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Ion channels are used by cells to regulate many cellular functions, from action potential conduction to water balance, which is sometimes achieved by using a single ion in the setting of different channels types. Although ion channels are described as transmembrane proteins that have a “pore” which allows for the diffusion of specific ions across a concentration gradient, other channels involved in ion transport include antiporters (exchange), symporters (cotransport in the same direction) and pumps (use energy from hydrolysis of ATP). Chloride channels are a remarkable example of this since they are involved in the control of transepithelial transport, membrane excitability, and the regulation of cell volume and intracellular and intraorganelle pH. All of this is achievable by the use of the many different types of chloride channels, of which there are three major families: the voltage-gated chloride channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and related channels, and the ligand-gated channels activated by gamma-aminobutyric acid (GABA) and glycine.[1][2]

Several human inherited diseases are associated with chloride channel mutations. Out of all of these, cystic fibrosis (CF) is probably the most popular and studied one. However, several others are being researched to find targeted therapies. CF is caused by abnormal salt and water transport across epithelia that affects multiple organ systems, most predominantly the lungs, pancreas, liver, and intestines. Altered composition of fluid films covering epithelia leads to obstruction of ducts, bacterial overgrowth, and decreased reabsorption. GABA and glycine receptors in the brain have an associated inhibitory chloride current and defects in these channels carry links with various symptoms of neuronal excitability. Mutations in genes that code for subunits of the GABA receptor correlate to different monogenic epilepsy syndromes, such as genetic epilepsy with febrile seizure plus (GEFS+) and its milder forms of febrile seizures, childhood absence epilepsy, autosomal dominant juvenile myoclonic epilepsy (ADJME), among others. Glycine receptor mutations cause hereditary hyperekplexia (HPX), also known as ‘stiff baby syndrome,’ a neurological disorder typically causing an exaggerated startle reflex with mild auditory, tactile, or visual stimuli. Mutations in the CLC channel and transports are associated with a variety of genetic diseases such as myotonia, kidney stones, renal salt loss, deafness, osteopetrosis, and lysosomal storage disease. CIC-1 channel mutations cause different types of myotonia depending on the degree of chloride conductance impairment. CIC-2 is important to establish the low intraneural Cl- concentration needed for inhibitory response to GABA and glycine, and mutations of these channels have links to epilepsy. ClC-K/barttin chloride channels mutations cause some types of Bartter syndrome with renal salt wasting and congenital deafness due to lack of basolateral chloride currents needed for NaCl- reabsorption, and maintenance of electrochemical potentials. Dent’s disease, a rare X-linked kidney stone disorder with proteinuria, is due to a mutation in CIC-5 leading to impaired endocytosis of proteins and hormones. CIC-7 is an H+/Cl- exchanger that is important in pH regulation and expressed in lysosome and osteoclast, and mutations lead to osteoporosis and lysosomal storage disorders.[1][8]