Cell volume regulation strongly depends on the swelling- and stretch-activated Cl
− channel (I
Cl,Swell, also known as VRAC, VSOR, VSOAC) in most cells
16 and specifically in human TM cells.
17 Following anisosmotic swelling, release of Cl
− through I
Cl,Swell and K
+ through parallel K
+ channels drives water release, as well, restoring cell volume to isosmotic levels (regulatory volume decrease [RVD]). Chloride ion release through swelling-activated channels also releases organic osmolytes, such as taurine.
18 Trabecular meshwok cells display an RVD, both as isolated cells
17 and in intact human outflow tissue.
19 Studies using genome-wide RNAi screens have demonstrated that heteromers A, C, D, and E of the Leucine-Rich Repeat-Containing Protein 8 (LRRC8A,C,D,E) form an essential component of I
Cl,Swell.
18,20 Published evidence also suggests that a 10-member vertebrate family of calcium-activated anoctamins, Ano1-10 (
TMEM16 genes
A–K) has an important role in cell volume regulation in other cells.
15 Agreement as to the role of anoctamins in cell volume regulation is incomplete, particularly since family members display several functions,
21 reportedly acting as CaCCs,
22–32 nonselective cation channels,
33 and scramblases or scramblase components, dissipating the phospholipid asymmetry across the plasma membrane.
34,35 Ano1
22–24,36,37 and Ano2
24,36,37 were the first and most clearly documented anoctamins to be CaCCs. More recently, Ano6 also has been demonstrated to function as an ion channel or channel component.
28,29,33,38 In contrast, Schreiber et al.
38 have reported that Ano9 and Ano10 expressed in Fisher Rat Thyroid (FRT) cells inhibit Ca
2+-activated Cl
− currents. However, the relative Na
+ to Cl
− permeability (P
Na/P
Cl) of Ano6 has been uncertain. In HEK293T cells overexpressing human Ano6, Shimizu et al.
29 found that Ano6 functioned exclusively as an anion channel, whereas Grubb et al.
28 reported that P
Na/P
Cl = 0.3. In contrast, Yang et al.
33 found that endogenous Ano6 in axolotl oocyte membranes and WT mouse megakaryocytes, as well as overexpressed mouse Ano6 in
Xenopus oocyte membranes, acted as a nonselective cation channel (P
Na/P
Cl∼7).