Chapter 4 Pharmacology of CLC Chloride Channels and Transporters

Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20246 Hamburg.
Current Opinion in Neurobiology (Impact Factor: 6.63). 07/2005; 15(3):319-25. DOI: 10.1016/j.conb.2005.05.002
Source: PubMed


CLC proteins are found in cells from prokaryotes to mammals and perform functions in plasma membranes and intracellular vesicles. Several genetic human diseases and mouse models underscore their broad physiological functions in mammals. These functions range from the control of excitability to transepithelial transport, endocytotic trafficking and acidification of synaptic vesicles. The recent crystallization of bacterial CLC proteins gave surprising insights into CLC Cl(-)-channel permeation and gating and provides an excellent basis for structure-function studies. Surprisingly, the CLC from Escherichia coli functions as a Cl-/H+ exchanger, thus demonstrating the thin line separating transporters and channels.

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Available from: Olaf Scheel, Aug 27, 2014
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    • "However, we report for the first time that these cells possess ClC-1 and ClC-2 (Figure 5(a2)), members of the ClC family known to be present on the plasma membrane. In addition, ClC-2 is associated with transepithelial Cl − transport [38] [39]. Realtime PCR was used to assess the mRNA expression of these transporters in response to the different hormonal regimens. "
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    ABSTRACT: Mammary gland ion transport is essential for lactation and is regulated by prolactin and glucocorticoids. This study delineates the roles of prolactin receptors (PRLR) and long-term prolactin and dexamethasone (P-D)-mediation of [Ca(2+)](i) and Cl(-) transport in HC-11 cells. P-D (24 h) suppressed ATP-induced [Ca(2+)](i). This may be due to decreased Ca(2+) entry since P-D decreased transient receptor potential channel 3 (TRPC3) but not secretory pathway Ca(2+)-ATPase 2 (SPCA2) mRNA. ATP increased Cl(-) transport, measured by iodide (I(-)) efflux, in control and P-D-treated cells. P-D enhanced I(-) efflux response to cAMP secretagogues without altering Cl(-) channels or NKCC cotransporter expression. HC-11 cells contain only the long form of PRLR (PRLR-L). Since the short isoform, PRLR-S, is mammopoietic, we determined if transfecting PRLR-S (rs) altered PRLR-L-mediated Ca(2+) and Cl(-) transport. Untreated rs cells showed an attenuated [Ca(2+)](i) response to ATP with no further response to P-D, in contrast to vector-transfected (vtc) controls. P-D inhibited TRPC3 in rs and vtc cells but increased SPCA2 only in rs cells. As in wild-type, cAMP-stimulated Cl(-) transport, in P-D-treated vtc and rs cells. In summary, 24 h P-D acts via PRLR-L to attenuate ATP-induced [Ca(2+)](i) and increase cAMP-activated Cl(-) transport. PRLR-S fine-tunes these responses underscoring its mammopoietic action.
    07/2012; 2012(10):192142. DOI:10.1155/2012/192142
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    • "The expression of ClCs 3–7 varies among cell types, however, expression has been demonstrated for each of these transporters in neuronal tissues [14], [15], [16], [17], [18]. Within cells, however, their distribution differs with respect to their position in the endosomal pathway. "
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    ABSTRACT: Members of the ubiquitously expressed CLC protein family of chloride channels and transporters play important roles in regulating cellular chloride and pH. The CLCs that function as Cl(-)/H(+) antiporters, ClCs 3-7, are essential in particular for the acidification of endosomal compartments and protein degradation. These proteins are broadly expressed in the nervous system, and mutations that disrupt their expression are responsible for several human genetic diseases. Furthermore, knock-out of ClC3 and ClC7 in the mouse result in the degeneration of the hippocampus and the retina. Despite this evidence of their importance in retinal function, the expression patterns of different CLC transporters in different retinal cell types are as yet undescribed. Previous work in our lab has shown that in chicken amacrine cells, internal Cl(-) can be dynamic. To determine whether CLCs have the potential to participate, we used PCR and immunohistochemical techniques to examine CLC transporter expression in the chicken retina. We observed a high level of variation in the retinal expression levels and patterns among the different CLC proteins examined. These findings, which represent the first systematic investigation of CLC transporter expression in the retina, support diverse functions for the different CLCs in this tissue.
    PLoS ONE 03/2011; 6(3):e17647. DOI:10.1371/journal.pone.0017647 · 3.23 Impact Factor
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    • "Related members of a multigene family are expected to have similar properties and physiological roles. This is not the case, however, for the CLC family of proteins, originally referred to as a family of voltage-gated chloride channels (reviewed in ref. 1). The Torpedo electroplax CLC-0 and its mammalian homologue, the skeletal muscle CLC-1, are indeed outwardly rectifying chloride channels. "
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    ABSTRACT: The family of CLC proteins comprises both Cl(-) channels and Cl(-)/H(+) exchange transporters with varying degrees of voltage dependence. The human CLC-5 is an electrogenic voltage-dependent 2Cl(-)/1H(+) exchanger that gives rise to strongly outwardly rectifying currents when expressed. We conducted whole-cell recordings from HEK293 cells transiently transfected with either wild-type CLC-5 or a permeation-deficient mutant, E268A. With E268A CLC-5 we recorded transient voltage-dependent currents that represent the gating currents associated with CLC-5 activation and had kinetics that could be described by voltage-dependent forward and reverse transition rates. In extracellular solutions rich in Cl(-) or Br(-), CLC-5 exhibited a gating charge of 1.3, but this was reduced to 0.9 in solutions comprising the impermeant anions aspartate, methanesulfonate, sulfate, or HEPES. Extracellular ion depletion by local perfusion with isotonic mannitol failed to reduce the gating charge further. Lowering intracellular pH from 7.4 to 5.4 did not shift the voltage-dependence of the gating currents, but reducing and increasing intracellular Cl(-) shifted the charge-voltage relationship to more negative and positive potentials, respectively. Our data suggest that voltage sensing is an intrinsic property of the CLC-5 protein and that permeant anions, particularly Cl(-), modulate a voltage-dependent transition to an activated state from which Cl(-)/H(+) exchange can occur.
    The FASEB Journal 10/2010; 24(10):3696-705. DOI:10.1096/fj.09-150649 · 5.04 Impact Factor
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