Chloride , channel

The mechanism by which the methylxanthines produce CNS stimulation is not clearly estabUshed. These agents may function, ia part, to limit chloride channel activation ia a manner similar to that of pentylenetetra2ol (7) or hicuculline (8). Another possibiUty is a specific antagonism of the inhibitory neurotransmitter adenosiae [58-61-7] (19) (19). 

Airway surface liquid (ASL) is the very thin fluid layer (<7 (llM) maintained at the apical membrane of airway epithelia. ASL thickness is maintained by a tight control of fluid reabsorption and/or secretion, mediated by sodium and/or chloride channels. 

Bartter s syndrome is caused by mutations in the basolateral chloride channel (CIC-Kb), an exit pathway for cellular Cl. 

CFTR has a single-channel conductance of about 8 pS. It is present in the apical membranes of many epithelia. Its mutation leads to the potentially lethal disease cystic fibrosis. In addition to acting as a chloride channel, CFTR is also thought to regulate, e.g., the epithelial sodium channel ENaC, a molecularly unknown outwardly-rectifying chloride channel, and possibly also potassium channels and water channels. Some of these potential regulatory processes, however, are controversial. CFTR also acts as a receptor for bacteria. 

Chloride channels are membrane proteins that allow for the passive flow of anions across biological membranes. As chloride is the most abundant anion under physiological conditions, these channels are often called chloride channels instead of anion channels, even though other anions (such as iodide or nitrate) may permeate better. As some CLC proteins function as CF-channels, whereas other perform CF/H+-exchangers are also mentioned here. 

There are nine different CLC isoforms in mammals. Based on homology, they can be classed into three branches. The first branch includes channels that reside predominantly in the plasma membrane. This includes C1C-1, a skeletal muscle chloride channel, C1C-2, a very broadly expressed channel, and CIC-Ka and CIC-Kb, which are expressed predominantly in the kidney but also in the ear. 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

Jentsch TJ, Stein V, Weinreich F et al (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82 503—568... 

Dutzler R, Campbell EB, Cadene M et al (2002) X-ray structure of the C1C chloride channel at 3.0 A resolution molecular basis of anion selectivity. Nature 415 287—294... 

Hartzell C, Qu Z, Putzier I et al (2005) Looking chloride channels straight in the eye bestrophins, lipofuscinosis, and retinal degeneration. Physiology (Bethesda) 20 292-302... 

Inhibitory glycine receptor Strychnine-sensitive glycine receptor Glycine-gated chloride channel Glycine-gated anion channel... 

Webb TI, Lynch JW (2007) Molecular pharmacology of the glycine receptor chloride channel. Curr Pharm Des 13 2350-2367... 

Myotonic dystrophy AD 19q13 Myotonin protein kinase Muscle chloride channel... 

Cystic Fibrosis Is Due to Mutations in the Gene Encoding a Chloride Channel... 

Myotonia congenita (MIM 160800) Chloride channel Skeletal muscle... 

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