Prof. Thomas J. Jentsch
MDC & FMP Berlin
The physiological role of ion transport proteins has often been gleaned from pathologies resulting from their inactivation in human diseases or in mouse models. We have discovered several human ‘channelopathies’ and have generated and analyzed many mouse models. We focus on CLC chloride channels and transporters, KCC potassium-chloride co-transporters, and KCNQ potassium channels, and are extending our studies to other channel classes. Their mutational Inactivation led to pathologies ranging from epilepsy, deafness, lysosomal storage disease to osteopetrosis, kidney stones and hypertension. We are particularly interested in the control of neuronal excitability and in the role of chloride and pH in endosomes and lysosomes.
Recently we have identified the long-sought volume-regulated anion channel VRAC by a genome-wide siRNA screen. This important channel has been known from biophysical studies for decades, but the underlying proteins have remained unknown in spite of many efforts. We showed that this channel is not only crucial for regulatory volume decrease of cells, but also for the uptake and efflux of organic substrates like taurine and glutamate, with profound implications for extracellular signaling and pathologies like stroke. This has swung open the door to an important new research area which we will vigorously explore in the next years.
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We use highly interdisciplinary approaches to mechanistically understand ion transport at all levels. Our investigations include biophysical structure-function analysis of mutated channels, address key cell biological aspects like endocytosis and lysosomal function, and elucidate the physiological and systemic role of particular transport proteins with extensive use of sophisticated genetic mouse models. We have identified ion channel mutations in several human diseases. These disorders include epilepsy and neurodegeneration, deafness, kidney stones, urinary protein loss, hypertension, and thick bones (osteopetrosis), among others.
We investigate the functions of CLC Cl- channels and transporters, KCNQ K+ channels, KCC K-Cl-cotransporters, and Anoctamin Ca2+-activated Cl- channels. Our recent work has revealed the long-sought molecular identity of VRAC, the volume-regulated anion channel that is ubiquitously expressed in mammalian cells. VRAC not only plays a central role in cell volume regulation, but also in amino-acid release and is believed to be important for cell proliferation, migration, apoptosis, and to be involved in several pathological conditions. Having finally identified VRAC, we have begun several projects concerning this important channel. The following gives short summaries of our past results and recent or ongoing projects.