Ano4, also known as TMEM16D, is a member of the anoctamin family. It functions as a Ca2+-dependent non-selective cation channel [3]. It is involved in multiple biological processes such as regulating aldosterone secretion in the zona glomerulosa of the human adrenal gland, and is also associated with neuronal functions [2,4]. In addition, it may play a role in regulating ADAM-dependent cellular functions through its scramblase activity [5].

Genetic disruption of the Ano4 gene in ventromedial hypothalamic nucleus (VMH) neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. This indicates that Ano4 channels in VMH neurons are functionally required for their activation in response to low glucose, and Ano4 channels and VMHAno4 neurons are potential therapeutic targets for diseases with abnormal feeding behavior or glucose imbalance [4]. Missense variants in ANO4 have been linked to sporadic encephalopathic or familial epilepsy. In vitro functional studies of these variants showed severe loss of ion channel function, and co-transfection with wild-type ANO4 suggested a dominant-negative effect, expanding the genetic base for these epilepsies [1].

In conclusion, Ano4 plays crucial roles in regulating aldosterone secretion, neuronal functions related to glucose regulation, and is associated with epilepsy. The gene knockout studies in mice have revealed its significance in specific biological processes and disease conditions, providing insights into potential therapeutic targets for diseases like epilepsy and those related to glucose metabolism [1,2,4].