Ca++/CaMKII switches nociceptor-sensitizing stimuli into desensitizing stimuli.
Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCε signaling pathway resulted in PKCε translocation. We identified a novel inhibitory cascade to branch off upstream of PKCε, but downstream of Epac via IP3-induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second 'sensitizing' stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII-dependent manner. This mechanism was also observed by in vivo C-fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.
Max Planck Institute for Molecular Genetics, Berlin, Germany. tim.hucho@uk-koeln.de
Tim
T
Hucho
Vanessa
V
Suckow
Elizabeth K
EK
Joseph
Julia
J
Kuhn
Jan
J
Schmoranzer
Olayinka A
OA
Dina
Xiaojie
X
Chen
Matthias
M
Karst
Michael
M
Bernateck
Jon D
JD
Levine
Hans-Hilger
HH
Ropers
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009619:Nociceptors / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; C520305:Gper1 protein, rat; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; D013873:Thionucleotides; C493922:Trpv1 protein, rat; D012433:Ryanodine; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D051744:Protein Kinase C-epsilon; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D002118:Calcium; D014544:Uridine Triphosphate