Inhibitor kappaB Kinase beta deficiency in primary nociceptive neurons increases TRP channel sensitivity.
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.
Bockhart
Vanessa
V
pharmazentrum frankfurt, Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Department of Clinical Pharmacology, Goethe University, 60590 Frankfurt, Germany.
Constantin
Cristina Elena
CE
Häussler
Annett
A
Wijnvoord
Nina
N
Kanngiesser
Maike
M
Myrczek
Thekla
T
Pickert
Geethanjali
G
Popp
Laura
L
Sobotzik
Jürgen-Markus
JM
Pasparakis
Manolis
M
Kuner
Rohini
R
Geisslinger
Gerd
G
Schultz
Christian
C
Kress
Michaela
M
Tegeder
Irmgard
I
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
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