Gain of function of TMEM16E/ANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia
| Autor: | Joachim Scholz-Starke, Anna Boccaccio, Eleonora Di Zanni, Antonella Gradogna |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Phospholipid scramblase Mutant Anoctamins CHO Cells Anoctamin5 medicine.disease_cause Calcium-activated chloride channels 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Cricetulus Phospholipid scrambling Cricetinae medicine Tumor Cells Cultured Animals Humans Phospholipid Transfer Proteins Molecular Biology Phosphatidylserine Phospholipids Pharmacology Membrane potential Mutation TMEM16E Cell Biology Osteogenesis Imperfecta Phenotype Molecular biology Enzyme Activation Cytosol 030104 developmental biology HEK293 Cells chemistry Gain of Function Mutation Molecular Medicine Original Article 030217 neurology & neurosurgery |
| Zdroj: | Cellular and molecular life sciences (Print. ed.) 75 (2018): 1657–1670. doi:10.1007/s00018-017-2704-9 info:cnr-pdr/source/autori:Di Zanni E, Gradogna A, Scholz-Starke J, Boccaccio A/titolo:Gain of function of TMEM16E%2FANO5 scrambling activity caused by a mutation associated with gnathodiaphyseal dysplasia/doi:10.1007%2Fs00018-017-2704-9/rivista:Cellular and molecular life sciences (Print. ed.)/anno:2018/pagina_da:1657/pagina_a:1670/intervallo_pagine:1657–1670/volume:75 Cellular and Molecular Life Sciences |
| Popis: | Mutations in the human TMEM16E (ANO5) gene are associated both with the bone disease gnathodiaphyseal dysplasia (GDD; OMIM: 166260) and muscle dystrophies (OMIM: 611307, 613319). However, the physiological function of TMEM16E has remained unclear. We show here that human TMEM16E, when overexpressed in mammalian cell lines, displayed partial plasma membrane localization and gave rise to phospholipid scrambling (PLS) as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials. While the activity of wild-type TMEM16E depended on elevated cytosolic Ca2+ levels, a mutant form carrying the GDD-causing T513I substitution showed PLS and large time-dependent ion currents even at low cytosolic Ca2+ concentrations. Contrarily, mutation of the homologous position in the Ca2+-activated Cl− channel TMEM16B paralog hardly affected its function. In summary, these data provide the first direct demonstration of Ca2+-dependent PLS activity for TMEM16E and suggest a gain-of-function phenotype related to a GDD mutation. Electronic supplementary material The online version of this article (doi:10.1007/s00018-017-2704-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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