Chloride channels and endocytosis: ClC-5 makes a dent.

Abstract

Ion channels are ubiquitous pore-forming membrane proteins found in virtually every cell of every living organism. In mammals, a vast array of ion channel types participate in numerous vital physiological processes such as membrane excitability, cell volume regulation, signal transduction, secretion, and absorption. Therefore, it is not surprising that hereditary conditions can occur because of mutations in genes which encode critical components of ion channel molecules (1). Since 1989, more than 25 human disease entities have been identified as “ion channelopathies.” Studies of ion channel disease syndromes have contributed greatly to our understanding of specific disease pathogenesis and, in some cases, have revealed new insights into the relationship between ion channel structure and function (2–6). In this issue of Proceedings , Gunther, et al . study the cellular localization of a kidney chloride channel (ClC-5) implicated in the pathogenesis of X-linked hypercalciuric nephrolithiasis (prototype syndrome, Dent’s disease) and infer the probable function of this molecule (7). The ClC chloride channel family, to which ClC-5 belongs, has been recognized only within the past decade (8); yet one-third of all identified mammalian ClC isoforms have been linked to human genetic diseases (Table 1) (9–12). Soon after the first member of this gene family was sequenced from Torpedo electric organ (ClC-0) (13), a mammalian homolog expressed exclusively in skeletal muscle (ClC-1) was identified as the gene for myotonia congenita (9, 10, 14), an unusual syndrome associated with muscular stiffness caused by delayed relaxation of muscle following voluntary contractions. The candidacy of ClC-1 was initially based on solid physiological evidence of diminished sarcolemmal chloride conductance in a curious animal model, the myotonic or “fainting” goat (15). Another mammalian ClC isoform expressed in the kidney (ClC-KB), was added recently to the list …