title: Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport.
abstract: Regulation of water homeostasis is a central feature of central nervous system pathophysiology. In this context, several lines of evidence suggest a crucial role for the water channel aquaporin-4 (AQP4) and its plasma membrane supramolecular organization as the key element. Here, we demonstrate the expression in tissues of additional isoforms of AQP4 characterized by a C-terminal extension generated by programmed translational readthrough. These extended isoforms (AQP4ex) display a perivascular polarization and expression in dystrophin-dependent pools. AQP4ex reduces supramolecular clustering tendency and allows AQP4 interactions with syntrophin. Furthermore, site-directed mutagenesis of two serines in the extended C-terminus of AQP4ex showed potential regulation of water permeability by phosphorylation. Finally, AQP4ex expression can be positively modulated by gentamicin treatment, demonstrating the possibility of regulating the AQP4 translational readthrough frequency. This novel regulatory mechanism could have important pathophysiological implications for conditions in which alternations have been reported in AQP4 structure.
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: De Bellis
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mola
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rosito
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.|IRCCS "Casa Sollievo della Sofferenza", Research Hospital, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Simone
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Buccoliero
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.|Dominick P. Purpura Department of Neuroscience, 840 Kennedy Center, Bronx, New York.
authors.forename: Grazia Paola
authors.initials: GP
authors.lastname: Nicchia
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutic and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.|Dominick P. Purpura Department of Neuroscience, 840 Kennedy Center, Bronx, New York.
authors.forename: Antonio
authors.identifier: 0000-0002-5284-2934
authors.initials: A
authors.lastname: Frigeri
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009457:Neuroglia / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D014867:Water / Q000378:metabolism*
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D014867:Water
keywords: aquaporin-4; astrocyte polarization; orthogonal arrays of particles; post-transcriptional regulation; translational readthrough; water transport regulation