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Brain Res. 2018 Jan 1;1678:356-366. doi: 10.1016/j.brainres.2017.10.020. Epub 2017 Oct 24.

A constitutively-active IKK-complex at the axon initial segment.

Author information

1
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland; Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: hgkoenig@rcsi.ie.
2
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland; Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: orlawatters@rcsi.ie.
3
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland; Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: sineadkinsella@rcsi.ie.
4
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: mohammedameen@rcsi.ie.
5
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: beau.fenner@mohh.com.sg.
6
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland; Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 Saint Stephen's Green, Dublin 2, Ireland. Electronic address: prehn@rcsi.ie.

Abstract

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.

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.

CONCLUSION:

Our data suggest the existence of a constitutively-active IKK signaling complex in the AIS.

KEYWORDS:

Ankyrin-G; Axon; Axon initial segment; IKK 2 Kinase; NF-κB; Proximity ligation assay

PMID:
29079505
DOI:
10.1016/j.brainres.2017.10.020
[Indexed for MEDLINE]

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