title: Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity.
abstract: 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.
authors.affiliation: pharmazentrum frankfurt, Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Department of Clinical Pharmacology, Goethe University, 60590 Frankfurt, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bockhart
authors.forename: Cristina Elena
authors.initials: CE
authors.lastname: Constantin
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Nina
authors.initials: N
authors.lastname: Wijnvoord
authors.forename: Maike
authors.initials: M
authors.lastname: Kanngiesser
authors.forename: Thekla
authors.initials: T
authors.lastname: Myrczek
authors.forename: Geethanjali
authors.initials: G
authors.lastname: Pickert
authors.forename: Laura
authors.initials: L
authors.lastname: Popp
authors.forename: Jürgen-Markus
authors.initials: JM
authors.lastname: Sobotzik
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Michaela
authors.initials: M
authors.lastname: Kress
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D019540:Area Under Curve; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000235:genetics; D051550:I-kappa B Kinase / Q000172:deficiency*; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D062559:NAV1.8 Voltage-Gated Sodium Channel; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010812:Physical Stimulation / Q000009:adverse effects; D011930:Reaction Time / Q000235:genetics; D012584:Sciatic Nerve; D018689:Sensory System Agents / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics; D050916:TRPV Cation Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D018689:Sensory System Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013779:Tetrodotoxin; D051550:I-kappa B Kinase; D002211:Capsaicin; D002118:Calcium