International Union of Basic and Clinical Pharmacology. LXXXV: calcium-activated chloride channels

Abstract

Calcium-activated chloride channels (CaCCs) are widely expressed in various tissues and implicated in physiological processes such as sensory transduction, epithelial secretion, and smooth muscle contraction. Transmembrane proteins with unknown function 16 (TMEM16A) has recently been identified as a major component of CaCCs. Detailed molecular analysis of TMEM16A will be needed to understand its structure-function relationships. The role this channel plays in physiological systems remains to be established and is currently a subject of intense investigation.

Fig. 1.

Examples of classic CaCCs recorded in X. laevis oocytes and mammalian cells. A, CaCC in X. laevis oocyte. The patches were clamped from a holding potential of 0 mV to potentials between 140 and −100 mV for 1 s, followed by a 500-ms pulse to −100 mV (Qu and Hartzell, 2000). B, CaCC recorded in rat pulmonary artery (PA) smooth muscle cells, representative current tracings recorded in the absence (Control) and presence of 100 μM NFA, voltage-dependent currents were evoked by 1-s step depolarization from a holding potential of −50 mV to +70 mV, followed by 1-s return steps to −80 mV (Greenwood et al., 2001). C, CaCC recorded in cultured rat dorsal root ganglia neurons activated by a depolarizing prepulse (Mayer, 1985). D, CaCC recorded in ICCs. ICCs were depolarized from −80 to +30 mV in 10-mV increments from a holding potential of −80 mV, and ECl⁻ was adjusted to 0 mV (Zhu et al., 2009).

Fig. 2.

Functional correlation between CaCC in native cells and TMEM16 family members. A, CaCC in submandibular salivary gland acinar cells is abolished in TMEM16A knock out mouse (Romanenko et al., 2010). B, CaCC in pulmonary arterial smooth muscle cells is greatly reduced by TMEM16A siRNA (Manoury et al., 2010). C, Slow wave activity in gastrointestinal muscles is abolished in TMEM16A knock out mouse (Hwang et al., 2009). D, CaCC is absent in the TMEM16B knockout mouse olfactory sensory neurons (Billig et al., 2011).

Fig. 3.

Proposed topology and functional domains of TMEM16A.

Fig. 4.

Phylogenetic analysis of 10 members of mouse TMEM16 proteins.