Research Report 2010 - MDC

Thomas J. JentschStructure of the GroupGroup LeaderGroup LeaderProf. Dr. Dr. Thomas J. JentschScientistsScientistsDr. Graduate MurielStudentsAuberson*Dr. Luiza Bengtsson*Dr. Pawel Fidzinski*Dr. Jens Fuhrmann*Technical AssistantsDr. Ioana NeagoeDr. Gaia NovarinoSecretariatDr. Vanessa Plans*Dr. Guillermo Spitzmaul**part Dr. Tobias of theStauberperiod reportedDr. Vitya Vardanyan*Physiology and Pathology Headof Ion TransportIon transport across cellular membranes is important for cellular homeostasis and hasintegrative functions such as transepithelial transport or neuronal signal transduction.We study these processes at various levels, from biophysical analysis of transport proteins,structure-function analysis, role in cellular functions such as cell volume regulation orendocytosis, to the role in the organism. The physiological role of ion transport proteins hasoften been gleaned from pathologies resulting from their inactivation in human diseases orin mouse models. We have discovered several human ‘channelopathies’ and have generatedand analyzed many mouse models.We focus on CLC chloride channels and transporters, KCC potassium-chloride cotransportersand KCNQ potassium channels, and are currently extending our interestto other channel classes. The mutational inactivation of these ion transport proteins ledto pathologies ranging from epilepsy, deafness, lysosomal storage disease to osteopetrosis,kidney stones and hypertension. We are particularly interested in the control of neuronalexcitability and in the role of chloride and pH in endosomes and lysosomes.Headline BlindtextHeadline BlindtextHeadline BlindtextCLC chloride channels and transportersPeoples names Peoples names Peoples names PeoplesThe CLC gene family, discovered in our laboratory innames Peoples names Peoples names1990, encodes plasma membrane chloride channelsReceptor-mediated endocytosis is the main mechanismand chloride transporters of intracellular membranes.that enables selective transport of macromolecules acrossIn the past couple of years, we identified associatedthe plasma membrane into cells. Significant progress hasβ-subunits, been made indiscovered elucidatingthat the various certainsteps vesicular of endocytosis CLCs areelectrogenic at the cellular level. Cl - /H However, + -exchangers, the physiological performedrelevance structurefunctionmany endocytic analysis, pathways and uncovered for organseveral functionnew remains patholo-elu-ofgies sive. resulting from their dysfunction.The main class of endocytic receptors is a group of proteinsAn known inner as the ear-specific LDL receptor knock-out gene family. ofNine thereceptors Cl - channel existβ-subunit in mammalian barttin organisms, explains all of which deafness sharein common humanstruc-tural motifs syndrome (Figure 1). type The prototype IV of the gene family isBartterthe LDL receptor, a protein that mediates cellular uptake ofGesa Rickheit, Hannes Maier, Anselm Zdebikcholesterol-rich lipoproteins. Since other family membersHuman Bartter syndrome type IV is associated withalso bind lipoprotein particles, contributions of these receptorsto cellular renal loss andof systemic fluid and lipidsalt, metabolism as well as arewith anticipat-con-severegenital ed. A major deafness. part ofWe ourhave workpreviously is dedicatedshown to the that functional barttin,characterization the proteinof encoded orphan receptors by the inBSND this genefamily that(soiscalled LRPs), particularly focusing on their diverse roles inlipid homeostasis.mutated in that disease, is an accessory β-subunit oftheSortilinschloridearechannelsa secondClC-Kagroupandof endocytic-Kb. Bothreceptorschannelsthatarerecently attracted our attention because of structural andexpressed in the kidney and in the epithelium of thefunctional similarities with LRPs. The founding member ofstria vascularis of the cochlea.We now generated a conditional‘floxed’ barttin KO mouse to delete barttinthis gene family is SorLA, a receptor that shares structuralelements found in the LDL receptor and that also bindsspecificallylipoproteinsin(Figurethe inner1). In addition,ear, therebySorLAavoidingincludesthea domainmassiveidentified salt and in the fluidvacuolar loss that protein leads sorting to early10postnatalproteindeath. (Vps10p), Like a sorting patients, protein thesein mice Yeastare that congenitally directs enzymes deaf.We fromshowed the Golgi that to the thisvacuole. due to Initially a collapse considered of theapositivemosaicvoltage receptorin of the LDL scala receptor media gene (the family, endocochlear subsequent potential) identificationisofnecessary four otherto mammalian drive a depolarizing proteins withinflux Vps10p-ofwhichpotassium domain (Sortilin, through SorCS-1, mechanosensitive -2, and -3) suggested channels the existence in sensoryhair cells. Outer hair cells were no longer able tomechanically Sortilin amplify sound in the inner ear and eventuallydegenerated. We have thus clarified the pathologicalmechanism underlying a form of human deafnessand have revealed a previously unknown role ofchloride channels in the generation of the endocochlearpotential.154 Function and Dysfunction of the Nervous System