of the Max - MDC

Technical Assistants
Alexander Fast*
Inga Freyert*
Nicole Krönke
Ina Lauterbach*
Rainer Leben*
Janet Liebold*
Ruth Pareja*
Patrick Seidler*
Stefanie Wernick*
Silke Zillmann*
Animal Care
Petra Göritz*
Secretariat
Dagmar Boshold*
Pia Philippi*
* part of the period reported
KCC1 and KCC3 in volume regulation of
erythrocytes – implications for sickle cell anemia
Marco Rust, Carsten Pfeffer, York Rudhard, Christian
Hübner, Seth Alper, Carlo Bugnara
Although KCC1 is expressed almost ubiquitously, our KCC1
KO mice have no apparent phenotype. However, erythrocytes
lacking both KCC1 and KCC1 displayed severely
reduced volume regulation. K-Cl cotransport is increased in
sickle cell anemia and may contribute to the pathology by
decreasing cell volume. We therefore crossed KCC1/3 double
KOs to SAD mice, a transgenic sickle cell anemia model.
Compared to SAD mice, erythrocyte cell volume was partially
normalized by the lack of both KCCs, indicating that a pharmacological
inhibition of KCC by itself may be insufficient to
symptomatically treat human sickle cell anemia.
KCNQ potassium channels
There are five different isoforms of KCNQ (Kv7) potassium
channels, KCNQ1- KCNQ5. KCNQ2-KCNQ5 mediate ‘M-currents’
that regulate neuronal excitability. We had previously
shown that KCNQ2 and KCNQ3 underlie a form of human
epilepsy and that dominant KCNQ4 mutations are a cause of
human deafness.
KCNQ4 mouse models for human deafness
Tatjana Kharkovets, Michaela Schweizer, Hannes Maier,
Tobias Moser, Vitya Vardanyan
We generated KCNQ4 KO mice and a knock-in that carries a
dominant negative KCNQ4 mutation we had identified in
human deafness. Both models developed a severe hearing
loss. Its progression was much slower with mice heterozygous
for the dominant mutant, mimicking the slowly progressive
hearing loss of DFNA2. The hearing loss was attributed
to a selective degeneration of sensory outer hair cells,
which had totally lost their M-type currents as revealed by
patch-clamping.
Figure 2. Cell model showing the progressive acidification in the endosomal/lysosomal
system. It depends on the pumping activity of a V-type ATPase, which needs a
parallel conductive pathway to neutralize its electrical current. This pathway may be
provided by different intracellular CLC isoforms. Surprising new data show that ClC-4
and ClC-5 are not chloride channels, as thought previously, but rather operate as electrogenic
Cl - /H + -exchangers. The direct coupling of Cl - to H + -fluxes suggests an important,
previously unrecognized role of intravesicular chloride.
Selected Publications
Scheel, O, Zdebik, AA, Lourdel, S, Jentsch, TJ. (2005). Voltagedependent
electrogenic chloride-proton exchange by endosomal
CLC proteins. Nature 436, 424-427.
Kharkovets, T, Dedek, K, Maier, H, Schweizer, M, Khimich, D,
Nouvian, R, Vardanyan, V, Leuwer, R, Moser, T, Jentsch, TJ.
(2006). Mice with altered KCNQ4 K + channels implicate sensory
outer hair cells in human progressive deafness. EMBO J. 25,
642-652.
Lange, PF, Wartosch, L, Jentsch, TJ, Fuhrmann, JC. (2006).
ClC-7 requires Ostm1 as a β-subunit to support bone resorption
and lysosomal function. Nature 440, 220-223.
Poet, M, Kornak, U, Schweizer, M, Zdebik, AA, Scheel, O, Hoelter,
S, Wurst, W, Schmitt, A, Fuhrmann, JC, Planells-Cases, R, Mole,
S, E, Hübner, CA, Jentsch TJ. (2006). Lysosomal storage disease
upon disruption of the neuronal chloride transport protein ClC-6.
Proc. Natl. Acad. Sci. USA 103, 13854-13859.
Rust, MB, Alper, SL, Rudhard, Y, Shmukler, BE, Vicente, R,
Brugnara, C, Trudel, M, Jentsch, TJ, Hübner, CA. (2007).
Disruption of erythroid KCl-cotransporters alters erythrocyte
volume and partially rescues erythrocyte dehydration in SAD
mice. J. Clin. Invest. 117, 1708-1717.
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Cardiovascular and Metabolic Disease Research 55