Ca++/CaMKII switches nociceptor‐sensitizing stimuli into desensitizing stimuli

Abstract

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 (PKCe) 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 PKCe signaling pathway resulted in PKCe translocation. We identified a novel inhibitory cascade to branch off upstream of PKCe, 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.

Transient Receptor Potential Vanilloid 1 Regulates Mitochondrial Membrane Potential and Myocardial Reperfusion Injury

“…When calmodulin is overexpressed, the TRPV1 gating response is significantly diminished . Also after TRPV1 stimulation, calmodulin switches the channel state from active to inactive, holding the TRPV1 channel in a closed state . Calcineurin alternatively dephosphorylates the TRPV1 channel after activation, priming the channel for reactivation.…”

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

“…phosphorylates, and thereby modulates, ion channels including TRPV1, and has been implicated in pain regulation (Chen et al, 2010;Ferrari et al, 2013Ferrari et al, , 2014Hucho et al, 2012;Jung et al, 2004). Microarray data suggest that CaMKIIα mRNA is upregulated fivefold between neonatal and adult DRG neurons (Zhu and Oxford, 2011), but measurements at the protein level are missing.…”

“…In addition, changes of pathway connectivity are exemplified by the phenomenon of pain priming, where PKA-dependent hyperalgesic signaling switches to PKCε and ERK1/2 involvement (Aley et al, 2000;Dina et al, 2003). We have also recently identified a switch of intracellular signaling turning a pro-nociceptive into an analgesic receptor input (Hucho et al, 2012). Thus, while intracellular sensitization signaling connectivity appears to be plastic, to-date it has not been analyzed whether signaling kinetics, signaling amplitude and pathway connectivity change during nociceptor development.…”

Neurotrophins, endocannabinoids and thermo‐transient receptor potential: a threesome in pain signalling

“…The signalling routes that contribute to the modulation of thermoTRPs function in nociceptors involve the protein kinase C (PKC), protein kinase A (PKA), Src, calcium–calmodulin kinase II (CAMKII), calcineurin, phosphatidylinositide‐3 kinase (PI3K), mitogen‐activated protein kinase (MAPK), phospholipase A 2 (PLA 2 ), and phosphatidylinositol 4,5 bisphosphate (PIP 2 ) cascades (see for reviews Planells‐Cases et al ., ; Yudin & Rohacs, ; Zheng, ). Interestingly, sensory neurons appear to have a PLC‐dependent, Ca 2+ /CAMKII‐based molecular switch that swaps their signalling form pro‐ to anti‐algesic (Hucho et al ., ), most likely by modulating thermoTRP channel activity.…”

“…Furthermore, because TRP channels are allosteric proteins, prolonged exposure to endocannabinoids could desensitise channel gating by inducing a high‐affinity closed conformation and/or by favouring receptor internalisation, similar to that produced by prolonged exposure of nociceptors to vanilloids (Sanz‐Salvador et al ., ). In contrast, endocannabinoids could produce nociceptor sensitisation by the PLC‐mediated activation of the Ca 2+ /CAMKII‐based molecular switch (Hucho et al ., ), which could up‐regulate the gating of thermoTRP channels. Additionally, spinal endocannabinoid mediation of activity‐dependent pain sensitisation in dorsal horn neuronal circuits has been ascribed to cannabinoid‐induced disinhibition of afferent synaptic inputs to nociceptive circuits (Pernía‐Andrade et al ., ).…”