FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Generation and analyses of R8L barttin knockin mouse
Nomura(*), N., Tajima(*), M., Sugawara(*), N., Morimoto(*), T., Kondo(*), Y., Ohno(*), M., Uchida(*), K., Mutig(*), K., Bachmann(*), S., Soleimani(*), M., Ohta(*), E., Ohta(*), A., Sohara(*), E., Okado(*), T., Rai(*), T., Jentsch, T. J., Sasaki(*), S.; Uchida(*), S.
Am J Physiol-Renal, 301:F297-F307
(2011)

Tags: Physiology and Pathology of Ion Transport (Jentsch

Abstract: Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, Jentsch TJ, Sasaki S, Uchida S. Generation and analyses of R8L barttin knockin mouse. Am J Physiol Renal Physiol 301: F297-F307, 2011. First published May 18, 2011; doi: 10.1152/ajprenal.00604.2010.-Barttin, a gene product of BSND, is one of four genes responsible for Bartter syndrome. Coexpression of barttin with ClC-K chloride channels dramatically induces the expression of ClC-K current via insertion of ClC-K-barttin complexes into plasma membranes. We previously showed that stably expressed R8L barttin, a disease-causing missense mutant, is retained in the endoplasmic reticulum (ER) of Madin-Darby canine kidney (MDCK) cells, with the barttin beta-subunit remaining bound to ClC-K alpha-subunits (Hayama A, Rai T, Sasaki S, Uchida S. Histochem Cell Biol 119: 485-493, 2003). However, transient expression of R8L barttin in MDCK cells was reported to impair ClC-K channel function without affecting its subcellular localization. To investigate the pathogenesis in vivo, we generated a knockin mouse model of Bartter syndrome that carries the R8L mutation. These mice display disease-like phenotypes (hypokalemia, metabolic alkalosis, and decreased NaCl reabsorption in distal tubules) under a low-salt diet. Immunofluorescence and immunoelectron microscopy revealed that the plasma membrane localization of both R8L barttin and the ClC-K channel was impaired in these mice, and transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) as well as thiazide-sensitive chloride clearance were significantly reduced. This reduction in transepithelial chloride transport in tAL, which is totally dependent on ClC-K1/barttin, correlated well with the reduction in the amount of R8L barttin localized to plasma membranes. These results suggest that the major cause of Bartter syndrome type IV caused by R8L barttin mutation is its aberrant intracellular localization.

Distinct Binding Properties Distinguish LQ-Type Calmodulin-Binding Domains in Cyclic Nucleotide-Gated Channels
Ungerer(*), N., Mücke(*), N., Broecker, J., Keller, S., Frings(*), S.; Möhrlen(*), F.
Biochemistry, 50:3221-3228
(2011)

Tags: Biophysics of Membrane Proteins (Keller)

Abstract: Cyclic nucleotide-gated (CNG) channels operate as transduction channels in photoreceptors and olfactory receptor neurons. Direct binding of cGMP or cAMP opens these channels which conduct a mixture of monovalent cations and Ca2+. Upon activation, CNG channels generate intracellular Ca2+ signals that play pivotal roles in the transduction cascades of the visual and olfactory systems. Channel activity is controlled by negative feedback mechanisms that involve Ca2+-calmodulin, for which all CNG channels possess binding sites. Here we compare the binding properties of the two LQ-type calmodulin binding sites, both of which are thought to be involved in channel regulation. They reside on the isoforms CNGB1 and CNGA4. The CNGB1 subunit is present in rod photoreceptors and olfactory receptor neurons. The CNGA4 subunit is only expressed in olfactory receptor neurons, and there are conflicting results as to its role in calmodulin-mediated feedback inhibition. We examined the interaction of Ca2+-calmodulin with two recombinant proteins that encompass either of the two LQ sites. Comparing binding properties, we found that the LQ site of CNGB1 binds Ca2+-calmodulin at 10-fold lower Ca2+ levels than the LQ site of CNGA4. Our data provide biochemical evidence against a contribution of CNGA4 to feedback inhibition. In accordance with previous work on photoreceptor CNG channels, our results indicate that feedback control is the exclusive role of the B-subunits in photoreceptors and olfactory receptor neurons.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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