TY  - JOUR
A1  - Saint Fleur-Lominy, Shella
A1  - Maus, Mate
A1  - Vaeth, Martin
A1  - Lange, Ingo
A1  - Zee, Isabelle
A1  - Suh, David
A1  - Liu, Cynthia
A1  - Wu, Xiaojun
A1  - Tikhonova, Anastasia
A1  - Aifantis, Iannis
A1  - Feske, Stefan
T1  - STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia
JF  - Cell Reports
N2  - T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.
KW  - T cell acute lymphoblastic leukemia
KW  - T-ALL
KW  - Notch1
KW  - STIM1
KW  - STIM2
KW  - calcium
KW  - Ca2+
KW  - CRAC
KW  - channel
KW  - inflammation
KW  - interferon
KW  - anemia
KW  - macrophages
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227259
VL  - 24
IS  - 11
ER  - 
TY  - JOUR
A1  - Beck, Sebastian
A1  - Yu-Strzelczyk, Jing
A1  - Pauls, Dennis
A1  - Constantin, Oana M.
A1  - Gee, Christine E.
A1  - Ehmann, Nadine
A1  - Kittel, Robert J.
A1  - Nagel, Georg
A1  - Gao, Shiqiang
T1  - Synthetic light-activated ion channels for optogenetic activation and inhibition
JF  - Frontiers in Neuroscience
N2  - Optogenetic manipulation of cells or living organisms became widely used in neuroscience following the introduction of the light-gated ion channel channelrhodopsin-2 (ChR2). ChR2 is a non-selective cation channel, ideally suited to depolarize and evoke action potentials in neurons. However, its calcium (Ca2\(^{2+}\)) permeability and single channel conductance are low and for some applications longer-lasting increases in intracellular Ca\(^{2+}\) might be desirable. Moreover, there is need for an efficient light-gated potassium (K\(^{+}\)) channel that can rapidly inhibit spiking in targeted neurons. Considering the importance of Ca\(^{2+}\) and K\(^{+}\) in cell physiology, light-activated Ca\(^{2+}\)-permeant and K\(^{+}\)-specific channels would be welcome additions to the optogenetic toolbox. Here we describe the engineering of novel light-gated Ca\(^{2+}\)-permeant and K\(^{+}\)-specific channels by fusing a bacterial photoactivated adenylyl cyclase to cyclic nucleotide-gated channels with high permeability for Ca\(^{2+}\) or for K\(^{+}\), respectively. Optimized fusion constructs showed strong light-gated conductance in Xenopus laevis oocytes and in rat hippocampal neurons. These constructs could also be used to control the motility of Drosophila melanogaster larvae, when expressed in motoneurons. Illumination led to body contraction when motoneurons expressed the light-sensitive Ca\(^{2+}\)-permeant channel, and to body extension when expressing the light-sensitive K\(^{+}\) channel, both effectively and reversibly paralyzing the larvae. Further optimization of these constructs will be required for application in adult flies since both constructs led to eclosion failure when expressed in motoneurons.
KW  - optogenetics
KW  - calcium
KW  - potassium
KW  - bPAC
KW  - CNG channel
KW  - cAMP
KW  - Drosophila melanogaster motoneuron
KW  - rat hippocampal neurons
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177520
VL  - 12
IS  - 643
ER  -