title: A novel human aquaporin-4 splice variant exhibits a dominant-negative activity: a new mechanism to regulate water permeability.
abstract: Two major isoforms of aquaporin-4 (AQP4) have been described in human tissue. Here we report the identification and functional analysis of an alternatively spliced transcript of human AQP4, AQP4-Δ4, that lacks exon 4. In transfected cells AQP4-Δ4 is mainly retained in the endoplasmic reticulum and shows no water transport properties. When AQP4-Δ4 is transfected into cells stably expressing functional AQP4, the surface expression of the full-length protein is reduced. Furthermore, the water transport activity of the cotransfectants is diminished in comparison to transfectants expressing only AQP4. The observed down-regulation of both the expression and water channel activity of AQP4 is likely to originate from a dominant-negative effect caused by heterodimerization between AQP4 and AQP4-Δ4, which was detected in coimmunoprecipitation studies. In skeletal muscles, AQP4-Δ4 mRNA expression inversely correlates with the level of AQP4 protein and is physiologically associated with different types of skeletal muscles. The expression of AQP4-Δ4 may represent a new regulatory mechanism through which the cell-surface expression and therefore the activity of AQP4 can be physiologically modulated.
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutics and Center of Excellence in Comparative Genomics, University of Bari "Aldo Moro," 70126 Bari, Italy Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland M. Sarcone Hospital, 70038 Terlizzi, Bari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: De Bellis
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mola
authors.forename: Davide
authors.initials: D
authors.lastname: Basco
authors.forename: Francesco
authors.initials: F
authors.lastname: Catalano
authors.forename: Grazia Paola
authors.initials: GP
authors.lastname: Nicchia
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.forename: Antonio
authors.initials: A
authors.lastname: Frigeri
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D001692:Biological Transport; D002531:Cerebellum / Q000378:metabolism; D005091:Exons; D005625:Frontal Lobe / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression; D015723:Gene Library; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017384:Sequence Deletion; D014867:Water / Q000378:metabolism*
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D020033:Protein Isoforms; D014867:Water