König, Hans-Georg Watters, Orla Kinsella, Sinéad Ameen, Mohammed Fenner, Beau J Prehn, Jochen H.M. A constitutively-active IKK-complex at the axon initial segment. <p>BACKGROUND: Previous studies provided evidence for an accumulation of IκB-kinase (IKK) α/β at the axon initial segment (AIS), a neuronal compartment defined by ankyrin-G expression. Here we explored whether the presence of the IKK-complex at the AIS was associated with the activation of IKK signaling at this site.</p> <p>METHODS AND RESULTS: Proximity-ligation assays (PLAs) using pan-IKKα/β, phospho-IKKα/β-specific as well as ankyrin-G specific antibodies validated their binding to proximal epitopes in the AIS, while antibodies to other phosphorylated signaling proteins showed no preference for the AIS. Small-hairpin mediated silencing of IKKβ significantly reduced anti-phospho-IKKα/β-immunoreactivities in the AIS. ank3 gene-deficient cerebellar Purkinje cells also exhibited no phosphorylated IKKα/β at the proximal region of their axons. Transient ankyrin-G overexpression in PC12 cells augmented NF-κB transactivation in an ankyrin-G death-domain dependent manner. Finally, small molecule inhibitors of IKK-activity, including Aspirin, inhibited the accumulation of activated IKK proteins in the AIS.</p> <p>CONCLUSION: Our data suggest the existence of a constitutively-active IKK signaling complex in the AIS.</p> Animals;Ankyrins;Aspirin;Axon Initial Segment;Calbindins;Cerebral Cortex;Dose-Response Relationship;Drug;Embryo;Mammalian;Enzyme Inhibitors;Flow Cytometry;Green Fluorescent Proteins;I-kappa B Kinase;I-kappa B Proteins;Ligation;Mice;Inbred C57BL;Neurons;Phosphorylation;RNA;Small Interfering;Rats;Serine;Signal Transduction;Time Factors;Transfection;Physiology;Medical Physics 2019-11-22
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