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dc.contributor.authorGomis-Perez, Carolina-
dc.contributor.authorSoldovieri, Maria V.-
dc.contributor.authorMalo, Covadonga-
dc.contributor.authorAmbrosino, Paolo-
dc.contributor.authorTaglialatela, Maurizio-
dc.contributor.authorAreso, Pilar-
dc.contributor.authorVillarroel, Alvaro-
dc.identifier.citationFrontiers in Molecular Neuroscience 10: 117 (2017)-
dc.description.abstractHIGHLIGHTS- Calmodulin-dependent Kv7.2 current density without the need of binding calcium.- Kv7.2 current density increase is accompanied with resistance to PI(4,5)P2 depletion.- Kv7.3 current density is insensitive to calmodulin elevation.- Kv7.3 is more sensitive to PI(4,5)P2 depletion in the presence of calmodulin.- Apo-calmodulin influences PI(4,5)P2 dependence in a subunit specific manner.The identification and understanding of critical factors regulating M-current functional density, whose main components are Kv7.2 and Kv7.3 subunits, has profound pathophysiological impact given the important role of the M-current in neuronal excitability control. We report the increase in current density of Kv7.2 channels by calmodulin (CaM) and by a mutant CaM unable to bind Ca2+ (CaM1234) revealing that this potentiation is calcium independent. Furthermore, after co-expressing a CaM binding protein (CaM sponge) to reduce CaM cellular availability, Kv7.2 current density was reduced. Current inhibition after transient depletion of the essential Kv7 co-factor phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) by activating Danio rerio voltage sensitive phosphatase (DrVSP) was blunted by co-expressing CaM1234 or the CaM sponge. In addition, CaM-dependent potentiation was occluded by tonic elevation of PI(4,5)P2 levels by PI(4)P5-kinase (PIP5K) expression. In contrast to the effect on homomeric Kv7.2 channels, CaM1234 failed to potentiate heteromeric Kv7.2/3 or homomeric Kv7.3 channels. Sensitivity to PI(4,5)P2 depletion of Kv7.2/3 channels was increased after expression of CaM1234 or the CaM sponge, while that of homomeric Kv7.3 was unaltered. Altogether, the data reveal that apo-CaM influences PI(4,5)P2 dependence of Kv7.2, Kv7.2/3, and of Kv7.3 channels in a subunit specific manner.-
dc.description.sponsorshipThis work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-66910-R). CM. was funded by the Spanish Ministry of Economy and Competitiveness (PTA2012) and co-financed by the BERC program of the Basque Government. MT was an Ikerbasque Visiting Professor funded by the Basque Government, and work in MT laboratories was supported by Telethon (GGP15113).-
dc.publisherFrontiers Media-
dc.relation.isversionofPublisher's version-
dc.titleDifferential Regulation of PI(4,5)P2 Sensitivity of Kv7.2 and Kv7.3 Channels by Calmodulin-
dc.description.peerreviewedPeer reviewed-
dc.description.versionPeer Reviewed-
dc.rights.holderCopyright © 2017 Gomis-Perez, Soldovieri, Malo, Ambrosino, Taglialatela, Areso and Villarroel.-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderEusko Jaurlaritza-
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