Research Report 2000 - MDC

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New modes of calcium signaling Maik Gollasch, Matthias Löhn, and Michael Fürstenau are making exciting advances in electrophysiology. During a Humboldt fellowship at the University of Vermont, Gollasch worked with Mark Nelson and studied local calcium transients termed calcium sparks. These sparks are apparently caused by opening of clustered ryanodine receptors in the sarcoplasmic reticulum. Gollasch’s team has investigated caveolae, cholesterol/sphingolipid-rich invaginations of the plasma membrane which colocalize with both the subsarcolemmal occurrence of calcium sparks and the junctional sarcoplasmic reticulum. They have found that a transient elevation in calcium at the inner mouth of a single L-type calcium channel within caveolae induces simultaneous activation and opens several ryanodine receptors to generate a local calcium spark. They are the first to show that a caveolae-calcium signaling pathway may regulate cellular functions via local ryanodine receptors in the sarcoplasmic reticulum. The first illustration of a calcium spark in man (from a coronary artery vascular smooth muscle cell) is shown in the figure. 96 Christian Maasch, Carsten Lindschau, Gabi Alexander and others are using green fluorescent protein technology to observe protein kinase Cα targeting in vascular smooth muscle cells. They recently showed that local changes in calcium regulate PKCα translocation. The targeting mechanism is dependent on the C2 and P domains of the enzyme. Their observations are the first to show that localized calcium changes determine the spatial and temporal targeting of PKCα. Gene therapy The group has relied on antisense strategy in a series of exciting studies aimed at treating ischemia-reperfusion injury occuring after organ transplantation and they have used a rat renal transplant model. Duska Dragun has recently completed a study in which she showed that the antisense treatment is very effective in the prevention of ischemia-reperfusion injury in transplantation. A chronic isograft transplantation study has also been completed. Patient-oriented research Hermann Haller, Volker Homuth, Friedrich C. Luft, and Gerd Wallukat have collaborated with obstetricians in Berlin to elucidate new mechanisms responsible for endothelial damage in preeclampsia. In a cell culture system of endothelial cell monolayers, the group showed that a factor from the serum of preeclamptic women stimulates increased cell-layer permeability. This process involves PKC signaling, principally PKCα and PKCε. The permeability increase was blocked with antisense against the mRNA of these enzymes. In subsequent studies, the team showed that women with preeclampsia produce agonist autoantibodies directed at the AT1 receptor. The antibodies are directed at the second extracellular loop. Colocalization studies have demonstrated the necessary specificity. The subsequent signaling proved to be a PKCmediated pathway. Very recently, the group has shown that the antibodies are capable of making vascular smooth muscle cells produce tissue factor. The work of the four investigators was awarded the Galenus von Pergamon prize for 1999. Figure 33: Calcium sparks are localized intracellular events released through ryanodine receptors. The sparks then control excitationcontraction coupling. The confocal line-scan image of a fluo-3-loaded human coronary artery vascular smooth muscle cell is shown. The fluoresence time course of the sparks was determined over the time indicated by the two arrows.
Selected Publications Gollasch, M., Haase, H., Ried, C., Lindschau, C,, Miethke. A., Morano, I., Luft, F.C., and Haller, H. (1998) Ltype calcium channel expression depends on the differentiated state of vascular smooth muscle cells. FASEB J. 12, 593-601. Kettritz, R., Xu, Y.-X., Kerren, T., Quass, P., Klein, J., Luft, F.C., and Haller, H. (1999) Extracellular matrix regulates apoptosis in human neutrophils. Kidney Int. 55, 562-571. Wellner, M., Kupprion, C., Maasch, C., Lindschau, C., Luft, F.C., and Haller, H. (1999) The proliferative effect of vascular endothelial growth factor (VEGF) requires protein kinase C α and ζ. Arterioscler Thromb. Vasc. Biol. 19, 178-185. Haller, H., Maasch, C., Dragun, D., Wellner, M., von Janta-Lipinski, M., and Luft, F.C. (1998) Antisense oligodinucleotide strategies in renal and cardiovascular disease. Kidney Int. 53, 1550-1558. Wallukat, G., Homuth, V., Fischer, T., Horstkamp, B., Jüpner, A., Baur, E., Nissen, E., Vetter, K., Dudenhausen, J.W., Haller, H., and Luft, F.C. (1999) Patients with preeclampsia develop agonistic antibodies against the angiotensin AT1 receptor. J. Clin. Invest. 103, 945-952. Köhler, M., Speck, C., Christiansen, M., Bischoff, F.R., Prehn, S., Haller, H., Görlich, D., and Hartmann, E. (1999) Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Mol. Cell Biol. 19, 7782-7791. Structure of the Group Group leader Prof. Dr. Hermann Haller Scientists Dr. Marek Drab Dr. Ralf Kettritz Dr. Elke Genersch Dr. Maik Gollasch Dr. Matthias Köhler Dr. Matthias Löhn Dr. Maren Wellner Doctoral students Gabriele Alexander Michael Fürstenau Christian Maasch Carsten Lindschau Olaf Schäfer Thorsten Kirsch Technical assistants Jana Czychi Petra Quass 97
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
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Selected Publications Müller, D.N.
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Selected Publications Hennies, H.C.
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Somatic genetic alterations in brea
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Clinical and Molecular Genetics of
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Selected Publications Toka, H.R., B
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Lbx1, c-met and the control of cell
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Selected Publications Moore, A., Mc
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Selected Publications Herz, J., Wil
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We aim to study the genetic epidemi
Page 45 and 46: Nucleation Nucleation as a pre-requ
Page 47 and 48: Selected Publications Damaschun, G.
Page 49 and 50: Selected Publications Yuan, T., Wal
Page 51 and 52: stability. By determining the struc
Page 53 and 54: Role of Protein Dynamics in Enzyme
Page 55 and 56: Modeling Nucleic Acid Structure and
Page 57 and 58: Conformation, Stability and Interac
Page 59 and 60: Protein Structure Analysis and Prot
Page 61 and 62: Cell Growth and Differentiation 61
Page 63 and 64: dendritic cells (DC). Adoptive tran
Page 65 and 66: developmental pathway that may invo
Page 67 and 68: Regulation of Transcription in Mamm
Page 69 and 70: Differentiation and Growth Control
Page 71 and 72: Cell cycle-dependent transcriptiona
Page 73 and 74: Cell Cycle Regulation Hans-Dieter R
Page 75 and 76: Epithelial Differentiation, Invasio
Page 77 and 78: Selected Publications Hartmann, G.,
Page 79 and 80: Selected Publications Behrens, J.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87 and 88: VSMCs. We have cloned and character
Page 89 and 90: Surgical Oncology Peter M. Schlag T
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95: Vascular Biology Hermann Haller Thi
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103 and 104: Hematology, Oncology and Tumor Immu
Page 105 and 106: Selected Publications Sturm, I., K
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113 and 114: Molecular Basis of Congestive Heart
Page 115 and 116: Selected Publications Schneider, G.
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
Page 129 and 130: Cellular Neurosciences Helmut Kette
Page 131 and 132: Growth Factor and Regeneration Gary
Page 133 and 134: Synapse Formation and Function Fran
Page 135 and 136: Developmental Neurobiology Fritz G.
Page 137 and 138: Selected Publications Volkmer, H.,
Page 139 and 140: Structure and Organization 139
Page 141 and 142: Prof. Dr. Hans Meyer President of t
Page 143 and 144: Supporting Divisions Safety The div
Page 145 and 146: Press and Public Relations Research
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Purchasing and Materials Management
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Computing The computing group of th
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Awards Thomas Biederer Boehringer-M
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Index A Abdul, Yetunde 90 Aguirre-A
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H Haase, Hannelore 85, 97, 100, 142
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Q Qin, Zhihai 107, 117 Quass, Petra
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Board of Trustees Chair Wolf-Michae
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