title: Coincident enrichment of phosphorylated IkappaBalpha, activated IKK, and phosphorylated p65 in the axon initial segment of neurons.
abstract: Phosphorylation of the inhibitory protein IkappaBalpha by the activated IkappaB kinase (IKK) is a crucial step in the activation of the transcription factor NF-kappaB. In neurons of the mammalian central nervous system, constitutive activation of NF-kappaB has been previously documented. The cellular compartments involved in this activation have not yet been fully identified. Here we document a striking enrichment of several molecules involved in NF-kappaB activation in the axon initial segment (AIS) of neurons: Phosphorylated-IkappaBalpha (pIkappaBalpha), activated IKK, and p65 phosphorylated at serine 536 were found to be enriched in the AIS in vivo as well as in vitro. Both, pIkappaBalpha and activated IKK, were associated with cytoskeletal components of the AIS. Activated IKK was associated with the membrane cytoskeleton, whereas pIkappaBalpha was sequestered to microtubules of the AIS. Colchicine-induced depolymerization of microtubules resulted in the loss of pIkappaBalpha in the AIS, demonstrating that the integrity of the axonal cytoskeleton is essential for the clustering of this NF-kappaB pathway component. These data provide the first evidence for a compartmentalized clustering of NF-kappaB pathway components in the AIS and implicate this neuronal compartment in the activation of NF-kappaB.
authors.affiliation: Institute for Clinical Neuroanatomy, J.W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. Schultz@em.uni-frankfurt.de
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: König
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.forename: Chrisoula
authors.initials: C
authors.lastname: Politi
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
authors.forename: Estifanos
authors.initials: E
authors.lastname: Ghebremedhin
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
mesh_terms: D000200:Action Potentials / Q000502:physiology; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D007527:Isoenzymes; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D013779:Tetrodotoxin; D051550:I-kappa B Kinase