{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T02:37:46Z","timestamp":1777603066072,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-24-00191"],"award-info":[{"award-number":["25-24-00191"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutation T226R in the Kv1.1 \u03b1-subunit of voltage-gated potassium Kv1 channels is associated with episodic ataxia type 1, severe neuromyotonia, and epilepsy. In vitro, this mutation was reported to considerably distort the functioning of homotetrameric channels Kv1.1; however, in the brain, Kv1.1 \u03b1-subunits form heterochannels predominantly associating with Kv1.2 \u03b1-subunits. Using the patch-clamp technique, fluorescent and F\u00f6rster resonance energy transfer confocal microscopy, we revealed that heterochannels Kv(1.1(T226R)-1.2)2 formed by concatemers Kv1.1(T226R)-Kv1.2 in Neuro-2a cells have significantly slower activation and deactivation rates, and their activation occurs at a much less negative membrane potential compared to channels Kv(1.1-1.2)2 formed by concatemers Kv1.1-Kv1.2. This mutation does not noticeably affect the formation of complexes between \u03b1-subunits Kv1.1 and Kv1.2, but it does induce a delayed and possibly decreased presentation of heterochannels Kv(1.1(T226R)-1.2)2 on the plasma membrane. At the same time, the T226R mutation has a much stronger negative effect on the membrane presentation of homotetrameric Kv1.1 channels. Since heterochannels Kv1.1-Kv1.2 but not homotetrameric channels Kv1.1 are present in the brain, the heterochannels bearing mutation T226R are most likely underlying the pathogenesis of the disease by decreasing the responsiveness of cells to mild membrane depolarization and, thus, increasing the excitability of neurons.<\/jats:p>","DOI":"10.3390\/ijms26199730","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T08:05:36Z","timestamp":1759824336000},"page":"9730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Properties of Heterochannels Kv(1.1-1.2)2 with Mutation T226R in the Kv1.1 Subunit"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5217-3937","authenticated-orcid":false,"given":"Anastasia A.","family":"Ignatova","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8263-3009","authenticated-orcid":false,"given":"Anastasia V.","family":"Efremenko","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis V.","family":"Abramochkin","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"},{"name":"Institute of Physiology, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5167-2112","authenticated-orcid":false,"given":"Irina","family":"Dzhumaniiazova","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan I.","family":"Shmatin","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail P.","family":"Kirpichnikov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1596-9506","authenticated-orcid":false,"given":"Alexey V.","family":"Feofanov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7216-1618","authenticated-orcid":false,"given":"Oksana V.","family":"Nekrasova","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kamaleddin, M.A. (2025). Biophysical Properties of the Membrane Influence Spike Initiation Dynamics and Neuronal Excitability: A Focus on Kv1 Channels in Myelinated Axons. Proc. R. Soc. B Biol. Sci., 292.","DOI":"10.1098\/rspb.2025.0687"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Shvetsova, A.A., Gaynullina, D.K., Tarasova, O.S., and Schubert, R. (2021). Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115413"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"34981","DOI":"10.1074\/jbc.R113.506782","article-title":"Evidence for Central Regulation of Glucose Metabolism","volume":"288","author":"Carey","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ki.2009.358","article-title":"New Molecular Players Facilitating Mg2+ Reabsorption in the Distal Convoluted Tubule","volume":"77","author":"Glaudemans","year":"2010","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1111\/j.1476-5381.2009.00362.x","article-title":"The K+ Channels KCa3.1 and Kv1.3 as Novel Targets for Asthma Therapy","volume":"157","author":"Bradding","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tao, M., Ye, W., Wu, Y., Chang, W., Liu, F., and Zhu, Y. (2025). Identification and Validation of Five Novel Protein Targets for Type 2 Diabetes Mellitus. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-97416-2"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.gim.2022.12.002","article-title":"Continuous Bayesian Variant Interpretation Accounts for Incomplete Penetrance among Mendelian Cardiac Channelopathies","volume":"25","author":"Sala","year":"2023","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Alam, K.A., Svalastoga, P., Martinez, A., Glennon, J.C., and Haavik, J. (2023). Potassium Channels in Behavioral Brain Disorders. Molecular Mechanisms and Therapeutic Potential: A Narrative Review. Neurosci. Biobehav. Rev., 152.","DOI":"10.1016\/j.neubiorev.2023.105301"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Villa, C., and Combi, R. (2016). Potassium Channels and Human Epileptic Phenotypes: An Updated Overview. Front. Cell. Neurosci., 10.","DOI":"10.3389\/fncel.2016.00081"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zheng, Y., and Chen, J. (2024). Voltage-Gated Potassium Channels and Genetic Epilepsy. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1466075"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Paulhus, K., Ammerman, L., and Glasscock, E. (2020). Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082802"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Paulhus, K., and Glasscock, E. (2023). Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202304.1118.v1"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"D\u2019adamo, M.C., Liantonio, A., Rolland, J.F., Pessia, M., and Imbrici, P. (2020). Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082935"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1002\/j.2040-4603.2012.tb00452.x","article-title":"K+ Channels: Function-Structural Overview","volume":"2","author":"Gonzalez","year":"2012","journal-title":"Compr. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1471-4159.1999.0730849.x","article-title":"Subunit Composition of Kv1 Channels in Human CNS","volume":"73","author":"Coleman","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1021\/bi00173a001","article-title":"Antibodies Specific for Distinct Kv Subunits Unveil a HeteroOligomeric Basis for Subtypes of \u03b1-Dendrotoxin-Sensitive K+ Channels in Bovine Brain","volume":"33","author":"Scott","year":"1994","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/365075a0","article-title":"Heteromultimeric K+ Channels in Terminal and Juxtaparanodal Regions of Neurons","volume":"365","author":"Wang","year":"1993","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14329","DOI":"10.1523\/JNEUROSCI.4833-08.2008","article-title":"Cell-Type-Dependent Molecular Composition of the Axon Initial Segment","volume":"28","author":"Lorincz","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pinatel, D., and Faivre-Sarrailh, C. (2020). Assembly and Function of the Juxtaparanodal Kv1 Complex in Health and Disease. Life, 11.","DOI":"10.3390\/life11010008"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.pharmthera.2016.01.005","article-title":"Distinctive Role of KV1.1 Subunit in the Biology and Functions of Low Threshold K(+) Channels with Implications for Neurological Disease","volume":"159","author":"Ovsepian","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.nbd.2013.02.009","article-title":"Loss of the Kv1.1 Potassium Channel Promotes Pathologic Sharp Waves and High Frequency Oscillations in in Vitro Hippocampal Slices","volume":"54","author":"Simeone","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S0896-6273(00)81018-1","article-title":"Deletion of the K(v)1.1 Potassium Channel Causes Epilepsy in Mice","volume":"20","author":"Smart","year":"1998","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bagchi, B., Al-Sabi, A., Kaza, S., Scholz, D., O\u2019Leary, V.B., Dolly, J.O., and Ovsepian, S.V. (2014). Disruption of Myelin Leads to Ectopic Expression of K(V)1.1 Channels with Abnormal Conductivity of Optic Nerve Axons in a Cuprizone-Induced Model of Demyelination. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087736"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1093\/brain\/122.5.817","article-title":"A Novel Mutation in the Human Voltage-Gated Potassium Channel Gene (Kv1.1) Associates with Episodic Ataxia Type 1 and Sometimes with Partial Epilepsy","volume":"122","author":"Zuberi","year":"1999","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s004390050722","article-title":"Three Novel KCNA1 Mutations in Episodic Ataxia Type I Families","volume":"102","author":"Scheffer","year":"1998","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/ana.410400422","article-title":"Episodic Ataxia and Myokymia Syndrome: A New Mutation of Potassium Channel Gene Kv1.1","volume":"40","author":"Giuliani","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s10048-006-0071-z","article-title":"Functional Analysis of a Novel Potassium Channel (KCNA1) Mutation in Hereditary Myokymia","volume":"8","author":"Chen","year":"2007","journal-title":"Neurogenetics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.nmd.2004.06.007","article-title":"Expanding the Phenotype of Potassium Channelopathy: Severe Neuromyotonia and Skeletal Deformities without Prominent Episodic Ataxia","volume":"14","author":"Kinali","year":"2004","journal-title":"Neuromuscul. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s10048-015-0460-2","article-title":"Clinical Heterogeneity Associated with KCNA1 Mutations Include Cataplexy and Nonataxic Presentations","volume":"17","author":"Brownstein","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1113\/jphysiol.2001.013242","article-title":"Variable K(+) Channel Subunit Dysfunction in Inherited Mutations of KCNA1","volume":"538","author":"Rea","year":"2002","journal-title":"J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/j.1749-6632.1999.tb11310.x","article-title":"Functional Characterization of a Novel Mutation in KCNA1 in Episodic Ataxia Type 1 Associated with Epilepsy","volume":"868","author":"Spauschus","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Efremenko, A.V., Kryukova, E.V., Kazakov, O.V., Ignatova, A.A., Shmatin, I.I., Korabeynikova, V.N., Toporova, V.A., Yakimov, S.A., Kirpichnikov, M.P., and Nekrasova, O.V. (2025). Heterochannels Kv(1.1-1.2)2 and Their Interactions with Pore Blockers. Cells, 14.","DOI":"10.3390\/cells14171364"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Orlov, N.A., Kryukova, E.V., Efremenko, A.V., Yakimov, S.A., Toporova, V.A., Kirpichnikov, M.P., Nekrasova, O.V., and Feofanov, A.V. (2023). Interactions of the Kv1.1 Channel with Peptide Pore Blockers: A Fluorescent Analysis on Mammalian Cells. Membranes, 13.","DOI":"10.3390\/membranes13070645"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1134\/S0006350925700095","article-title":"Formation of Heterotetrameric Potassium Channels Kv1.1\u2013Kv1.2 in Neuro-2A Cells: Analysis by the F\u00f6rster Resonance Energy Transfer Technique","volume":"70","author":"Efremenko","year":"2025","journal-title":"Biophysics"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ignatova, A.A., Kryukova, E.V., Novoseletsky, V.N., Kazakov, O.V., Orlov, N.A., Korabeynikova, V.N., Larina, M.V., Fradkov, A.F., Yakimov, S.A., and Kirpichnikov, M.P. (2024). New High-Affinity Peptide Ligands for Kv1.2 Channel: Selective Blockers and Fluorescent Probes. Cells, 13.","DOI":"10.3390\/cells13242096"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Capera, J., Serrano-Novillo, C., Navarro-P\u00e9rez, M., Cassinelli, S., and Felipe, A. (2019). The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030734"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14055","DOI":"10.1073\/pnas.241403898","article-title":"Identification of a Trafficking Determinant Localized to the Kv1 Potassium Channel Pore","volume":"98","author":"Manganas","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39419","DOI":"10.1074\/jbc.M107399200","article-title":"Determinants Involved in Kv1 Potassium Channel Folding in the Endoplasmic Reticulum, Glycosylation in the Golgi, and Cell Surface Expression","volume":"276","author":"Zhu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Orlov, N.A., Ignatova, A.A., Kryukova, E.V., Yakimov, S.A., Kirpichnikov, M.P., Nekrasova, O.V., and Feofanov, A.V. (2022). Combining MKate2-Kv1.3 Channel and Atto488-Hongotoxin for the Studies of Peptide Pore Blockers on Living Eukaryotic Cells. Toxins, 14.","DOI":"10.3390\/toxins14120858"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T08:10:38Z","timestamp":1759824638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,6]]},"references-count":39,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199730"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199730","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,6]]}}}