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Anoctamin 1 (ANO1) Calcium-activated chloride channels are widely distributed in various tissues of the body, promote cell proliferation, participate in sensory transmission, regulate blood pressure, promote epithelial cell secretion, and promote tumor cell migration. Abnormal dysfunction of ANO1 can lead to many diseases such as cancer, hypertension, gastrointestinal motility disorders, cystic fibrosis.
There is a significant difference in calcium-activated chloride channels activated by different concentrations of calcium ions in ANO1. In the case of intracellular low calcium (<1 μM), the calcium-activated chloride current exhibits a slow activation characteristic with strong outward rectification and a small tail current at repolarization. In the case of intracellular high calcium (> 1 μM), calcium-activated chloride currents exhibit rapid activation kinetics and reduced rectification. In the recently discovered X-ray crystal structure of nhANO1, it was also confirmed that a calcium binding site consisting of five acidic residues and one asparagine residue in the sixth, seventh and eighth transmembrane regions of ANO1 (N650, E654, E702, E705, E734, D738).
Studies have found that Ca2+-dependent regulation of endogenous CaCCs requires the involvement of calmodulin in many cells, such as olfactory sensory cells, pulmonary endothelial cells, airway epithelial cells, and lymphocytes. In the heterologous expression system, Vocke et al. used immunoprecipitation and pull down experiments to confirm the direct interaction between ANO1 and calmodulin. However, different calmodulin binding sites on the ANO1 channel were proposed, including the N-terminal, N-terminal region immediately adjacent to the first transmembrane domain, the first transmembrane domain, and the seventh transmembrane domain. Since calmodulin cannot be eluted together with the purified ANO1 protein and does not regulate the recombinant ANO1 activity in the liposome, the two cannot form a stable complex. Therefore, some studies do not support a direct interaction between calmodulin and ANO1.
How calmodulin regulates the activity of ANO1 remains controversial. Calmodulin has been reported to be important for ANO1 activation, and calcium ions activate ANO1 via calmodulin. Wall et al.'s view is that calmodulin regulates calcium-activated chloride channels for HCO3- permeability. Yu et al. showed that calmodulin does not mediate ANO1 activation via Ca2+ and suggests that calmodulin-mediated HCO3- permeation may be due to a series of resistance problems (electrode resistance), ion accumulation effects, or both.
Figure 1. Schematic pathways depicting roles of ANO1 in VSMC. (Wang, et al. 2015).
ANO1 and Cardiovascular System
ANO1 calcium-activated chloride channels are expressed on cell membranes such as vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, and cardiac fibroblasts. ANO1, which is highly expressed in vascular smooth muscle cells, is involved in the maintenance and contraction of vascular tone and is closely related to pulmonary hypertension and hypertension. Activation of ANO1 leads to depolarization of the cell membrane, which in turn activates voltage-dependent calcium channels, causes Ca2+ to rise, promotes vascular tone, and increases vasoconstriction. In addition, Wang et al found that activation of ANO1 can promote vascular smooth muscle cell proliferation, increase vessel wall thickness, and promote vascular remodeling. Heinze et al. showed that ANO1 is highly expressed in peripheral arterioles and capillary contractile intermediate cells and pericytes. Activation of ANO1 can increase peripheral resistance and further increase systemic blood pressure.
ANO1 is expressed on many vascular endothelial cells including cardiac blood vessels and umbilical veins. It plays a role in regulating endothelial cell membrane potential, promoting Ca influx, activating Ca signaling pathway, and maintaining cell volume, morphology, and proliferation. In the ischemic state, endothelial and smooth muscle cells promote their proliferation and angiogenesis by promoting high expression of ANO1, mediating the response of blood vessels in an ischemic state. In addition, ANO1 is involved in maintaining cardiomyocyte action potential, regulating self-discipline, and is closely related to myocardial ischemia-induced arrhythmia. On the one hand, myocardial ischemia can promote the expression of ANO1 in cardiomyocytes, accelerate the repolarization of the action potential in 1 phase, and induce arrhythmia. On the other hand, ischemia can promote the secretion of angiotensin II (Ang II), AngII activates ANO1 on cardiac fibroblasts, promotes fibroblast proliferation and collagen secretion, triggers cardiac hypertrophy, and indirectly leads to arrhythmia.
ANO1 Digestive System
ANO1 is widely expressed in epithelial cells throughout the digestive system and is involved in water and electrolyte secretion. ANO1 present on the apical membrane of salivary acinar cells promotes salivation by regulating Cl-outflow. ANO1 is expressed in the gut and is involved in the secretion of digestive juice at the apical and basal sides of epithelial cells. ATP-Ca2+-PKCα signaling can activate ANO1 in biliary epithelial cells and promote bile secretion. Wang et al found that ANO1 in the epithelial cells of pancreatic duct epithelial cells is activated by ATP/UTP binding to purinergic receptors, providing a new idea for the treatment of cystic fibrosis of pancreatic diseases. In the regulation of islet function, ANO1 is involved in glucose-promoting insulin secretion in pancreatic islet B cells. ANO1 is highly expressed on the membrane of interstitial cells (ICC) of Cajal, and its expression intensity is about 26.5 times that of smooth muscle. It then promotes ICC proliferation, participates in the generation and conduction of ICC slow-wave currents, regulates cell excitability, and promotes intestinal peristalsis and muscle tone maintenance.