAC9 enhanced Kcnn1 expression in HL-1 atrial myocytes. Tachypacing-induced downregulation of HDACs 1, 3, 4, 6, and 7 was associated with a tendency toward reduced Kcnn1 levels.","method":"siRNA knockdown of individual HDACs, tachypacing of HL-1 cells, qRT-PCR measurement of Kcnn1 mRNA","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function siRNA for multiple HDAC isoforms with defined transcriptional readout for KCNN1, single lab","pmids":["34111326"],"is_preprint":false},{"year":2023,"finding":"SS-lncRNA (a sensory neuron-specific lncRNA) regulates KCNN1 expression in dorsal root ganglion (DRG) neurons through two mechanisms: (1) direct binding of SS-lncRNA to the Kcnn1 promoter and recruitment of hnRNPM to activate Kcnn1 transcription; (2) in a separate study, SS-lncRNA downregulation reduces recruitment of the histone demethylase KDM6B to the Kcnn1 promoter, increasing H3K27me3 enrichment and silencing Kcnn1. Loss of KCNN1 in DRG neurons decreased total potassium currents and afterhyperpolarization currents, increased neuronal excitability, and produced neuropathic pain symptoms.","method":"ChIP, RNA immunoprecipitation, promoter binding assays, nerve injury mouse models, patch-clamp electrophysiology, conditional knockout/knock-in of SS-lncRNA in Mrgprd+ neurons","journal":"Brain : a journal of neurology; Life sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, RIP, electrophysiology, conditional genetic rescue/mimicry) replicated across two independent papers from same group","pmids":["37012681","37741322"],"is_preprint":false},{"year":2024,"finding":"ESRRG (estrogen-related receptor gamma), a transcription factor, directly binds the Kcnn1 promoter and activates its transcription in DRG neurons. Nerve injury reduces DRG ESRRG levels, which decreases ESRRG binding to the Kcnn1 promoter and downregulates KCNN1 expression, leading to reduced AHP currents, increased neuronal excitability, and neuropathic pain. Rescuing KCNN1 downregulation prevented these electrophysiological and pain phenotypes.","method":"ChIP (ESRRG binding to Kcnn1 promoter), AAV-mediated KCNN1 rescue and knockdown in DRG, patch-clamp electrophysiology, behavioral pain assays in CCI and L4 ligation nerve injury mouse models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-validated transcription factor–promoter interaction combined with in vivo genetic rescue/mimicry and direct electrophysiological readouts","pmids":["38912580"],"is_preprint":false},{"year":2024,"finding":"The oncofusion protein EWS::FLI1 (and EWS::ERG) directly drives KCNN1 transcription by binding GGAA microsatellites near the KCNN1 promoter, leading to SK1 channel overexpression in Ewing sarcoma cells. KCNN1 silencing slows the cell cycle; KCNN1 expression modulates membrane potential and calcium flux, affecting cell proliferation.","method":"Bioinformatics, ChIP/promoter binding assays for EWS::FLI1 at GGAA microsatellites, siRNA knockdown of KCNN1, patch-clamp electrophysiology, calcium imaging, cell proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-validated direct transcription factor binding plus functional loss-of-function and electrophysiological readouts, single lab","pmids":["39487324"],"is_preprint":false},{"year":2022,"finding":"In Ewing sarcoma (EwS) cells, KCNN1 is overexpressed and its expression is regulated by the disease-driving oncoprotein EWSR1-FLI1. However, patch-clamp experiments showed no evidence for functional KCa2.1 channel activity in EwS cells, indicating that elevated KCNN1 mRNA/protein does not translate to functional channel activity in this context.","method":"Patch-clamp electrophysiology (negative result for functional channel), RT-qPCR, western blot, gene expression profiling in EwS cell lines","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological measurement establishing absence of functional channel activity despite elevated expression, single lab","pmids":["36230742"],"is_preprint":false},{"year":2023,"finding":"KCNN1 interacts with ERLIN2 in breast cancer cells and enhances ERLIN2-mediated stabilization of Cyclin B1, promoting its K63-linked ubiquitination. Overexpression of KCNN1 increased Cyclin B1 protein stability and K63-dependent ubiquitination; knockdown had the opposite effect. ERLIN2 knockdown/overexpression partially rescued the effects of KCNN1 manipulation on Cyclin B1 and on cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, western blot, CCK8/clone formation/EdU/wound healing/transwell assays, transcriptomic analysis, KCNN1 overexpression and knockdown in breast cancer cells","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP establishing KCNN1–ERLIN2 interaction, epistasis via double knockdown/overexpression with defined functional readouts, single lab","pmids":["37831636"],"is_preprint":false},{"year":2021,"finding":"Inhibition of ALS-upregulated KCNN1-3 (Drosophila SK ortholog) channels in C9ORF72-ALS patient-derived motor neurons and Drosophila motor neurons mitigates neurodegeneration and motor deficits, placing SK channel activity as a disease-modifying factor downstream of C9ORF72 repeat toxicity.","method":"Pharmacological inhibition of SK channels in C9ORF72-ALS patient-derived neurons and Drosophila motor neurons with functional (motor deficit) and cell survival readouts; genome-wide RNA analysis","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis in human patient-derived neurons and in vivo Drosophila model, single lab, multiple orthogonal systems","pmids":["34376242"],"is_preprint":false},{"year":2025,"finding":"Neuronal overexpression of Kcnn1 (as a monomeric, channel-inactive subunit, because it cannot assemble without Kcnn2) extends survival in SOD1-linked ALS and A53T alpha-synuclein mouse models. The overexpressed Kcnn1 subunit is diffusely cytoplasmic (not at the plasma membrane) in motor neurons and induces a multifaceted stress response (ER stress, mitochondrial stress, integrated stress response) as assessed by RNAseq and immunostaining, suggesting that a nonassembled/potentially misfolded ER-targeted state of Kcnn1 is responsible for the neuroprotective stress induction rather than K+ channel activity.","method":"Transgenic mouse overexpression (Thy1.2-driven Kcnn1 cDNA), survival analysis, RNAseq, immunostaining for stress response markers and Kcnn1 localization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic inference (nonassembled state induces stress response) is supported by localization and RNAseq but not by direct reconstitution or mutagenesis of the proposed mechanism","pmids":["bio_10.1101_2024.10.11.617887"],"is_preprint":true},{"year":2025,"finding":"Osimertinib (third-generation EGFR inhibitor) downregulates KCNN1 protein expression in cardiomyocytes as an off-target effect, leading to prolonged action potential duration and early afterdepolarizations. Modulating KCNN1 expression reversed these electrophysiological alterations, establishing KCNN1 downregulation as a mechanistic basis for osimertinib-induced arrhythmia.","method":"RNA sequencing, qRT-PCR and western blot for KCNN1, optical mapping of action potential duration in hiPSC-derived cardiomyocytes, zebrafish in vivo model, KCNN1 rescue experiments","journal":"Heart rhythm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA sequencing plus rescue experiments with direct electrophysiological readout, single lab, multiple complementary methods","pmids":["40653133"],"is_preprint":false},{"year":2022,"finding":"KCNN1 mRNA is subject to N6-methyladenosine (m6A) hypermethylation mediated by METTL3 in myocardial infarction, which is associated with downregulated KCNN1 expression. Inhibition of METTL3 reduced m6A methylation of Kcnn1 mRNA and restored its expression. Functional validation showed that Kcnn1 expression influences apoptosis and angiogenesis in H9c2 cardiomyocytes and HUVECs under hypoxic conditions.","method":"MeRIP-seq, MeRIP-qRT-PCR, siRNA knockdown of METTL3, cell viability (CCK-8, EdU), tube formation assay, flow cytometry/TUNEL for apoptosis in rat MI model and cell lines","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq identification plus METTL3 knockdown rescue and functional cellular assays, single lab, multiple orthogonal methods","pmids":["35155564"],"is_preprint":false}],"current_model":"KCNN1 encodes the SK1 (KCa2.1) small-conductance Ca2+-activated K+ channel, which is gated exclusively by intracellular Ca2+ through constitutive and Ca2+-dependent interactions of both calmodulin lobes with the channel's proximal C-terminal domain; channel activity is further modulated by EGFR-mediated tyrosine phosphorylation at Tyr109 in its N-terminus; transcription is regulated by ESRRG and hnRNPM (via SS-lncRNA) at the Kcnn1 promoter, by HDAC isoforms in cardiomyocytes, and by the EWS::FLI1 oncofusion at GGAA microsatellites; in DRG neurons, KCNN1 mediates afterhyperpolarization currents that limit neuronal excitability and neuropathic pain; in kidney collecting duct, SK1 channels couple TRPV4-mediated Ca2+ influx to BK channel activation; and in breast cancer cells, KCNN1 interacts with ERLIN2 to stabilize Cyclin B1 via K63-linked ubiquitination, promoting proliferation and metastasis independently of its canonical channel function."},"narrative":{"mechanistic_narrative":"KCNN1 encodes SK1 (KCa2.1), a small-conductance Ca2+-activated K+ channel gated by intracellular Ca2+ through calmodulin, whose activity sets neuronal afterhyperpolarization and contributes to coordinated K+ secretion in epithelia [PMID:36583726, PMID:37012681, PMID:37741322]. Channel gating requires Ca2+-dependent conformational changes in both the N- and C-lobes of calmodulin engaging the channel's proximal C-terminal domain, with full-length calmodulin needed for full activation; isolated lobes bind but cannot rescue activity [PMID:36583726]. Activity is additionally tuned by EGFR-mediated tyrosine phosphorylation at Tyr109 in the N-terminus, which is required for normal current density [PMID:23496660]. In dorsal root ganglion neurons, KCNN1 mediates afterhyperpolarization currents that limit excitability, and its transcription is controlled by ESRRG and by SS-lncRNA acting through hnRNPM recruitment and KDM6B-dependent H3K27me3 remodeling at the Kcnn1 promoter; nerve injury downregulates KCNN1 to produce hyperexcitability and neuropathic pain, which is reversed by restoring KCNN1 [PMID:37012681, PMID:37741322, PMID:38912580]. In the connecting tubule/collecting duct, SK1 couples TRPV4-mediated Ca2+ influx to BK channel activation [PMID:28274924]. KCNN1 expression is further regulated transcriptionally by HDAC isoforms in atrial myocytes and post-transcriptionally by METTL3-mediated m6A methylation in ischemic myocardium, and its loss prolongs cardiomyocyte action potentials [PMID:34111326, PMID:40653133, PMID:35155564]. KCNN1 also has channel-independent roles in cancer: it is overexpressed downstream of the EWS::FLI1 oncofusion in Ewing sarcoma without producing functional channel activity, and in breast cancer it binds ERLIN2 to stabilize Cyclin B1 via K63-linked ubiquitination, promoting proliferation and invasion [PMID:39487324, PMID:36230742, PMID:37831636].","teleology":[{"year":1999,"claim":"Before functional study, the genomic identity of human KCNN1 was unknown; mapping the locus and exon-intron structure established the gene as a discrete entity for downstream analysis.","evidence":"Radiation hybrid mapping and gene structure analysis localizing KCNN1 to 19p13.1","pmids":["10516439"],"confidence":"Medium","gaps":["No functional or expression data","No protein-level characterization"]},{"year":2001,"claim":"It was unclear how transcript diversity could tune SK1 function; characterization of extensive alternative splicing showed that variants alter the S6 span and calmodulin-binding domain, with only a minority preserving Ca2+-independent calmodulin binding.","evidence":"Genomic cloning, RT-PCR and calmodulin-binding domain assessment in mouse","pmids":["11267657"],"confidence":"Medium","gaps":["Functional consequences of individual splice variants on channel gating not tested","Tissue distribution of variants not resolved"]},{"year":2013,"claim":"Whether KCNN1 activity is regulated beyond Ca2+/calmodulin was unknown; identification of EGFR-dependent phosphorylation at Tyr109 established a kinase input controlling channel current.","evidence":"Patch-clamp, immunoprecipitation, and Y109F mutagenesis in HEK-293 cells","pmids":["23496660"],"confidence":"High","gaps":["Whether EGFR phosphorylates KCNN1 directly versus via an intermediate not established","Physiological context of this regulation untested"]},{"year":2017,"claim":"The role of SK1 in epithelial K+ handling was undefined; pharmacological epistasis showed SK1/3 activation by TRPV4 Ca2+ influx is required to raise [Ca2+]i sufficiently to activate BK channels.","evidence":"Apamin/TRAM-34/iberiotoxin inhibition with membrane potential and Ca2+ imaging in mCCDcl1 cells","pmids":["28274924"],"confidence":"Medium","gaps":["SK1 versus SK3 contributions not separated (both apamin-sensitive)","In vivo relevance to renal K+ secretion not directly tested"]},{"year":2021,"claim":"How KCNN1 abundance is set in the heart was unknown; siRNA screening of HDAC isoforms revealed isoform-specific transcriptional control of Kcnn1 in atrial myocytes.","evidence":"Individual HDAC siRNA knockdown and tachypacing with qRT-PCR in HL-1 cells","pmids":["34111326"],"confidence":"Medium","gaps":["Direct HDAC occupancy at the Kcnn1 promoter not shown","Functional electrophysiological consequence not measured"]},{"year":2021,"claim":"The contribution of SK channels to motor neuron disease was unclear; pharmacological inhibition of upregulated SK channels in C9ORF72-ALS neurons and Drosophila mitigated degeneration, placing SK activity downstream of repeat toxicity.","evidence":"SK channel inhibition with survival/motor readouts in patient-derived neurons and Drosophila","pmids":["34376242"],"confidence":"Medium","gaps":["KCNN1-specific contribution among SK isoforms not isolated","Mechanism linking SK activity to neurodegeneration not defined"]},{"year":2022,"claim":"It was assumed elevated KCNN1 in cancer implies channel activity; electrophysiology in Ewing sarcoma cells found no functional KCa2.1 current despite high expression, uncoupling KCNN1 abundance from channel function.","evidence":"Patch-clamp (negative), RT-qPCR, and western blot in EwS cell lines","pmids":["36230742"],"confidence":"Medium","gaps":["Reason for absent channel activity (assembly, trafficking) not determined","Channel-independent function not yet identified here"]},{"year":2022,"claim":"Post-transcriptional control of KCNN1 in ischemic heart was unknown; MeRIP and METTL3 knockdown showed m6A hypermethylation downregulates KCNN1 and affects cardiomyocyte apoptosis and angiogenesis.","evidence":"MeRIP-seq/qPCR, METTL3 siRNA, and viability/apoptosis/tube-formation assays in rat MI model and cell lines","pmids":["35155564"],"confidence":"Medium","gaps":["Direct m6A reader linking methylation to KCNN1 decay not identified","Channel-dependence of the apoptosis/angiogenesis phenotype unresolved"]},{"year":2022,"claim":"The prevailing model held that calmodulin's C-lobe binds SK channels purely Ca2+-independently; reconstitution showed both lobes undergo Ca2+-dependent changes and full-length calmodulin is required for activation, revising the gating model.","evidence":"Inside-out patch-clamp with exogenous calmodulin, CG-MALS, and tryptophan emission spectroscopy on SK2/SKp","pmids":["36583726"],"confidence":"High","gaps":["Experiments performed on SK2 (KCa2.2); direct extension to SK1/KCa2.1 not shown","Structural basis of the C-lobe Ca2+-dependent transition not resolved"]},{"year":2023,"claim":"The transcriptional basis of KCNN1 loss in neuropathic pain was unknown; SS-lncRNA was shown to control Kcnn1 via hnRNPM recruitment and KDM6B/H3K27me3 remodeling, with KCNN1 loss driving hyperexcitability and pain.","evidence":"ChIP, RIP, conditional knockout/knock-in in Mrgprd+ neurons, and patch-clamp in nerve injury models","pmids":["37012681","37741322"],"confidence":"High","gaps":["How the two regulatory arms (hnRNPM activation vs KDM6B silencing) are coordinated not fully reconciled","Whether human pain involves the same axis untested"]},{"year":2023,"claim":"A channel-independent oncogenic role was unsuspected; KCNN1 was shown to bind ERLIN2 and stabilize Cyclin B1 via K63-linked ubiquitination, driving breast cancer proliferation and invasion.","evidence":"Co-IP, ubiquitination assays, and proliferation/migration/invasion assays with KCNN1/ERLIN2 epistasis in breast cancer cells","pmids":["37831636"],"confidence":"Medium","gaps":["Single Co-IP context; direct versus indirect KCNN1–ERLIN2 binding not fully resolved","The ubiquitin ligase mediating K63 linkage not identified"]},{"year":2024,"claim":"Additional transcriptional regulators of KCNN1 in pain and cancer were sought; ESRRG was shown to directly activate Kcnn1 in DRG neurons, and EWS::FLI1 to drive KCNN1 via GGAA microsatellites in Ewing sarcoma affecting the cell cycle.","evidence":"ChIP for ESRRG and EWS::FLI1 promoter binding, AAV/siRNA manipulation, electrophysiology, calcium imaging, and proliferation assays","pmids":["38912580","39487324"],"confidence":"High","gaps":["Interplay between ESRRG, SS-lncRNA and HDAC inputs at the promoter not integrated","In Ewing sarcoma, channel-versus-expression-dependent proliferation effect unresolved given prior negative current data"]},{"year":2025,"claim":"The cardiotoxicity mechanism of osimertinib and a possible neuroprotective role of KCNN1 were addressed; KCNN1 downregulation prolongs cardiomyocyte action potentials, and channel-inactive monomeric Kcnn1 overexpression extends ALS/synuclein model survival via a stress response.","evidence":"RNA-seq, optical mapping and rescue in hiPSC-cardiomyocytes/zebrafish; transgenic mouse overexpression with survival, RNAseq and immunostaining (preprint)","pmids":["40653133","bio_10.1101_2024.10.11.617887"],"confidence":"Medium","gaps":["The neuroprotective stress-induction mechanism rests on a Low-confidence preprint and lacks reconstitution or mutagenesis of the proposed misfolded state","Whether the cardiac and neuronal effects depend on channel activity not fully separated"]},{"year":null,"claim":"How the diverse transcriptional, post-transcriptional and post-translational inputs are integrated to set KCNN1 channel versus channel-independent functions in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the SK1/KCa2.1 channel-calmodulin complex","Mechanism switching KCNN1 between channel and scaffolding (ERLIN2/Cyclin B1) roles undefined","No direct E3 ligase for the K63-ubiquitination of Cyclin B1 identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[3,4,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["CALM1","EGFR","ERLIN2","HNRNPM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92952","full_name":"Small conductance calcium-activated potassium channel protein 1","aliases":["KCa2.1"],"length_aa":543,"mass_kda":60.0,"function":"Small conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening (PubMed:17142458, PubMed:8781233, PubMed:9287325). The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 3 picosiemens (PubMed:8781233). Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV (Probable). Activation is followed by membrane hyperpolarization (By similarity). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (By similarity)","subcellular_location":"Membrane; Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q92952/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNN1","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNN1","total_profiled":1310},"omim":[{"mim_id":"602983","title":"POTASSIUM CHANNEL, CALCIUM-ACTIVATED, INTERMEDIATE/SMALL CONDUCTANCE, SUBFAMILY N, MEMBER 3; KCNN3","url":"https://www.omim.org/entry/602983"},{"mim_id":"602982","title":"POTASSIUM CHANNEL, CALCIUM-ACTIVATED, INTERMEDIATE/SMALL CONDUCTANCE, SUBFAMILY N, MEMBER 1; KCNN1","url":"https://www.omim.org/entry/602982"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Actin filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":23.3}],"url":"https://www.proteinatlas.org/search/KCNN1"},"hgnc":{"alias_symbol":["KCa2.1","hSK1"],"prev_symbol":[]},"alphafold":{"accession":"Q92952","domains":[{"cath_id":"1.10.287.70","chopping":"372-493","consensus_level":"medium","plddt":90.3532,"start":372,"end":493},{"cath_id":"1.20.58","chopping":"91-204","consensus_level":"medium","plddt":91.5311,"start":91,"end":204}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92952","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92952-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92952-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNN1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNN1"},"sequence":{"accession":"Q92952","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92952.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92952/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92952"}},"corpus_meta":[{"pmid":"15347667","id":"PMC_15347667","title":"Physiological 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Insulin Synthesis and Secretion through PDX1.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37175791","citation_count":6,"is_preprint":false},{"pmid":"29412518","id":"PMC_29412518","title":"Atrium-specific ion channels in the zebrafish-A role of IKACh in atrial repolarization.","date":"2018","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29412518","citation_count":6,"is_preprint":false},{"pmid":"39487324","id":"PMC_39487324","title":"Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39487324","citation_count":5,"is_preprint":false},{"pmid":"36583726","id":"PMC_36583726","title":"Calcium dependence of both lobes of calmodulin is involved in binding to a cytoplasmic domain of SK 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Alternative splicing can alter the putative S6 transmembrane span, modify the C-terminal cytoplasmic calmodulin-binding domain, and generate alternate predicted PDZ domain-binding sites. Only four of sixteen predicted polypeptide variants preserve the ability to bind calmodulin in a Ca2+-independent manner.\",\n      \"method\": \"Genomic cloning, RT-PCR, sequence analysis, calmodulin-binding domain assessment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genomic and transcript characterization with calmodulin-binding domain analysis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11267657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human KCNN1 gene (encoding SK1 small-conductance calcium-activated potassium channel) was mapped by radiation hybrid mapping to chromosome 19p13.1, and its exon-intron gene structure was defined.\",\n      \"method\": \"Radiation hybrid mapping, gene structure analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping experiment, single lab, established gene locus\",\n      \"pmids\": [\"10516439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KCNN1 (hSKCa1) channel activity is regulated by EGFR tyrosine kinase phosphorylation at Tyr109 in the N-terminus. Inhibition of EGFR kinase (by genistein, tyrphostin T25, or AG556) reduced tyrosine phosphorylation of hSKCa1 and inhibited channel current; the Y109F mutant lost the inhibitory response to EGFR inhibitors and showed dramatically reduced tyrosine phosphorylation and current density.\",\n      \"method\": \"Whole-cell patch voltage-clamp, immunoprecipitation, Western blotting, site-directed mutagenesis (Y109F) in HEK-293 cells expressing KCNN1\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology combined with mutagenesis and biochemical phosphorylation assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23496660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Calmodulin gating of SK (KCa2.x) channels requires Ca2+-dependent conformational changes in both the N-lobe and C-lobe of calmodulin interacting with the proximal C-terminal domain (SKp) of the channel. Isolated calmodulin lobes bind SKp with high affinity but fail to rescue SK2 (KCa2.2) activity; full-length calmodulin with both lobes is required for full activation. C-lobe binding to SKp changes with Ca2+ at concentrations that activate SK2, challenging the prior model that C-lobe binding is purely Ca2+-independent.\",\n      \"method\": \"Inside-out patch-clamp recording of SK2 channels with exogenous calmodulin application; composition-gradient multi-angle light-scattering; tryptophan emission spectra for calmodulin–SKp binding\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of calmodulin binding with multiple orthogonal biophysical methods plus electrophysiology, rigorous controls including isolated lobe experiments\",\n      \"pmids\": [\"36583726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SK1 (KCNN1) and SK3 (KCNN3) channels are expressed in kidney connecting tubule/cortical collecting duct (CNT/CCD) cells and are activated by TRPV4-mediated Ca2+ influx. Early activation of SK1/3 and IK1 (KCNN4) channels is required for sufficient Ca2+ entry and intracellular Ca2+ elevation needed to activate the BK channel (KCNMA1), thereby coupling TRPV4 to BK-dependent K+ secretion.\",\n      \"method\": \"Pharmacological inhibition (apamin for SK1/3, TRAM-34 for IK1, iberiotoxin for BK) with membrane potential measurement and intracellular Ca2+ imaging in mCCDcl1 cells\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with functional readouts (membrane potential + [Ca2+]i), single lab, two complementary measurement methods\",\n      \"pmids\": [\"28274924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KCNN1 (KCa2.1) channel expression in atrial myocytes is directly regulated by histone deacetylases (HDACs). Knockdown of HDAC2, 3, 6, or 7 decreased Kcnn1 mRNA levels, while knockdown of HDAC9 enhanced Kcnn1 expression in HL-1 atrial myocytes. Tachypacing-induced downregulation of HDACs 1, 3, 4, 6, and 7 was associated with a tendency toward reduced Kcnn1 levels.\",\n      \"method\": \"siRNA knockdown of individual HDACs, tachypacing of HL-1 cells, qRT-PCR measurement of Kcnn1 mRNA\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function siRNA for multiple HDAC isoforms with defined transcriptional readout for KCNN1, single lab\",\n      \"pmids\": [\"34111326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SS-lncRNA (a sensory neuron-specific lncRNA) regulates KCNN1 expression in dorsal root ganglion (DRG) neurons through two mechanisms: (1) direct binding of SS-lncRNA to the Kcnn1 promoter and recruitment of hnRNPM to activate Kcnn1 transcription; (2) in a separate study, SS-lncRNA downregulation reduces recruitment of the histone demethylase KDM6B to the Kcnn1 promoter, increasing H3K27me3 enrichment and silencing Kcnn1. Loss of KCNN1 in DRG neurons decreased total potassium currents and afterhyperpolarization currents, increased neuronal excitability, and produced neuropathic pain symptoms.\",\n      \"method\": \"ChIP, RNA immunoprecipitation, promoter binding assays, nerve injury mouse models, patch-clamp electrophysiology, conditional knockout/knock-in of SS-lncRNA in Mrgprd+ neurons\",\n      \"journal\": \"Brain : a journal of neurology; Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, RIP, electrophysiology, conditional genetic rescue/mimicry) replicated across two independent papers from same group\",\n      \"pmids\": [\"37012681\", \"37741322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESRRG (estrogen-related receptor gamma), a transcription factor, directly binds the Kcnn1 promoter and activates its transcription in DRG neurons. Nerve injury reduces DRG ESRRG levels, which decreases ESRRG binding to the Kcnn1 promoter and downregulates KCNN1 expression, leading to reduced AHP currents, increased neuronal excitability, and neuropathic pain. Rescuing KCNN1 downregulation prevented these electrophysiological and pain phenotypes.\",\n      \"method\": \"ChIP (ESRRG binding to Kcnn1 promoter), AAV-mediated KCNN1 rescue and knockdown in DRG, patch-clamp electrophysiology, behavioral pain assays in CCI and L4 ligation nerve injury mouse models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-validated transcription factor–promoter interaction combined with in vivo genetic rescue/mimicry and direct electrophysiological readouts\",\n      \"pmids\": [\"38912580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The oncofusion protein EWS::FLI1 (and EWS::ERG) directly drives KCNN1 transcription by binding GGAA microsatellites near the KCNN1 promoter, leading to SK1 channel overexpression in Ewing sarcoma cells. KCNN1 silencing slows the cell cycle; KCNN1 expression modulates membrane potential and calcium flux, affecting cell proliferation.\",\n      \"method\": \"Bioinformatics, ChIP/promoter binding assays for EWS::FLI1 at GGAA microsatellites, siRNA knockdown of KCNN1, patch-clamp electrophysiology, calcium imaging, cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-validated direct transcription factor binding plus functional loss-of-function and electrophysiological readouts, single lab\",\n      \"pmids\": [\"39487324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Ewing sarcoma (EwS) cells, KCNN1 is overexpressed and its expression is regulated by the disease-driving oncoprotein EWSR1-FLI1. However, patch-clamp experiments showed no evidence for functional KCa2.1 channel activity in EwS cells, indicating that elevated KCNN1 mRNA/protein does not translate to functional channel activity in this context.\",\n      \"method\": \"Patch-clamp electrophysiology (negative result for functional channel), RT-qPCR, western blot, gene expression profiling in EwS cell lines\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological measurement establishing absence of functional channel activity despite elevated expression, single lab\",\n      \"pmids\": [\"36230742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KCNN1 interacts with ERLIN2 in breast cancer cells and enhances ERLIN2-mediated stabilization of Cyclin B1, promoting its K63-linked ubiquitination. Overexpression of KCNN1 increased Cyclin B1 protein stability and K63-dependent ubiquitination; knockdown had the opposite effect. ERLIN2 knockdown/overexpression partially rescued the effects of KCNN1 manipulation on Cyclin B1 and on cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, western blot, CCK8/clone formation/EdU/wound healing/transwell assays, transcriptomic analysis, KCNN1 overexpression and knockdown in breast cancer cells\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP establishing KCNN1–ERLIN2 interaction, epistasis via double knockdown/overexpression with defined functional readouts, single lab\",\n      \"pmids\": [\"37831636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Inhibition of ALS-upregulated KCNN1-3 (Drosophila SK ortholog) channels in C9ORF72-ALS patient-derived motor neurons and Drosophila motor neurons mitigates neurodegeneration and motor deficits, placing SK channel activity as a disease-modifying factor downstream of C9ORF72 repeat toxicity.\",\n      \"method\": \"Pharmacological inhibition of SK channels in C9ORF72-ALS patient-derived neurons and Drosophila motor neurons with functional (motor deficit) and cell survival readouts; genome-wide RNA analysis\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis in human patient-derived neurons and in vivo Drosophila model, single lab, multiple orthogonal systems\",\n      \"pmids\": [\"34376242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Neuronal overexpression of Kcnn1 (as a monomeric, channel-inactive subunit, because it cannot assemble without Kcnn2) extends survival in SOD1-linked ALS and A53T alpha-synuclein mouse models. The overexpressed Kcnn1 subunit is diffusely cytoplasmic (not at the plasma membrane) in motor neurons and induces a multifaceted stress response (ER stress, mitochondrial stress, integrated stress response) as assessed by RNAseq and immunostaining, suggesting that a nonassembled/potentially misfolded ER-targeted state of Kcnn1 is responsible for the neuroprotective stress induction rather than K+ channel activity.\",\n      \"method\": \"Transgenic mouse overexpression (Thy1.2-driven Kcnn1 cDNA), survival analysis, RNAseq, immunostaining for stress response markers and Kcnn1 localization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic inference (nonassembled state induces stress response) is supported by localization and RNAseq but not by direct reconstitution or mutagenesis of the proposed mechanism\",\n      \"pmids\": [\"bio_10.1101_2024.10.11.617887\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Osimertinib (third-generation EGFR inhibitor) downregulates KCNN1 protein expression in cardiomyocytes as an off-target effect, leading to prolonged action potential duration and early afterdepolarizations. Modulating KCNN1 expression reversed these electrophysiological alterations, establishing KCNN1 downregulation as a mechanistic basis for osimertinib-induced arrhythmia.\",\n      \"method\": \"RNA sequencing, qRT-PCR and western blot for KCNN1, optical mapping of action potential duration in hiPSC-derived cardiomyocytes, zebrafish in vivo model, KCNN1 rescue experiments\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA sequencing plus rescue experiments with direct electrophysiological readout, single lab, multiple complementary methods\",\n      \"pmids\": [\"40653133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KCNN1 mRNA is subject to N6-methyladenosine (m6A) hypermethylation mediated by METTL3 in myocardial infarction, which is associated with downregulated KCNN1 expression. Inhibition of METTL3 reduced m6A methylation of Kcnn1 mRNA and restored its expression. Functional validation showed that Kcnn1 expression influences apoptosis and angiogenesis in H9c2 cardiomyocytes and HUVECs under hypoxic conditions.\",\n      \"method\": \"MeRIP-seq, MeRIP-qRT-PCR, siRNA knockdown of METTL3, cell viability (CCK-8, EdU), tube formation assay, flow cytometry/TUNEL for apoptosis in rat MI model and cell lines\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq identification plus METTL3 knockdown rescue and functional cellular assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35155564\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNN1 encodes the SK1 (KCa2.1) small-conductance Ca2+-activated K+ channel, which is gated exclusively by intracellular Ca2+ through constitutive and Ca2+-dependent interactions of both calmodulin lobes with the channel's proximal C-terminal domain; channel activity is further modulated by EGFR-mediated tyrosine phosphorylation at Tyr109 in its N-terminus; transcription is regulated by ESRRG and hnRNPM (via SS-lncRNA) at the Kcnn1 promoter, by HDAC isoforms in cardiomyocytes, and by the EWS::FLI1 oncofusion at GGAA microsatellites; in DRG neurons, KCNN1 mediates afterhyperpolarization currents that limit neuronal excitability and neuropathic pain; in kidney collecting duct, SK1 channels couple TRPV4-mediated Ca2+ influx to BK channel activation; and in breast cancer cells, KCNN1 interacts with ERLIN2 to stabilize Cyclin B1 via K63-linked ubiquitination, promoting proliferation and metastasis independently of its canonical channel function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNN1 encodes SK1 (KCa2.1), a small-conductance Ca2+-activated K+ channel gated by intracellular Ca2+ through calmodulin, whose activity sets neuronal afterhyperpolarization and contributes to coordinated K+ secretion in epithelia [#3, #6]. Channel gating requires Ca2+-dependent conformational changes in both the N- and C-lobes of calmodulin engaging the channel's proximal C-terminal domain, with full-length calmodulin needed for full activation; isolated lobes bind but cannot rescue activity [#3]. Activity is additionally tuned by EGFR-mediated tyrosine phosphorylation at Tyr109 in the N-terminus, which is required for normal current density [#2]. In dorsal root ganglion neurons, KCNN1 mediates afterhyperpolarization currents that limit excitability, and its transcription is controlled by ESRRG and by SS-lncRNA acting through hnRNPM recruitment and KDM6B-dependent H3K27me3 remodeling at the Kcnn1 promoter; nerve injury downregulates KCNN1 to produce hyperexcitability and neuropathic pain, which is reversed by restoring KCNN1 [#6, #7]. In the connecting tubule/collecting duct, SK1 couples TRPV4-mediated Ca2+ influx to BK channel activation [#4]. KCNN1 expression is further regulated transcriptionally by HDAC isoforms in atrial myocytes and post-transcriptionally by METTL3-mediated m6A methylation in ischemic myocardium, and its loss prolongs cardiomyocyte action potentials [#5, #13, #14]. KCNN1 also has channel-independent roles in cancer: it is overexpressed downstream of the EWS::FLI1 oncofusion in Ewing sarcoma without producing functional channel activity, and in breast cancer it binds ERLIN2 to stabilize Cyclin B1 via K63-linked ubiquitination, promoting proliferation and invasion [#8, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Before functional study, the genomic identity of human KCNN1 was unknown; mapping the locus and exon-intron structure established the gene as a discrete entity for downstream analysis.\",\n      \"evidence\": \"Radiation hybrid mapping and gene structure analysis localizing KCNN1 to 19p13.1\",\n      \"pmids\": [\"10516439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or expression data\", \"No protein-level characterization\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"It was unclear how transcript diversity could tune SK1 function; characterization of extensive alternative splicing showed that variants alter the S6 span and calmodulin-binding domain, with only a minority preserving Ca2+-independent calmodulin binding.\",\n      \"evidence\": \"Genomic cloning, RT-PCR and calmodulin-binding domain assessment in mouse\",\n      \"pmids\": [\"11267657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of individual splice variants on channel gating not tested\", \"Tissue distribution of variants not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether KCNN1 activity is regulated beyond Ca2+/calmodulin was unknown; identification of EGFR-dependent phosphorylation at Tyr109 established a kinase input controlling channel current.\",\n      \"evidence\": \"Patch-clamp, immunoprecipitation, and Y109F mutagenesis in HEK-293 cells\",\n      \"pmids\": [\"23496660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EGFR phosphorylates KCNN1 directly versus via an intermediate not established\", \"Physiological context of this regulation untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The role of SK1 in epithelial K+ handling was undefined; pharmacological epistasis showed SK1/3 activation by TRPV4 Ca2+ influx is required to raise [Ca2+]i sufficiently to activate BK channels.\",\n      \"evidence\": \"Apamin/TRAM-34/iberiotoxin inhibition with membrane potential and Ca2+ imaging in mCCDcl1 cells\",\n      \"pmids\": [\"28274924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SK1 versus SK3 contributions not separated (both apamin-sensitive)\", \"In vivo relevance to renal K+ secretion not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How KCNN1 abundance is set in the heart was unknown; siRNA screening of HDAC isoforms revealed isoform-specific transcriptional control of Kcnn1 in atrial myocytes.\",\n      \"evidence\": \"Individual HDAC siRNA knockdown and tachypacing with qRT-PCR in HL-1 cells\",\n      \"pmids\": [\"34111326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HDAC occupancy at the Kcnn1 promoter not shown\", \"Functional electrophysiological consequence not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The contribution of SK channels to motor neuron disease was unclear; pharmacological inhibition of upregulated SK channels in C9ORF72-ALS neurons and Drosophila mitigated degeneration, placing SK activity downstream of repeat toxicity.\",\n      \"evidence\": \"SK channel inhibition with survival/motor readouts in patient-derived neurons and Drosophila\",\n      \"pmids\": [\"34376242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KCNN1-specific contribution among SK isoforms not isolated\", \"Mechanism linking SK activity to neurodegeneration not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"It was assumed elevated KCNN1 in cancer implies channel activity; electrophysiology in Ewing sarcoma cells found no functional KCa2.1 current despite high expression, uncoupling KCNN1 abundance from channel function.\",\n      \"evidence\": \"Patch-clamp (negative), RT-qPCR, and western blot in EwS cell lines\",\n      \"pmids\": [\"36230742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reason for absent channel activity (assembly, trafficking) not determined\", \"Channel-independent function not yet identified here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Post-transcriptional control of KCNN1 in ischemic heart was unknown; MeRIP and METTL3 knockdown showed m6A hypermethylation downregulates KCNN1 and affects cardiomyocyte apoptosis and angiogenesis.\",\n      \"evidence\": \"MeRIP-seq/qPCR, METTL3 siRNA, and viability/apoptosis/tube-formation assays in rat MI model and cell lines\",\n      \"pmids\": [\"35155564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A reader linking methylation to KCNN1 decay not identified\", \"Channel-dependence of the apoptosis/angiogenesis phenotype unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The prevailing model held that calmodulin's C-lobe binds SK channels purely Ca2+-independently; reconstitution showed both lobes undergo Ca2+-dependent changes and full-length calmodulin is required for activation, revising the gating model.\",\n      \"evidence\": \"Inside-out patch-clamp with exogenous calmodulin, CG-MALS, and tryptophan emission spectroscopy on SK2/SKp\",\n      \"pmids\": [\"36583726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Experiments performed on SK2 (KCa2.2); direct extension to SK1/KCa2.1 not shown\", \"Structural basis of the C-lobe Ca2+-dependent transition not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The transcriptional basis of KCNN1 loss in neuropathic pain was unknown; SS-lncRNA was shown to control Kcnn1 via hnRNPM recruitment and KDM6B/H3K27me3 remodeling, with KCNN1 loss driving hyperexcitability and pain.\",\n      \"evidence\": \"ChIP, RIP, conditional knockout/knock-in in Mrgprd+ neurons, and patch-clamp in nerve injury models\",\n      \"pmids\": [\"37012681\", \"37741322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the two regulatory arms (hnRNPM activation vs KDM6B silencing) are coordinated not fully reconciled\", \"Whether human pain involves the same axis untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A channel-independent oncogenic role was unsuspected; KCNN1 was shown to bind ERLIN2 and stabilize Cyclin B1 via K63-linked ubiquitination, driving breast cancer proliferation and invasion.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and proliferation/migration/invasion assays with KCNN1/ERLIN2 epistasis in breast cancer cells\",\n      \"pmids\": [\"37831636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP context; direct versus indirect KCNN1\\u2013ERLIN2 binding not fully resolved\", \"The ubiquitin ligase mediating K63 linkage not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional transcriptional regulators of KCNN1 in pain and cancer were sought; ESRRG was shown to directly activate Kcnn1 in DRG neurons, and EWS::FLI1 to drive KCNN1 via GGAA microsatellites in Ewing sarcoma affecting the cell cycle.\",\n      \"evidence\": \"ChIP for ESRRG and EWS::FLI1 promoter binding, AAV/siRNA manipulation, electrophysiology, calcium imaging, and proliferation assays\",\n      \"pmids\": [\"38912580\", \"39487324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between ESRRG, SS-lncRNA and HDAC inputs at the promoter not integrated\", \"In Ewing sarcoma, channel-versus-expression-dependent proliferation effect unresolved given prior negative current data\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cardiotoxicity mechanism of osimertinib and a possible neuroprotective role of KCNN1 were addressed; KCNN1 downregulation prolongs cardiomyocyte action potentials, and channel-inactive monomeric Kcnn1 overexpression extends ALS/synuclein model survival via a stress response.\",\n      \"evidence\": \"RNA-seq, optical mapping and rescue in hiPSC-cardiomyocytes/zebrafish; transgenic mouse overexpression with survival, RNAseq and immunostaining (preprint)\",\n      \"pmids\": [\"40653133\", \"bio_10.1101_2024.10.11.617887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The neuroprotective stress-induction mechanism rests on a Low-confidence preprint and lacks reconstitution or mutagenesis of the proposed misfolded state\", \"Whether the cardiac and neuronal effects depend on channel activity not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse transcriptional, post-transcriptional and post-translational inputs are integrated to set KCNN1 channel versus channel-independent functions in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the SK1/KCa2.1 channel-calmodulin complex\", \"Mechanism switching KCNN1 between channel and scaffolding (ERLIN2/Cyclin B1) roles undefined\", \"No direct E3 ligase for the K63-ubiquitination of Cyclin B1 identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"GO:0005267\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CALM1\", \"EGFR\", \"ERLIN2\", \"hnRNPM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}