TY - JOUR
T1 - Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport
AU - De Bellis, Manuela
AU - Pisani, Francesco
AU - Mola, Maria Grazia
AU - Rosito, Stefania
AU - Simone, Laura
AU - Buccoliero, Cinzia
AU - Trojano, Maria
AU - Nicchia, Grazia Paola
AU - Svelto, Maria
AU - Frigeri, Antonio
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - aquaporin-4
KW - astrocyte polarization
KW - orthogonal arrays of particles
KW - post-transcriptional regulation
KW - translational readthrough
KW - water transport regulation
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UR - http://www.scopus.com/inward/citedby.url?scp=85013277050&partnerID=8YFLogxK
U2 - 10.1002/glia.23126
DO - 10.1002/glia.23126
M3 - Article
AN - SCOPUS:85013277050
VL - 65
SP - 790
EP - 803
JO - GLIA
JF - GLIA
SN - 0894-1491
IS - 5
ER -