Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport

Manuela De Bellis, Francesco Pisani, Maria Grazia Mola, Stefania Rosito, Laura Simone, Cinzia Buccoliero, Maria Trojano, Grazia Paola Nicchia, Maria Svelto, Antonio Frigeri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)790-803
Number of pages14
JournalGLIA
Volume65
Issue number5
DOIs
Publication statusPublished - May 1 2017

Keywords

  • aquaporin-4
  • astrocyte polarization
  • orthogonal arrays of particles
  • post-transcriptional regulation
  • translational readthrough
  • water transport regulation

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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