2021
An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel
Urrutia J, Aguado A, Gomis-Perez C, Muguruza-Montero A, Ballesteros OR, Zhang J, Nuñez E, Malo C, Chung HJ, Leonardo A, Bergara A, Villarroel A. An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel. BMC Biology 2021, 19: 109. PMID: 34020651, PMCID: PMC8138981, DOI: 10.1186/s12915-021-01040-1.Peer-Reviewed Original ResearchConceptsKv7.2 channelsChannel functionSequences of proteinsNon-native configurationsNascent chainsProper foldingEpilepsy-causing mutationsIQ motifResponsive domainHuman diseasesHelix ANative conformationFolding routeIon channelsKCNQ2 geneMutationsNeuronal compartmentsFoldingMisfoldingProteinKey pathogenic mechanismsPathogenic variantsSilico studiesPathogenic mechanismsSide chains
2018
Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy
Gomis‐Pérez C, Urrutia J, Marcé‐Grau A, Malo C, López‐Laso E, Felipe‐Rucián A, Raspall‐Chaure M, Macaya A, Villarroel A. Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy. Epilepsia 2018, 60: 139-148. PMID: 30478917, DOI: 10.1111/epi.14609.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBrain DiseasesChildChild, PreschoolEpilepsy, GeneralizedFemaleHumansInfantKCNQ2 Potassium ChannelMalePedigreeProtein Structure, SecondaryConceptsKv7.2 channelsDe novo mutantsWild type Kv7.2Dominant-negative behaviorGenotype-phenotype relationshipsGenetic balanceBisphosphate depletionMutantsHomomeric channelsDNA ratioSubunitsKv7.3 subunitsKv7.2Kv7.3Milder phenotypeMutationsM-currentKCNQ2Common featureNeuronal connectionsRescueKv7.2/Kv7.3 channelsPhenotypeKv7.3 channelsCellsStructural basis and energy landscape for the Ca2+ gating and calmodulation of the Kv7.2 K+ channel
Bernardo-Seisdedos G, Nuñez E, Gomis-Perez C, Malo C, Villarroel Á, Millet O. Structural basis and energy landscape for the Ca2+ gating and calmodulation of the Kv7.2 K+ channel. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 2395-2400. PMID: 29463698, PMCID: PMC5873240, DOI: 10.1073/pnas.1800235115.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCalmodulinCattleHEK293 CellsHumansKCNQ2 Potassium ChannelProtein ConformationStatic ElectricityThermodynamicsConceptsC-lobeKey biological signalsPrincipal molecular componentsAssociation of helicesTransmembrane regionStructural basisFunction of CaKv7.2 channelsBasal cytosolic CaConformational rearrangementsN-lobeInactive stateKey controllerMolecular componentsCytosolic CaIntracellular CaKv7.2HelixInactive channelsM-currentBiological signalsCalcification stateMillisecond timeNeuronal excitabilityPopulated excited statesLack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants
Alaimo A, Etxeberria A, Gómez-Posada JC, Gomis-Perez C, Fernández-Orth J, Malo C, Villarroel A. Lack of correlation between surface expression and currents in epileptogenic AB-calmodulin binding domain Kv7.2 potassium channel mutants. Channels 2018, 12: 299-310. PMID: 30126342, PMCID: PMC6161613, DOI: 10.1080/19336950.2018.1511512.Peer-Reviewed Original ResearchAnimalsCalmodulinHEK293 CellsHumansKCNQ2 Potassium ChannelProtein BindingProtein DomainsSurface PropertiesXenopus
2017
Calmodulin confers calcium sensitivity to the stability of the distal intracellular assembly domain of Kv7.2 channels
Alaimo A, Nuñez E, Aivar P, Fernández-Orth J, Gomis-Perez C, Bernardo-Seisdedos G, Malo C, Villarroel A. Calmodulin confers calcium sensitivity to the stability of the distal intracellular assembly domain of Kv7.2 channels. Scientific Reports 2017, 7: 13425. PMID: 29044210, PMCID: PMC5647379, DOI: 10.1038/s41598-017-13811-4.Peer-Reviewed Original ResearchBinding SitesCalciumCalmodulinHEK293 CellsHumansKCNQ2 Potassium ChannelProtein BindingProtein Multimerization
2016
Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3)*
Anta B, Martín-Rodríguez C, Gomis-Perez C, Calvo L, López-Benito S, Calderón-García AA, Vicente-García C, Villarroel Á, Arévalo JC. Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3)*. Journal Of Biological Chemistry 2016, 291: 19132-19145. PMID: 27445338, PMCID: PMC5009282, DOI: 10.1074/jbc.m116.722637.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationEndosomal Sorting Complexes Required for TransportGene Expression RegulationHEK293 CellsHumansKCNQ2 Potassium ChannelKCNQ3 Potassium ChannelMiceNedd4 Ubiquitin Protein LigasesNeural Stem CellsPC12 CellsProtein BindingRatsReceptor, trkAUbiquitin ThiolesteraseUbiquitin-Protein LigasesConceptsNedd4-2Association of TrkAE3 ubiquitin ligasesTrkA ubiquitinationPC12 cell differentiationTrkA neurotrophin receptorTrkA activationNeuronal precursor cellsUbiquitin ligasesExpression disruptsChannel regulationUbiquitinationUSP36Cell differentiationImportant regulatorPrecursor cellsComplex formationActivation kineticsNeurotrophin receptors TrkAReceptor TrkATrkARegulationExpressionLigasesNeurotrophin receptor
2015
Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation
Alberdi A, Gomis-Perez C, Bernardo-Seisdedos G, Alaimo A, Malo C, Aldaregia J, Lopez-Robles C, Areso P, Butz E, Wahl-Schott C, Villarroel A. Uncoupling PIP2-calmodulin regulation of Kv7.2 channels by an assembly destabilizing epileptogenic mutation. Journal Of Cell Science 2015, 128: 4014-4023. PMID: 26359296, DOI: 10.1242/jcs.176420.Peer-Reviewed Original ResearchCalmodulinCell LineHumansKCNQ2 Potassium ChannelMutationPhosphatidylinositol 4,5-DiphosphateProtein BindingAn unconventional calmodulin-anchoring site within the AB module of Kv7.2 channels
Gomis-Perez C, Alaimo A, Fernandez-Orth J, Alberdi A, Aivar-Mateo P, Bernardo-Seisdedos G, Malo C, Areso P, Felipe A, Villarroel A. An unconventional calmodulin-anchoring site within the AB module of Kv7.2 channels. Journal Of Cell Science 2015, 128: 3155-3163. PMID: 26148514, DOI: 10.1242/jcs.174128.Peer-Reviewed Original Research
2014
Pivoting between Calmodulin Lobes Triggered by Calcium in the Kv7.2/Calmodulin Complex
Alaimo A, Alberdi A, Gomis-Perez C, Fernández-Orth J, Bernardo-Seisdedos G, Malo C, Millet O, Areso P, Villarroel A. Pivoting between Calmodulin Lobes Triggered by Calcium in the Kv7.2/Calmodulin Complex. PLOS ONE 2014, 9: e86711. PMID: 24489773, PMCID: PMC3904923, DOI: 10.1371/journal.pone.0086711.Peer-Reviewed Original ResearchConceptsC-lobeC-terminal segmentPrincipal molecular componentsAssociation of CaMChannel traffickingKv7.2 channelsMolecular mechanismsMolecular eventsEndoplasmic reticulumN-lobeMolecular componentsHelix BCalmodulin complexHelix A.CalmodulinData highlightKv7.2Calmodulin lobesM channelsComplementary approachesNeuronal excitabilityFluorometric assayTraffickingReporterReticulum
2012
Cooperativity between calmodulin-binding sites in Kv7.2 channels
Alaimo A, Alberdi A, Gomis-Perez C, Fernández-Orth J, Gómez-Posada JC, Areso P, Villarroel A. Cooperativity between calmodulin-binding sites in Kv7.2 channels. Journal Of Cell Science 2012, 126: 244-253. PMID: 23203804, DOI: 10.1242/jcs.114082.Peer-Reviewed Original ResearchSurface Expression and Subunit Specific Control of Steady Protein Levels by the Kv7.2 Helix A-B Linker
Aivar P, Fernández-Orth J, Gomis-Perez C, Alberdi A, Alaimo A, Rodríguez MS, Giraldez T, Miranda P, Areso P, Villarroel A. Surface Expression and Subunit Specific Control of Steady Protein Levels by the Kv7.2 Helix A-B Linker. PLOS ONE 2012, 7: e47263. PMID: 23115641, PMCID: PMC3480381, DOI: 10.1371/journal.pone.0047263.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsHEK293 CellsHumansKCNQ2 Potassium ChannelMicroscopy, ConfocalMolecular Sequence DataPatch-Clamp TechniquesXenopusConceptsB linkerPlasma membraneHelix ATetrameric channel assemblyIntracellular C-terminusAmino acid sequenceSteady-state amountsSurface expressionSteady-state levelsProtein degradationAcid sequenceC-terminusChannel assemblyFunctional channelsIntracellular distributionProtein levelsProteinSpecific controlKv7.2Detectable impactM-currentExpressionNeuronal excitabilityMembraneIntrinsic signals