Intracellular Chloride Regulation

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Intracellular chloride (Cl), together with bicarbonate (HCO3), is the most abundant free anion in living cells. Most animal cells exhibit a non-equilibrium distribution of Cl across their plasma membranes. Some cells actively extrude Cl, others actively accumulate it, but few cells ignore it. By virtue of being distributed out of electrochemical equilibrium, Cl serves as a key player in a variety of cellular functions, such as intracellular pH (pHi) regulation, cell volume regulation, transepithelial salt transport, synaptic signaling (in both the depolarizing and hyperpolarizing directions), neuronal growth, migration and targeting, membrane potential stabilization, sensory transduction including nociception and extracellular K+ scavenging. Intracellular [Cl] is determined by the interaction of various anion-transporting systems present in a cell, including Clchannels as well as several cotransporters and exchangers. The carrier protein molecules that transport Clinclude the electroneutral Cl/HCO3 exchangers that play a central role in pHi regulation and serve as uphill Cl-accumulating mechanisms and the family of electroneutral cation-chloride cotransporters. This family encompasses nine members, seven of which exhibit transport activity: a Na+-Clcotransporter (NCC), two Na+-K+-Cl cotransporters (NKCC1 and NKCC2) and four Na+-independent K+-Cl cotransporters (KCC1, KCC2, KCC3 and KCC4). The cotransporter proteins share a common predicted membrane topology, with 12 putative transmembrane segments flanked by long hydrophilic amino- and carboxyl-terminal cytoplasmic domains. These carrier proteins are of high significance in the pathophysiology of several abnormalities and, because of this, they are ideal targets for translational research. Therefore, understanding their structure, function, regulation, distribution and pharmacological sensitivities is of fundamental importance.



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