JOURNAL ARTICLE

Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity

Vanessa Bockhart, Cristina Elena Constantin, Annett Häussler, Nina Wijnvoord, Maike Kanngiesser, Thekla Myrczek, Geethanjali Pickert, Laura Popp, Jürgen-Markus Sobotzik, Manolis Pasparakis, Rohini Kuner, Gerd Geisslinger, Christian Schultz, Michaela Kress, Irmgard Tegeder
Journal of Neuroscience 2009 October 14, 29 (41): 12919-29
19828806
Inhibitor kappaB kinase (IKK) regulates the activity of the transcription factor nuclear factor-kappa B that normally protects neurons against excitotoxicity. Constitutively active IKK is enriched at axon initial segments and nodes of Ranvier (NR). We used mice with a Cre-loxP-mediated specific deletion of IKKbeta in sensory neurons of the dorsal root ganglion (SNS-IKKbeta(-/-)) to evaluate whether IKK plays a role in sensory neuron excitability and nociception. We observed increased sensitivity to mechanical, cold, noxious heat and chemical stimulation in SNS-IKKbeta(-/-) mice, with normal proprioceptive and motor functions as revealed by gait analysis. This was associated with increased calcium influx and increased inward currents in small- and medium-sized primary sensory neurons of SNS-IKKbeta(-/-) mice during stimulation with capsaicin or Formalin, specific activators of transient receptor potentials TRPV1 and TRPA1 calcium channels, respectively. In vitro stimulation of saphenous nerve preparations of SNS-IKKbeta(-/-) mice showed increased neuronal excitability of A- and C-fibers but unchanged A- and C-fiber conduction velocities, normal voltage-gated sodium channel currents, and normal accumulation of ankyrin G and the sodium channels Nav1.6 at NR. The results suggest that IKKbeta functions as a negative modulator of sensory neuron excitability, mediated at least in part by modulation of TRP channel sensitivity.

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