1.A.17.1.25
TMem16A or Anoctamin-1 (Ano1) Ca²⁺-activated anion (Cl^-) channel of 960 aas and 10 TMSs.  Its structure has been solved by cryoEM (Paulino et al. 2017). The protein shows a similar organization to the fungal nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices, constituting a membrane-spanning furrow that provides a path for lipids in scramblases, is replaced to form an enclosed aqueous pore that is largely shielded from the membrane (Paulino et al. 2017). It thus provides a pathway for anions such as Cl^-.  During activation, the binding of Ca²⁺ to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an α-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening (Paulino et al. 2017).  The E143A mutant showed reduced sensitivity to Ca²⁺ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca²⁺ and noxious heat (Choi et al. 2018). Loss of TMEM16A resulted in reduced nephron number and, subsequently, albuminuria and tubular damage (Schenk et al. 2018). mAno1 expression is regulated via alternative promoters, and its transcriptional variation results in variation of the N-terminal sequence of the Ano1 protein due to alternative translation initiation sites (Kamikawa et al. 2018). The Ca²⁺ gating mechanism of TMEM16A, involving a Ca²⁺-sensing element close to the anion pore, alters conduction and substrate selection. De Jesús-Pérez et al. 2022 studied the gating-permeant anion relationship using mouse TMEM16A, showing that the apparent Ca²⁺ sensitivity increases with highly permeant anions and SCN^- mole fractions, likely by stabilizing bound Ca²⁺. Conversely, mutations in crucial gating elements, including the Ca²⁺-binding site 1,TMS 6, and the hydrophobic gate, impaired anion permeability and selectivity. Thus, there is a reciprocal rationship between gating and selectivity (De Jesús-Pérez et al. 2022).  Propagation of pacemaker activity and peristaltic contractions in the mouse renal pelvis rely on Ca²⁺-activated Cl^- Channels such as Ano1 and T-type Ca²⁺ channels (Grainger et al. 2022).