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Ca++/CaMKII switches nociceptor‐sensitizing stimuli into desensitizing stimuli
Author(s) -
Hucho Tim,
Suckow Vanessa,
Joseph Elizabeth K.,
Kuhn Julia,
Schmoranzer Jan,
Dina Olayinka A.,
Chen Xiaojie,
Karst Matthias,
Bernateck Michael,
Levine Jon D.,
Ropers HansHilger
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07920.x
Subject(s) - nociceptor , protein kinase c , microbiology and biotechnology , stimulation , chemistry , signal transduction , calcium signaling , nociception , inhibitory postsynaptic potential , extracellular , neuroscience , biology , receptor , biochemistry
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 ( PKC ε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKC s is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKC ε signaling pathway resulted in PKC ε translocation. We identified a novel inhibitory cascade to branch off upstream of PKC ε, but downstream of Epac via IP 3‐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 Ca MKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a Ca MKII ‐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.