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PRIZE LECTURE |
1 FMP/MDC (Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Zentrum für Molekulare Medizin), Robert-Rössle Strasse 10, D-13125 Berlin, FRG
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Abstract |
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 Top Abstract IntroductionReferences |
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-subunit Ostm1, are mutated in human disease. The associated mouse and human pathologies, ranging from impaired endocytosis and nephrolithiasis (ClC-5) to neurodegeneration (ClC-3), lysosomal storage disease (ClC-6, ClC-7/Ostm1) and osteopetrosis (ClC-7/Ostm1), were crucial in identifying the physiological roles of vesicular CLCs. Whereas the intracellular localization of ClC-6 and ClC-7/Ostm1 precluded biophysical studies, the partial expression of ClC-4 and -5 at the cell surface allowed the detection of strongly outwardly rectifying currents that depended on anions and pH. Surprisingly, ClC-4 and ClC-5 (and probably ClC-3) do not function as Cl– channels, but rather as electrogenic Cl––H+ exchangers. This hints at an important role for luminal chloride in the endosomal–lysosomal system.
(Received 9 November 2006;
accepted after revision 14 November 2006;
first published online 16 November 2006)
Corresponding author T. J. Jentsch: FMP/MDC, Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Zentrum für Molekulare Medizin, Robert-Rössle Strasse 10, D-13125 Berlin, FRG. Email: jentsch{at}fmp-berlin.de
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Introduction |
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TopAbstractIntroductionReferences |
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The molecular identification in my laboratory of ClC-0, a voltage-gated chloride channel from the electric organ of the marine ray Torpedo marmorata (Jentsch et al. 1990), led to the identification of all nine members of the mammalian CLC gene family (Jentsch et al. 2005). By their degree of homology, they can be grouped into three branches. Similar to ClC-0, members of the first branch (ClC-1, -2, -Ka, -Kb) are plasma membrane Cl– channels, whereas members of the two other branches (ClC-3, -4 and -5, and ClC-6 and -7, respectively) reside predominantly on intracellular vesicles (Fig. 1). ClC-4 and ClC-5 are now known to operate as voltage-dependent Cl––H+ exchangers (Picollo & Pusch, 2005; Scheel et al. 2005).
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-subunits of CLC proteins are known: Barttin for both ClC-K isoforms (Estévez et al. 2001) and Ostm1 for ClC-7 (Lange et al. 2006). Loss of ClC-5: impaired renal endocytosis leads to kidney stones
Human mutations in ClCN-5 lead to low molecular weight proteinuria, urinary loss of phosphate and calcium, and frequently to kidney stones in a syndrome called Dent's disease (Lloyd et al. 1996). ClC-5 is expressed in renal proximal tubule (PT) cells. In these cells, ClC-5 co-localizes with proton pumps in apical endosomes, suggesting that the lack of ClC-5 might impair endosomal acidification, thereby compromising the reabsorption of filtered proteins and causing proteinuria (Günther et al. 1998). Indeed, ClC-5 KO mice from two independent strains (Piwon et al. 2000; Wang et al. 2000) lose low molecular weight proteins into the urine. In vivo endocytosis experiments revealed that the broad defect in endocytosis is cell-autonomous. It affects receptor-mediated endocytosis, fluid-phase endocytosis and the retrieval of plasma membrane proteins such as the sodium–phosphate cotransporter NaPi-2a and the Na+–H+ exchanger NHE3 (Piwon et al. 2000). The abundance of the endocytotic receptor megalin was decreased in KO PT cells, possibly pointing to a defect in recycling it back to the surface (Piwon et al. 2000). As a consequence, receptor-mediated endocytosis is reduced more severely than fluid-phase endocytosis. The role of ClC-5 in endosomal acidification was tested with suspensions of renal cortical endosomes (Piwon et al. 2000; Günther et al. 2003) and in cell culture (Hara-Chikuma et al. 2005a). In both protocols, the disruption of ClC-5 reduced endosomal acidification. The concomitant increase in luminal Cl– concentration was blunted as well (Hara-Chikuma et al. 2005a).
The impairment of proximal tubular endocytosis might be explained by a reduced electrical shunt for endosomal proton pumps, but how can one explain the kidney stones observed in many, but not all patients with Dent's disease? A unifying, experimentally supported hypothesis (Piwon et al. 2000) links these symptoms to the primary defect in endocytosis (Fig. 2). The small peptide hormone parathyroid hormone (PTH) passes the glomerular filter into the primary urine and is normally endocytosed by PT cells (Fig. 2A). The lack of ClC-5 severely impairs PTH endocytosis, leading to higher than normal PTH levels in the lumen of the nephron even when the blood concentration of PT is normal. This leads to an excessive stimulation of apical PTH receptors in the late PT, triggering the endocytic removal of the phosphate transporter NaPi-2a from the plasma membrane and thereby causing hosphaturia (Piwon et al. 2000) (Fig. 2B). The increased stimulation of apical PTH receptors in the PT also augments the transcription of 1
-25(OH)-VitD3-hydroxylase (Günther et al. 2003), a mitochondrial enzyme that converts the inactive precursor 25(OH)-VitD3 into the active form 1,25-(OH)2-VitD3. This active hormone, which is slightly increased in the serum of patients with Dent's disease (Scheinman, 1998), is expected to stimulate the intestinal resorption of Ca2+, which then must be eliminated by the kidney. On the other hand, the main supply of 25(OH)-VitD3 to the activating hydroxylase occurs through apical, megalin-dependent endocytosis, which is severely impaired in the absence of ClC-5. The outcome of these opposing mechanisms (increase in hydroxylase activity versus decreased precursor availability; Fig. 2B) determines whether there is an increase in serum 1,25-(OH)2-VitD3 and hence hypercalciuria and kidney stones. This model thereby can account for the clinical variability of Dent's disease.
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Lack of ClC-3, ClC-6 or ClC-7 causes neurodegeneration
Surprisingly, the disruption in mice of ClC-3, -6, or -7 led to a neurodegeneration in the central nervous system (Stobrawa et al. 2001; Kasper et al. 2005; Poët et al. 2006). The severity and the morphological and biochemical characteristics of the degeneration differed significantly between the genotypes. In mice lacking ClC-6 or ClC-7, neurons displayed intracellular, electron-dense deposits that stained for lysosomal marker proteins and the subunit c of ATP-synthase, a protein typically accumulated in a subset of human lysosomal storage disease called neuronal ceroid lipofuscinosis (NCL). Storage occurred throughout neuronal cell bodies in ClC-7 KO mice (Kasper et al. 2005), whereas it accumulated specifically in initial axon segments of mice lacking ClC-6 (Poët et al. 2006) (Fig. 3). In comparison, no severe intraneuronal storage was observed in ClC-3 KO mice (Stobrawa et al. 2001; Kasper et al. 2005), although Clcn3–/– mice were reported to display NCL-like features (Yoshikawa et al. 2002). The neuronal cell loss was severe in mice lacking ClC-3 or ClC-7, leading to a complete loss of the hippocampus in adult Clcn3–/– mice (Stobrawa et al. 2001). These latter mice, however, survived quite happily for more than a year, whereas Clcn7–/– mice died after about 2 months even if their osteopetrosis (see below) was cured (Kasper et al. 2005). Neuronal cell loss was nearly absent in ClC-6 KO mice, which showed nearly normal life span and only mild neurological abnormalities that included a reduced sensitivity to pain (Poët et al. 2006). Whereas the combination of severe osteopetrosis with lysosomal storage disease may also occur in human patients homozygous for severe CLCN7 mutations, it is currently unclear whether human mutations in CLCN3 or CLCN6 may cause phenotypes similar to ClC-3 and ClC-6 KO mice.
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Thick bones, grey hair and lysosomal storage: identification of a new ClC-7 -subunit
The immediately obvious phenotype of Clcn7–/– mice, however, is not lysosomal storage, but rather a severe osteopetrosis that leads to skeletal deformities, lack of tooth eruption, and impaired growth (Kornak et al. 2001). The bone marrow cavity is replaced by calcified bone. ClC-7 is highly expressed in osteoclasts, where it can be inserted into the ‘ruffled border’ together with the vacuolar proton pump (Fig. 1B). This specialized membrane secretes acid into the resorption lacuna that directly faces the calcified bone and that may be regarded as an ‘extracellular lysosome’. The acidic pH in this extracellular compartment is necessary both for the chemical dissolution of inorganic bone and for the activity of secreted lysosomal enzymes that degrade organic bone material. Clcn7–/– osteoclasts still attached to ivory (a bone surrogate) in vitro, but did neither acidify a resorption lacuna nor degrade bone like wild-type (Kornak et al. 2001). As their ‘ruffled border’ was underdeveloped, ClC-7 might contribute to the exocytotic build-up of this membrane. Our mouse model suggested that ClC-7 might also play a role in human osteopetrosis. Indeed, CLCN7 was mutated on both alleles in patients with malignant infantile osteopetrosis (Kornak et al. 2001), and heterozygous missense mutations of CLCN7 underlie the less severe osteopetrosis of the dominant Albers-Schönberg disease (Cleiren et al. 2001). Mutations in the a3 subunit of the H+-ATPase, a subunit highly expressed in osteoclasts, may also underlie severe infantile osteopetrosis (Frattini et al. 2000; Kornak et al. 2000), again highlighting the importance of having an acidic resorption lacuna.
Grey lethal mice, a spontaneous, severely osteopetrotic mouse mutant, resemble Clcn7–/– mice not only in their severe osteopetrosis, but also in having grey fur in an agouti background. We therefore searched for a possible link between ClC-7 and Ostm1, the protein encoded by the grey lethal gene (Chalhoub et al. 2003). Ostm1 is a type I membrane protein with a heavily glycosylated amino-terminal portion and a short cytoplasmic tail (Lange et al. 2006). It co-localizes with ClC-7 in lysosomes and in the ruffled border of osteoclasts. Ostm1 needs ClC-7 to travel to lysosomes, whereas ClC-7 reaches lysosomes also without Ostm1. ClC-7 could be co-immunoprecipitated with Ostm1 and vice versa, identifying Ostm1 as a novel -subunit of ClC-7 (Lange et al. 2006). Importantly, the stability of either protein depends on the coexpression with its partner. The pathology observed upon a loss of Ostm1 may be entirely due to the ensuing instability of the ClC-7 chloride transporter. Indeed, grey lethal mice do not only resemble Clcn7–/– mice in their osteopetrosis, but also display similar lysosomal storage disease (Lange et al. 2006). The grey hair of either mouse model is not yet fully understood, but may be related to a dysfunction of melanosomes, lysosome-related organelles.
Lysosomal storage, but normal lysosomal pH: a clue for Cl––H+ exchange?
The subcellular localization of ClC-6 and ClC-7 indicated that the lysosomal storage disease observed upon their loss might be a consequence of impaired late endosomal–lysosomal function. Because ClC-5 facilitates the acidification of renal endosomes (Günther et al. 2003), and as ClC-3 plays a similar role in endosomes (Hara-Chikuma et al. 2005b) and synaptic vesicles (Stobrawa et al. 2001), we expected Clcn6–/– and Clcn7–/– lysosomes to be more alkaline. However, steady-state lysosomal pH was unchanged in either mouse model (Kasper et al. 2005; Poët et al. 2006). Several hypotheses may reconcile these findings with the assumed role of vesicular CLCs: even if ClC-6 and -7 would account for the bulk of lysosomal membrane conductance, other smaller conductances remaining after their elimination may suffice to neutralize proton pump currents over the long run, leading to identical lysosomal pH under our experimental conditions where we had chased a pH-sensitive dye into lysosomes overnight (Kasper et al. 2005; Poët et al. 2006). The observed pathology might be due to a slower rate of acidification on the way to lysosomes (fitting to the likely late endosomal localization of ClC-6), or might hint at an important role of lysosomal chloride.
A very relevant recent discovery is that ClC-4 and ClC-5, just like the E. coli protein ClC-e1 (Accardi & Miller, 2004), function as electrogenic Cl––H+ exchangers rather than being Cl– channels (Picollo & Pusch, 2005; Scheel et al. 2005). While residing mainly in intracellular vesicles, a minor portion of ClC-4 and ClC-5 reaches the plasma membrane, at least upon heterologous expression. This localization allowed biophysical studies that showed that either protein mediates anion currents which decrease with extracellular (and, by extension, luminal) acidification (Friedrich et al. 1999). These currents displayed a Cl– > I– conductance sequence, as found in other CLC proteins. These currents, as it has emerged now, reflect an electrogenic exchange of Cl– for H+ (Fig. 4). Whereas the stoichiometry of the ion exchange could not be determined precisely for ClC-4 and -5 (Picollo & Pusch, 2005; Scheel et al. 2005), it is 2Cl– for 1H+ in the bacterial ClC-e1 (Accardi & Miller, 2004). Mutating a key ‘gating’ glutamate in ClC-e1, ClC-4 or ClC-5 uncouples the Cl– conductance from H+ countertransport and abolishes the rectification of ClC-4 and -5 currents (Friedrich et al. 1999; Accardi & Miller, 2004; Picollo & Pusch, 2005; Scheel et al. 2005). It is unknown whether ClC-6 and ClC-7 also function as Cl––H+ exchangers, but the presence of another glutamate typically found in CLC exchangers, but not channels (Accardi et al. 2005), suggests that they do. Several mutually incompatible channel functions were assigned to ClC-3 (e.g. Duan et al. 1997; Wang et al. 2006), but it is very likely that ClC-3 rather functions as a Cl––H+ antiport as well. ClC-3, -4, and -5 share the same high degree of sequence homology (including the two critical glutamate residues), and Weinman's group reported ClC-3 currents that were nearly identical to those of ClC-4 and -5 (Li et al. 2000). Importantly, these currents were affected similarly by mutating the key ‘gating’ glutamate (Friedrich et al. 1999; Li et al. 2002). Unfortunately, the low currents obtained with ClC-3 did not allow direct tests for Cl––H+ exchange activity (Picollo & Pusch, 2005).
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Footnotes |
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7.4) to the acidic pH (
