VSI: The anoctamins: Structure and function: "Intracellular" anoctamins.

• ANO3,4,5,7,8,9,10 have been detected in intracellular compartments ANO4,5,9 are also expressed in the plasma membrane. • The so-called intracellular anoctamins are all scramblases and ion channels except of ANO8; they are coexpressed in most cell types. • ANO3,4,8,9,10 shape intracellular Ca²⁺ signals, some have a role in forming ER/PM membrane contact sides. • ANO5 and ANO10 have specific cellular functions in cell membrane repair and endosomal trafficking, respectively. • A diversity of diseases is caused by genetic variations of these anoctamins, like dystonia (ANO3), obesity (ANO4), limb-girdle muscular dystrophy and gnathodiaphyseal dysplasia (ANO5), chronic kidney disease (ANO9), and ataxia (ANO10). Plasma membrane localized anoctamin 1, 2 and 6 (TMEM16A, B, F) have been examined in great detail with respect to structure and function, but much less is known about the other seven intracellular members of this exciting family of proteins. This is probably due to their limited accessibility in intracellular membranous compartments, such as the endoplasmic reticulum (ER) or endosomes. However, these so-called intracellular anoctamins are also found in the plasma membrane (PM) which adds to the confusion regarding their cellular role. Probably all intracellular anoctamins except of ANO8 operate as intracellular phospholipid (PL) scramblases, allowing for Ca²⁺-activated, passive transport of phospholipids like phosphatidylserine between both membrane leaflets. Probably all of them also conduct ions, which is probably part of their physiological function. In this brief overview, we summarize key findings on the biological functions of ANO3, 4, 5, 7, 8, 9 and 10 (TMEM16C, D, E, G, H, J, K) that are gradually coming to light. Compartmentalized regulation of intracellular Ca²⁺ signals, tethering of the ER to specific PM contact sites, and control of intracellular vesicular trafficking appear to be some of the functions of intracellular anoctamins, while loss of function and abnormal expression are the cause for various diseases. [Display omitted] [ABSTRACT FROM AUTHOR]