Abstract

Members of the TMEM16 or anoctamin membrane protein family are involved in a variety of functions that include ion transport, phospholipid scrambling and regulation of other membrane proteins. In particular, TMEM16A, 16B and 16F have a clear plasma membrane localization but while 16A and 16B work as ‘pure’ ion channels, TMEM16F shows both ion channel and scramblase activities. Recent data suggest that also TMEM16E, the closest relative of TMEM16F, may work as a phospholipid scramblase, although a direct confirmation is missing. TMEM16E is highly expressed in bone tissue and skeletal muscle and different mutations in the human TMEM16E (ANO5) gene are associated with the bone disease gnathodiaphyseal dysplasia (GDD) or to different forms of muscular dystrophy (LGMD2L, limb-girdle muscular dystrophy-2l and distal MMD3, miyoshi muscular dystrophy-3). Our data show that human TMEM16E, when overexpressed in mammalian cell lines, displays partial plasma membrane localization and give rise to phospholipid scrambling as well as non-selective ionic currents with slow time-dependent activation at highly depolarized membrane potentials and in presence of high intracellular Ca2+. We address the effect of the GDD-causing mutation T513I, located in the second extracellular loop, on TMEM16E and we show phospholipid scrambling activity and large time-dependent ion currents even at low cytosolic Ca2+ concentrations. Our data provide the first direct demonstration of Ca2+-dependent current and phospholipid scrambling activity for TMEM16E and suggest a gain-of-function phenotype related to a GDD mutation.

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