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, Ca²⁺-activated Cl^- channels (Cl_Ca; 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 Ca²⁺ signals. An elevation in cytosolic [Ca²⁺] triggers physiological and pathological responses in most cells. However, the roles of Cl^- channels have not yet been examined as extensively as cation (Na⁺, Ca²⁺, and K⁺) channels. We recently reported the functional expression of: (i) TMEM16A/Cl_Ca channels in portal vein and pulmonary arterial smooth muscle cells (PASMC), pinealocytes, and brain capillary endothelial cells; (ii) TMEM16B/Cl_Ca 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.