The anoctamin family: TMEM16A and TMEM16B as calcium‐activated chloride channels

Abstract

The Ca2+ -activated Cl − channels (CaCCs) are involved in a variety of physiological functions, such as transepithelial anion transport, smooth muscle contraction and olfaction. Recently, the question of the molecular identity of CaCCs has apparently been resolved with the identification of TMEM16A protein (also known as anoctamin-1). Expression of TMEM16A is associated with the appearance of Ca 2+ -and voltage-dependent Cl − currents with properties similar to those of native CaCCs. The putative structure of TMEM16A consists of eight transmembrane domains, with both the amino-and the carboxy-terminus protruding in the cytosol. TMEM16A is also characterized by the existence of different protein variants generated by alternative splicing. A close paralogue of TMEM16A, TMEM16B (anoctamin-2), is also associated with CaCC activity, although with different properties. The TMEM16B-dependent channels require higher intracellular Ca 2+ concentrations and have faster activation and deactivation kinetics. Expression of other anoctamins is devoid of detectable channel activity. These proteins, such as TMEM16F (anoctamin-6), may have different functions.

Conditional knockout of TMEM16A/anoctamin1 abolishes the calcium-activated chloride current in mouse vomeronasal sensory neurons

“…Other recent studies showed that Ca 2+ -activated Cl  channels contribute to the response of mouse vomeronasal neurons to urine (Yang and Delay, 2010;Kim et al, 2011). Furthermore, the presence of Ca 2+ -activated Cl  channels in the apical portion of vomeronasal sensory neurons was confirmed by local photorelease of Ca 2+ from caged Ca 2+ (Dibattista et al, 2012) and by the expression of TMEM16A and TMEM16B (Dibattista et al, 2012), two proteins forming Ca 2+ -activated Cl  channels (Caputo et al, 2008;Schroeder et al, 2008;Yang et al, 2008;Pifferi et al, 2009a;Stephan et al, 2009;Stöhr et al, 2009;Scudieri et al, 2012;Pedemonte and Galietta, 2014). The aim of this study was to further characterize the ionic nature (in the absence of intracellular K + to avoid the contribution of Ca…”

Interactions between permeation and gating in the TMEM16B/anoctamin2 calcium-activated chloride channel

“…The standard intracellular solution contained (mM) 140 CsCl, 10 HEPES, 10 HEDTA (or 5 EGTA), pH 7.2, and no added Ca 2+ for the nominally 0 Ca 2+ solution, or various amounts of CaCl 2 , as calculated with the program WinMAXC (C. Patton, Stanford University, Stanford, CA), to photoreceptors (Stöhr et al, 2009;Billig et al, 2011;Dauner et al, 2013), in hippocampal cells (Huang et al, 2012b), in the cilia of olfactory sensory neurons, and in the microvilli of vomeronasal sensory neurons (Stephan et al, 2009;Hengl et al, 2010;Rasche et al, 2010;Sagheddu et al, 2010;Billig et al, 2011;Dauner et al, 2012;Dibattista et al, 2012;Maurya and Menini, 2013). Studies with knockout mice for TMEM16A or TMEM16B (Rock and Harfe, 2008;Billig et al, 2011) or knockdown of these channels further confirmed a reduction in CaCC activity (Flores et al, 2009;Galietta, 2009;Hartzell et al, 2009;Huang et al, 2012a;Kunzelmann et al, 2012a,b;Pifferi et al, 2012;Sanders et al, 2012;Scudieri et al, 2012).…”

Etiology of distinct membrane excitability in pre- and posthearing auditory neurons relies on activity of Cl − channel TMEM16A

“…However, the molecular identity of CaCCs has only been reported recently (27,29,30). TMEM16A and its close paralogue TMEM16B have been demonstrated to encode for CaCCs (31), whereby in the presence of permissive [Ca 2+ ] i membrane depolarization enhances the current magnitude. The activity of the two proteins confers transepithelial anion transport and smooth muscle contraction, as well as amplifies olfactory signal transduction (28).…”