Ano2, also known as TMEM16B, is a gene encoding a protein that functions as a Ca2+-activated Cl- channel (CaCC) [1]. CaCCs are involved in multiple physiological functions such as transepithelial ion transport, smooth muscle contraction, olfaction, phototransduction, nociception, and control of neuronal excitability [1]. Ano2 has been linked to pathways related to olfaction, retinal function, and may play a role in some autoimmune conditions [2,3,5]. Genetic models, like knockout mice, can be valuable for studying Ano2's functions.

In Ano2 knockout mice, studies have shown that while it was initially thought to amplify transduction currents in olfactory receptor neurons (ORNs), paradoxically, the spike output for odor stimuli may be higher in Ano2-/- ORNs. Ano2-/- animals also took longer to approach a localized odor source, indicating olfactory behavioral deficits. This suggests Ano2 may serve as a feedback mechanism to clamp ORN spike output [6]. In taste cells, Ano2 transcripts were detected in type I and type II cells, suggesting it may form CaCCs that serve as effectors downstream of P2Y receptors in type I cells [4]. Additionally, preliminary analyses suggest an association of ANO2 genetic variants with retinal function, potentially impacting vision [2].

In conclusion, Ano2, as a Ca2+-activated Cl- channel, plays essential roles in olfaction, possibly by regulating ORN spike output, and may have an impact on retinal function. The use of Ano2 knockout mouse models has been crucial in revealing these functions, especially in the context of olfactory and potentially visual processes. The association with some autoimmune conditions also indicates its importance in understanding related disease mechanisms [2,4,5,6].

References:

1. Pedemonte, Nicoletta, Galietta, Luis J V. . Structure and function of TMEM16 proteins (anoctamins). In Physiological reviews, 94, 419-59. doi:10.1152/physrev.00039.2011. https://pubmed.ncbi.nlm.nih.gov/24692353/

2. Guymer, Robyn H, Silva, Rufino, Ghadessi, Mercedeh, Paulding, Charles, Rittenhouse, Kay D. . ANO2 Genetic Variants and Anti-VEGF Treatment Response in Neovascular AMD: A Pharmacogenetic Substudy of VIEW 1 and VIEW 2. In Investigative ophthalmology & visual science, 65, 17. doi:10.1167/iovs.65.8.17. https://pubmed.ncbi.nlm.nih.gov/38980270/

3. Stephan, Aaron B, Shum, Eleen Y, Hirsh, Sarah, Reisert, Johannes, Zhao, Haiqing. 2009. ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification. In Proceedings of the National Academy of Sciences of the United States of America, 106, 11776-81. doi:10.1073/pnas.0903304106. https://pubmed.ncbi.nlm.nih.gov/19561302/

4. Cherkashin, Alexander P, Kolesnikova, Alisa S, Tarasov, Michail V, Bystrova, Marina F, Kolesnikov, Stanislav S. 2015. Expression of calcium-activated chloride channels Ano1 and Ano2 in mouse taste cells. In Pflugers Archiv : European journal of physiology, 468, 305-19. doi:10.1007/s00424-015-1751-z. https://pubmed.ncbi.nlm.nih.gov/26530828/

5. Sattarnezhad, Neda, Kockum, Ingrid, Thomas, Olivia G, Olsson, Tomas, Lanz, Tobias V. 2025. Antibody reactivity against EBNA1 and GlialCAM differentiates multiple sclerosis patients from healthy controls. In Proceedings of the National Academy of Sciences of the United States of America, 122, e2424986122. doi:10.1073/pnas.2424986122. https://pubmed.ncbi.nlm.nih.gov/40063790/

6. Zak, Joseph D, Grimaud, Julien, Li, Rong-Chang, Lin, Chih-Chun, Murthy, Venkatesh N. 2018. Calcium-activated chloride channels clamp odor-evoked spike activity in olfactory receptor neurons. In Scientific reports, 8, 10600. doi:10.1038/s41598-018-28855-3. https://pubmed.ncbi.nlm.nih.gov/30006552/