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

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Konig HG, Watters O, Kinsella S, Ameen M, Fenner BJ, Prehn JHM

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

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

PubMed ID

29079505 [ View in PubMed

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Abstract

BACKGROUND: Previous studies provided evidence for an accumulation of IkappaB-kinase (IKK) alpha/beta 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-IKKalpha/beta, phospho-IKKalpha/beta-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 IKKbeta significantly reduced anti-phospho-IKKalpha/beta-immunoreactivities in the AIS. ank3 gene-deficient cerebellar Purkinje cells also exhibited no phosphorylated IKKalpha/beta at the proximal region of their axons. Transient ankyrin-G overexpression in PC12 cells augmented NF-kappaB 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Acetylsalicylic acid	Inhibitor of nuclear factor kappa-B kinase subunit beta	Protein	Humans	Unknown	Not Available	Details