Chloride channel diseases resulting from impaired transepithelial transport or vesicular function

Abstract

The transport of anions across cellular membranes is crucial for various functions, including the control of electrical excitability of muscle and nerve, transport of salt and water across epithelia, and the regulation of cell volume or the acidification and ionic homeostasis of intracellular organelles. Given this broad range of functions, it is perhaps not surprising that mutations in Cl- channels lead to a large spectrum of diseases. These diverse pathologies include the muscle disorder myotonia, cystic fibrosis, renal salt loss in Bartter syndrome, kidney stones, deafness, and the bone disease osteopetrosis. This review will focus on diseases related to transepithelial transport and on disorders involving vesicular Cl- channels.

Figure 1

Diverse roles of Cl^– channels in transepithelial transport. In colonic epithelia, cells at the luminal surface (A) express a Cl^–/HCO₃^– exchanger (which may be electrogenic) and the Na⁺/H⁺ exchanger NHE3 in their apical membrane, allowing for net NaCl reabsorption. Chloride probably crosses the basolateral membrane through ClC-2. Cells at the crypt base (B) secrete chloride, which is taken up by basolateral NKCC1, through apical CFTR channels. KCNQ1/KCNE3 heteromeric K⁺ channels are needed for K⁺ recycling. (C) Model for K⁺ secretion in the stria vascularis of the cochlea. K⁺ is taken up by the basolateral isoform of the NKCC cotransporter, NKCC1, and the Na,K-ATPase. Chloride is recycled by basolateral ClC-Ka and ClC-Kb/barttin channels. (D) Model for NaCl reabsorption in the thick ascending limb of Henle (TAL). NaCl is taken up by the apical NKCC2 transporter that needs the apical ROMK channel for K⁺ recycling. Cl^– leaves the cell through basolateral ClC-Kb/barttin channels. (E) Model for intercalated cells of the collecting duct. α-Intercalated cells (α-IC) secrete protons using a proton ATPase, while basolateral transport of acid equivalents is via the anion exchanger AE1. It is proposed that both KCC4 cotransporters (65) and ClC-K/barttin channels recycle Cl^–. It is unknown whether ClC-K/barttin is involved in Cl^– reabsorption in β-intercalated cells as shown below.

Figure 2

General concept of vesicular acidification exemplified by ClC-7. (A) Vesicles of the endosomal and lysosomal pathway are acidified by H⁺-ATPases. Their current is neutralized by Cl^– channels. In their absence, efficient proton pumping is prevented. (B) Model for the resorption lacuna acidification in osteoclasts. The H⁺-ATPase and ClC-7 are trafficked to the “ruffled border” membrane of osteoclasts. The acidification of the resorption lacuna is required for dissolving the mineral phase of bone, as well as for the enzymatic degradation of the organic bone matrix by lysosomal enzymes. It depends on the presence of both ClC-7 and the H⁺-ATPase in the ruffled border.

Figure 3

Model to explain hypercalciuria and hyperphosphaturia in Dent disease. (A) Alterations in vitamin D metabolism. Parathyroid hormone (PTH) is filtered into the primary urine from which it is normally cleared by megalin-mediated endocytosis and subsequent degradation. The impaired endocytosis due to a disruption of ClC-5 results in an increased luminal PTH concentration that leads to an enhanced activation of luminal PTH receptors (PTH-R). This stimulates the transcription of the mitochondrial enzyme 1α-hydroxylase (1α-HYD) that catalyzes the conversion of the vitamin D precursor 25(OH)-VitD₃ into the active metabolite 1,25(OH)₂-VitD₃. Increased enzyme activity would be expected to lead to an increased production of 1,25(OH)₂-VitD₃ that in turn would indirectly cause hypercalciuria by stimulating intestinal Ca²⁺ reabsorption. However, 25(OH)-VitD₃ (bound to its binding protein DBP) is mainly taken up apically by megalin- and ClC-5_dependent endocytosis. Hence, the endocytosis defect in Dent disease leads to a decreased availability of the substrate for 1α-HYD. Thus there is a delicate balance between enzyme activation and precursor scarcity that can turn toward decreased as well as increased production of 1,25(OH)₂-VitD₃. Furthermore, the active hormone is also lost into the urine. This may account for the variability of hypercalciuria observed in Dent disease patients as well as in ClC-5 KO mouse models. (B) Mechanism causing phosphaturia. The apical Na phosphate cotransporter NaPi-2a is regulated by PTH, which causes its endocytosis and degradation. The increased stimulation of apical PTH receptors that is due to the increased luminal PTH concentration caused by an impaired endocytosis of PTH in the absence of ClC-5 leads to less NaPi-2a in the apical membrane, resulting in a urinary loss of phosphate.