following anions to pass through, from most selected to least: SCN−, Cl−, Br−, NO, I−. Altering a serine residue at the selectivity filter, labeled Sercen, to a different amino acid alters the selectivity. Gating and kinetics Gating occurs through two mechanisms: protopore or fast gating and common or slow gating. Common gating involves both protein subunits closing their pores at the same time (cooperation), while protopore gating involves independent opening and closing of each pore. As the names imply, fast gating occur at a much faster rate than slow gating. Precise molecular mechanisms for gating are still being studied. For the channels, when the slow gate is closed, no ions permeate through the pore. When the slow gate is open, the fast gates open spontaneously and independently of one another. Thus, the protein could have both gates open, or both gates closed, or just one of the two gates open. Single-channel patch-clamp studies demonstrated this biophysical property even before the dual-pore structure of CLC channels had been resolved. Each fast gate opens independently of the other and the ion conductance measured during these studies reflects a binomial distribution. H+ transport promotes opening of the common gate in CLC channels. For every opening and closing of the common gate, one H+ is transported across the membrane. The common gate is also affected by the bonding of adenosine nucleotides to the intracellular CBS domains. Inhibition or activation of the protein by these domains is specific to each protein. Function The CLC channels allow chloride to flow down its electrochemical gradient, when open. These channels are expressed on the cell membrane. CLC channels contribute to the excitability of these membranes as well as transport ions across the membrane. The CLC exchangers are localized to intracellular components like endosomes or lysosomes and help regulate the pH of their compartments. Pathology Bartter's syndrome, which is associated with renal salt wasting and hypokalemic alkalosis, is due to the defective transport of chloride ions and associated ions in the thick ascending loop of Henle. CLCNKB has been implicated. Another inherited disease that affects the kidney organs is Dent's Disease, characterised by low molecular weight proteinuria and hypercalciuria where mutations in CLCN5 are implicated. Thomsen disease is associated with dominant mutations and Becker disease with recessive mutations in CLCN1. Genes CLCN1, CLCN2, CLCN3, CLCN4, CLCN5, CLCN6, CLCN7, CLCNKA, CLCNKB BSND - encodes barttin, accessory subunit beta for CLCNKA