10779/rcsi.10790825.v1
Hans-Georg König
Hans-Georg
König
Orla Watters
Orla
Watters
Sinéad Kinsella
Sinéad
Kinsella
Mohammed Ameen
Mohammed
Ameen
Beau J Fenner
Beau J
Fenner
Jochen H.M. Prehn
Jochen H.M.
Prehn
A constitutively-active IKK-complex at the axon initial segment.
Royal College of Surgeons in Ireland
2019
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 16:56:46
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/A_constitutively-active_IKK-complex_at_the_axon_initial_segment_/10790825
<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>