Physiological and Pathological Significance of Chloride Channels.

Cl influx and efflux through Cl channels play a role in regulating the homeostasis of biological functions. Therefore, the hyperfunction or dysfunction of Cl channels elicits pathological mechanisms. The Cl channel superfamily includes voltage-gated Cl (ClC) channels, Ca-activated Cl channels (Cl; TMEM16A/TMEM16B), cystic fibrosis transmembrane conductance regulator channels, and ligand-gated Cl channels. These channels are ubiquitously expressed to regulate ion homeostasis, muscle tonus, membrane excitability, cell volume, survival, neurotransmission, and transepithelial transport. The activation or inhibition of Cl channels changes the membrane potential, thereby affecting cytosolic Ca signals. An elevation in cytosolic [Ca] triggers physiological and pathological responses in most cells. However, the roles of Cl channels have not yet been examined as extensively as cation (Na, Ca, and K) channels. We recently reported the functional expression of: (i) TMEM16A/Cl channels in portal vein and pulmonary arterial smooth muscle cells (PASMC), pinealocytes, and brain capillary endothelial cells; (ii) TMEM16B/Cl channels in pinealocytes; (iii) ClC-3 channels in PASMC and chondrocytes; and (iv) ClC-7 channels in chondrocytes. We also showed that the down-regulation of TMEM16A and ClC-7 channel expression was associated with cirrhotic portal hypertension and osteoarthritis, respectively, whereas the enhanced expression of TMEM16A and ClC-3 channels was involved in the pathogenesis of cerebral ischemia and pulmonary arterial hypertension, respectively. Further investigations on the physiological/pathological functions of Cl channels will provide insights into biological functions and contribute to the screening of novel target(s) of drug discovery for associated diseases.