ClC - Chloride Carrier/Channel

Family:
The Chloride Carrier/Channel Family is a large but poorly understood family consisting of several hundred sequenced proteins from bacteria and eucaryotes. Although structurally similar, the individual proteins act either as chloride channels or as chloride/proton exchangers. Most CIC proteins are located in the plasma membrane, but several are predominantly in intracellular membranes.

Subgroups:
The mammalian CLC family contains 9 members, four of them (CIC-1, ClC-2, ClC-Ka, and ClC-Kb) are located on the plasma membrane where they act as chloride ion channels whereas the remaining five are located in intracellular organelles (CIC-3-7) and are chloride-proton exchangers. There is also a wide variety of bacterial CLC types.

Topology:
The structures of two bacterial and one eukaryotic ClC proteins have been reported so far. CLS subunits have a complex topology of up to 18 transmembrane segments and form homodimers. However, each of the identical subunits contributes an individually functional ion transport pathway.

Function:
ClC Cl- channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis.1 

1.  Saier Lab. Group, Transporter Classification Database

Data and Applications

ClC - Proteoliposomes with different lipid-to-protein ratios

Clc Figure 4   LPRsIcon N1   SURFE2R N1 data and applications:

We tested proteoliposomes with different densities of reconstituted ClC protein for their signal-to-noise ratios and compared the obtained signal amplitudes with a negative control: liposomes without reconstituted protein.

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ClC - Inward and outward directed chloride flux

Clc Figure 1   transient currents Influx vs EffluxIcon N1   SURFE2R N1 data and applications:

According to the transport direction of 2Cl-/1H+ exchange, we observed positive (Cl- efflux) or negative (Cl- influx) transient currents.



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ClC - Inhibition with OADS

Clc Figure 3   OADS inhibitionIcon N1   SURFE2R N1 data and applications:

We investigated the effect of the specific ClC inhibitor OADS on the transport activity of ClC and its reversibility.



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ClC - EC50 for inward and outward directed chloride flux

Clc Figure 2   EC50 Efflux vs InfluxIcon N1   SURFE2R N1 data and applications:

We determined EC50 and relative Vmax for Cl- in an Cl-/H+ exchange assay for both transport directions and found a slight asymmetry in transporter kinetics.

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Data and Applications (Ion Channels)

Posters

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Publications

2019 - Structure of the human ClC-1 chloride channel

icon pap   Port-a-Patch,  icon vpp   Vesicle Prep Pro and   Icon Orbit Mini   Orbit mini publication in PLOS Biology (2019)

Authors:
Wang K., Preisler, SS, Zhang, L., Cui, Y., Missel, JW., Grønberg C., Gotfryd, K., Lindahl E., Andersson, M., Calloe, K., Egea P.F., Klaerke D.A., Pusch M., Pedersen P.A., Zhou, Z.H., Gourdon, P.

2013 - Functional characterization of a ClC transporter by solid-supported membrane electrophysiology

Icon N1   SURFE²R-technology (custom-built system) publication in Journal of General Physiology (2013)

Authors:
Garcia-Celma J., Szydelko A., Dutzler R.

2010 - The G215R Mutation in the Cl−/H+-Antiporter ClC-7 Found in ADO II Osteopetrosis Does Not Abolish Function but Causes a Severe Trafficking Defect

Icon N1   SURFE²R ONE (a predecessor model of SURFE²R N1) publication in PLoS ONE (2010)

Authors:
Schulz P., Werner J., Stauber T., Henriksen K., Fendler K.

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