FMP Publications

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

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VRAC: molecular identification as LRRC8 heteromers with differential functions
Jentsch, T. J., Lutter, D., Planells-Cases, R., Ullrich, F.; Voss, F. K.
Pflugers Arch, 468:385-393

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: A major player of vertebrate cell volume regulation is the volume-regulated anion channel (VRAC), which conducts halide ions and organic osmolytes to counteract osmotic imbalances. The molecular entity of this channel was unknown until very recently, although its biophysical characteristics and diverse physiological roles have been extensively studied over the last 30 years. On the road to the molecular identification of VRAC, experimental difficulties led to the proposal of a variety of false candidates. In 2014, in a final breakthrough, two groups independently identified LRRC8A as indispensable component of VRAC. LRRC8A is part of the leucine-rich repeat containing 8 family, which is comprised of five members (LRRC8A-E). Of those, LRRC8A is an obligatory subunit of VRAC but it needs at least one of the other family members to mediate the swelling-induced Cl(-) current ICl,vol. This review discusses the remarkable journey which led to the molecular identification of VRAC, evidence for LRRC8 proteins forming the VRAC pore and their heteromeric assembly. Furthermore, first major insights on the role of LRRC8 proteins in cancer drug resistance and apoptosis and the role of LRRC8D in cisplatin and taurine transport will be summarized.

Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop
Ullrich, F., Reincke, S. M., Voss, F. K., Stauber, T.; Jentsch, T. J.
J Biol Chem, 291:17040-17048

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Canonical volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have many other important roles, including tumor drug resistance and release of neurotransmitters. Although VRAC-mediated swelling-activated chloride currents (ICl,vol) have been studied for decades, exploration of the structure-function relationship of VRAC has become possible only after the recent discovery that VRACs are formed by differently composed heteromers of LRRC8 proteins. Inactivation of ICl,vol at positive potentials, a typical hallmark of VRACs, strongly varies between native cell types. Exploiting the large differences in inactivation between different LRRC8 heteromers, we now used chimeras assembled from isoforms LRRC8C and LRRC8E to uncover a highly conserved extracellular region preceding the second LRRC8 transmembrane domain as a major determinant of ICl,vol inactivation. Point mutations identified two amino acids (Lys-98 and Asp-100 in LRRC8A and equivalent residues in LRRC8C and -E), which upon charge reversal strongly altered the kinetics and voltage dependence of inactivation. Importantly, charge reversal at the first position also reduced the iodide > chloride permeability of ICl,vol This change in selectivity was stronger when both the obligatory LRRC8A subunit and the other co-expressed isoform (LRR8C or -E) carried such mutations. Hence, the C-terminal part of the first extracellular loop not only determines VRAC inactivation but might also participate in forming its outer pore. Inactivation of VRACs may involve a closure of the extracellular mouth of the permeation pathway.

Bimodal antagonism of PKA signalling by ARHGAP36
Eccles(*), R. L., Czajkowski(*), M. T., Barth(*), C., Müller(*), P. M., McShane(*), E., Grunwald(*), S., Beaudette(*), P., Mecklenburg(*), N., Volkmer, R., Zühlke(*), K., Dittmar(*), G., Selbach(*), M., Hammes(*), A., Daumke(*), O., Klussmann(*), E., Urbe(*), S.; Rocks(*), O.
Nat Commun, 7:12963

Tags: Peptide Synthesis (Hackenberger/Volkmer)

Abstract: Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors. ARHGAP36 thus dampens the sensitivity of cells to cAMP. We show that PKA inhibition by ARHGAP36 promotes derepression of the Hedgehog signalling pathway, thereby providing a simple rationale for the upregulation of ARHGAP36 in medulloblastoma. Our work reveals a new layer of PKA regulation that may play an important role in development and disease.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
Hu(*), H., Haas(*), S. A., Chelly(*), J., Van Esch(*), H., Raynaud(*), M., de Brouwer(*), A. P., Weinert, S., Froyen(*), G., Frints(*), S. G., Laumonnier, F., Zemojtel(*), T., Love(*), M. I., Richard(*), H., Emde(*), A. K., Bienek(*), M., Jensen(*), C., Hambrock(*), M., Fischer(*), U., Langnick(*), C., Feldkamp(*), M., Wissink-Lindhout(*), W., Lebrun(*), N., Castelnau(*), L., Rucci(*), J., Montjean(*), R., Dorseuil(*), O., Billuart(*), P., Stuhlmann, T., Shaw(*), M., Corbett(*), M. A., Gardner(*), A., Willis-Owen(*), S., Tan(*), C., Friend(*), K. L., Belet(*), S., van Roozendaal(*), K. E., Jimenez-Pocquet(*), M., Moizard(*), M. P., Ronce(*), N., Sun(*), R., O'Keeffe(*), S., Chenna(*), R., van Bommel(*), A., Goke(*), J., Hackett(*), A., Field(*), M., Christie(*), L., Boyle(*), J., Haan(*), E., Nelson(*), J., Turner(*), G., Baynam(*), G., Gillessen-Kaesbach(*), G., Müller, U., Steinberger(*), D., Budny(*), B., Badura-Stronka(*), M., Latos-Bielenska(*), A., Ousager(*), L. B., Wieacker(*), P., Rodriguez Criado(*), G., Bondeson(*), M. L., Anneren(*), G., Dufke(*), A., Cohen(*), M., Van Maldergem(*), L., Vincent-Delorme(*), C., Echenne(*), B., Simon-Bouy(*), B., Kleefstra(*), T., Willemsen(*), M., Fryns(*), J. P., Devriendt(*), K., Ullmann(*), R., Vingron(*), M., Wrogemann(*), K., Wienker(*), T. F., Tzschach(*), A., van Bokhoven(*), H., Gecz(*), J., Jentsch, T. J., Chen(*), W., Ropers(*), H. H.; Kalscheuer(*), V. M.
Molecular psychiatry, 21:133-148

Tags: Physiology and Pathology of Ion Transport (Jentsch

Abstract: X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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