{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:20:14Z","timestamp":1789086014487,"version":"build-2803163510"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL148609"],"award-info":[{"award-number":["R01HL148609"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Introduction<\/jats:title>\n Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We show that\n Kcnj8<\/jats:italic>\n , which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (K\n ATP<\/jats:sub>\n ) channel, is highly expressed in murine splenic and uterine NK cells compared to other K\n +<\/jats:sup>\n channels previously identified in NK cells.\n Kcnj8<\/jats:italic>\n expression is highest in the most mature subset of splenic NK cells (CD27\n -<\/jats:sup>\n \/CD11b\n +<\/jats:sup>\n ) and in NKG2A\n +<\/jats:sup>\n or Ly49C\/I\n +<\/jats:sup>\n educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A.\n Kcnj8<\/jats:italic>\n does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells\n in vivo<\/jats:italic>\n , or IFN-\u03b3 release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27\n -<\/jats:sup>\n \/CD11b\n +<\/jats:sup>\n NK cells deficient for\n Kcnj8<\/jats:italic>\n . Indeed, we found that mice with NK-cell specific\n Kcnj8<\/jats:italic>\n gene ablation have fewer CD27\n -<\/jats:sup>\n \/CD11b\n +<\/jats:sup>\n and KLRG-1\n +<\/jats:sup>\n NK cells in the bone barrow and spleen.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n These results show that the K\n ATP<\/jats:sub>\n subunit Kir6.1 has a key role in NK-cell development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1490250","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:10:28Z","timestamp":1733098228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development"],"prefix":"10.3389","volume":"15","author":[{"given":"Natalie","family":"Samper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilja","family":"Hardardottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine M.","family":"Depierreux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soomin C.","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayano","family":"Nakazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Gando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoe Y.","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Sharkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla R.","family":"Nowosad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Feske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Colucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Coetzee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1359-6101(01)00038-7","article-title":"The roles of IFN gamma in protection against tumor development and cancer immunoediting","volume":"13","author":"Ikeda","year":"2002","journal-title":"Cytokine Growth Factor Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00739-z","article-title":"Biology and pathology of the uterine microenvironment and its natural killer cells","volume":"18","author":"Wang","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01869","article-title":"Natural killer cells: development, maturation, and clinical utilization","volume":"9","author":"Abel","year":"2018","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/imm.2017.152.issue-4","article-title":"Killer-cell immunoglobulin-like receptors on the cusp of modern immunogenetics","volume":"152","author":"Colucci","year":"2017","journal-title":"Immunology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni0902-807","article-title":"Natural killer cell activation in mice and men: different triggers for similar weapons","volume":"3","author":"Colucci","year":"2002","journal-title":"Nat Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.06.013","article-title":"Human NK cell education by inhibitory receptors for MHC class I","volume":"25","author":"Anfossi","year":"2006","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaw8014","article-title":"Eye on ion channels in immune cells","volume":"12","author":"Feske","year":"2019","journal-title":"Sci Signal"},{"key":"B8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1146\/annurev-immunol-032414-112212","article-title":"Ion channels in innate and adaptive immunity","volume":"33","author":"Feske","year":"2015","journal-title":"Annu Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0192-0561(85)90079-7","article-title":"Effect of cations and cation channel blockers on human natural killer cells","volume":"7","author":"Huwyler","year":"1985","journal-title":"Int J Immunopharmacol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.2.451","article-title":"Potassium channels mediate killing by human natural killer cells","volume":"83","author":"Schlichter","year":"1986","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.137.5.1650","article-title":"Potassium channels in human NK cells are involved in discrete stages of the killing process","volume":"137","author":"Sidell","year":"1986","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1085\/jgp.89.3.379","article-title":"Two types of potassium channels in murine T lymphocytes","volume":"89","author":"Decoursey","year":"1987","journal-title":"J Gen Physiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.13.040195.003203","article-title":"Potassium and calcium channels in lymphocytes","volume":"13","author":"Lewis","year":"1995","journal-title":"Annu Rev Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e76740","DOI":"10.1371\/journal.pone.0076740","article-title":"Blocking KCa3.1 channels increases tumor cell killing by a subpopulation of human natural killer lymphocytes","volume":"8","author":"Koshy","year":"2013","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/cells12162065","article-title":"Reduction of ca(2+) entry by a specific block of KCa3.1 channels optimizes cytotoxic activity of NK cells against T-ALL jurkat cells","volume":"12","author":"Olivas-Aguirre","year":"2023","journal-title":"Cells"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445208","article-title":"The two-pore domain K2 P channel TASK2 drives human NK-cell proliferation and cytolytic function","volume":"45","author":"Schulte-Mecklenbeck","year":"2015","journal-title":"Eur J Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e0151031","DOI":"10.1371\/journal.pone.0151031","article-title":"NK cells respond to haptens by the activation of calcium permeable plasma membrane channels","volume":"11","author":"Grandclement","year":"2016","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12882","article-title":"Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome\/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels","volume":"187","author":"Nguyen","year":"2017","journal-title":"Clin Exp Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12865-019-0293-0","article-title":"Identification and characterisation of transient receptor potential melastatin 2 and CD38 channels on natural killer cells using the novel application of flow cytometry","volume":"20","author":"Balinas","year":"2019","journal-title":"BMC Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013285108","article-title":"ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis","volume":"108","author":"Maul-Pavicic","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B21","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1152\/physrev.00003.2015","article-title":"KATP channels in the cardiovascular system","volume":"96","author":"Foster","year":"2016","journal-title":"Physiol Rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c170048","article-title":"ATP-sensitive potassium channels and their physiological and pathophysiological roles","volume":"8","author":"Tinker","year":"2018","journal-title":"Compr Physiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/0014-5793(87)80103-5","article-title":"ATP-sensitive K+ channels in human isolated pancreatic B-cells","volume":"215","author":"Ashcroft","year":"1987","journal-title":"FEBS Lett"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.24149","article-title":"Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating","volume":"6","author":"Martin","year":"2017","journal-title":"eLife"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109441118","article-title":"Vascular K(ATP) channel structural dynamics reveal regulatory mechanism by Mg-nucleotides","volume":"118","author":"Sung","year":"2021","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160726","article-title":"Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection","volume":"213","author":"Nabekura","year":"2016","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112064108","article-title":"Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor","volume":"108","author":"Narni-Mancinelli","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e90","DOI":"10.1002\/cpz1.v1.3","article-title":"Gene set knowledge discovery with enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr Protoc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3791\/62670-v","article-title":"Isolation of uterine innate lymphoid cells for analysis by flow cytometry","volume":"176","author":"Depierreux","year":"2021","journal-title":"J Vis Exp"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1093381","article-title":"Transcriptional reprogramming of natural killer cells by vaccinia virus shows both distinct and conserved features with mCMV","volume":"14","author":"Depierreux","year":"2023","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"5446","DOI":"10.1038\/s41467-021-25758-2","article-title":"Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","first-page":"eabe5380","DOI":"10.1126\/scisignal.abe5380","article-title":"Dynamic variability in SHP-1 abundance determines natural killer cell responsiveness","volume":"14","author":"Wu","year":"2021","journal-title":"Sci Signal"},{"key":"B34","doi-asserted-by":"publisher","first-page":"eabq0752","DOI":"10.1126\/scisignal.abq0752","article-title":"SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency","volume":"16","author":"Schmied","year":"2023","journal-title":"Sci Signal"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705670","article-title":"Molecular analysis of the subtype-selective inhibition of cloned KATP channels by PNU-37883A","volume":"141","author":"Kovalev","year":"2004","journal-title":"Br J Pharmacol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705228","article-title":"Different molecular sites of action for the KATP channel inhibitors, PNU-99963 and PNU-37883A","volume":"139","author":"Cui","year":"2003","journal-title":"Br J Pharmacol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3769590","DOI":"10.1155\/2016\/3769590","article-title":"A modified NK cell degranulation assay applicable for routine evaluation of NK cell function","volume":"2016","author":"Shabrish","year":"2016","journal-title":"J Immunol Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/35093109","article-title":"Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity","volume":"413","author":"Diefenbach","year":"2001","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5377","article-title":"Cutting edge: tumor rejection mediated by NKG2D receptor-ligand interaction is dependent upon perforin","volume":"169","author":"Hayakawa","year":"2002","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2014","article-title":"Store-operated calcium channels","volume":"95","author":"Prakriya","year":"2015","journal-title":"Physiol Rev"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.5.2648","article-title":"Differentiation of NK1.1+, Ly49+ NK cells from flt3+ multipotent marrow progenitor cells","volume":"163","author":"Williams","year":"1999","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.11.6336","article-title":"Requirement for membrane lymphotoxin in natural killer cell development","volume":"96","author":"Iizuka","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.3.984.003k40_984_991","article-title":"The receptor tyrosine kinase c-kit provides a critical signal for survival, expansion, and maturation of mouse natural killer cells","volume":"95","author":"Colucci","year":"2000","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3363","DOI":"10.1038\/srep03363","article-title":"Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection","volume":"3","author":"Kewcharoenwong","year":"2013","journal-title":"Sci Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciq192","article-title":"Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis","volume":"52","author":"Koh","year":"2011","journal-title":"Clin Infect Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6349com","article-title":"Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia","volume":"20","author":"Kane","year":"2006","journal-title":"FASEB J"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2007.25","article-title":"ATP-sensitive potassium channels mediate survival during infection in mammals and insects","volume":"39","author":"Croker","year":"2007","journal-title":"Nat Genet"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1805757115","article-title":"Kv2 potassium channels form endoplasmic reticulum\/plasma membrane junctions via interaction with VAPA and VAPB","volume":"115","author":"Johnson","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1359-0","article-title":"MaxiK channel and cell signalling","volume":"466","author":"Toro","year":"2014","journal-title":"Pflugers Arch"},{"key":"B50","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1146\/annurev-physiol-021014-071846","article-title":"Sodium channel beta subunits: emerging targets in channelopathies","volume":"77","author":"O\u2019Malley","year":"2015","journal-title":"Annu Rev Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(87)90462-X","article-title":"Studies on the calcium dependence of human NK cell killing","volume":"36","author":"Ng","year":"1987","journal-title":"Biochem Pharmacol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.150.7.2620","article-title":"Calcium oscillations in human T and natural killer cells depend upon membrane potential and calcium influx","volume":"150","author":"Hess","year":"1993","journal-title":"J Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"11171","DOI":"10.1038\/ncomms11171","article-title":"GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate","volume":"7","author":"Van de Walle","year":"2016","journal-title":"Nat Commun"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1117320","article-title":"The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56(bright) NK cells","volume":"14","author":"Ziegler","year":"2023","journal-title":"Front Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/eji.2015.45.issue-10","article-title":"TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals","volume":"45","author":"Wang","year":"2015","journal-title":"Eur J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0132-0","article-title":"Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity","volume":"19","author":"Zhang","year":"2018","journal-title":"Nat Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007502","article-title":"Knockout of the inhibitory receptor TIGIT enhances the antitumor response of ex vivo expanded NK cells and prevents fratricide with therapeutic Fc-active TIGIT antibodies","volume":"11","author":"Hasan","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2017.04.001","article-title":"Contribution of inhibitory receptor TIGIT to NK cell education","volume":"81","author":"He","year":"2017","journal-title":"J Autoimmun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1490250\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:10:32Z","timestamp":1733098232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1490250\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2024.1490250"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1490250","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.08.14.608003","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"article-number":"1490250"}}